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Sapp C, Rich M, Hess K, Losco A, Zupancic A, Caldwell HK. Disruptions of the oxytocin system impair sociability and cognitive flexibility in a subchronic phencyclidine model of schizophrenia. Neuropharmacology 2025; 273:110442. [PMID: 40185363 DOI: 10.1016/j.neuropharm.2025.110442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 03/28/2025] [Accepted: 03/31/2025] [Indexed: 04/07/2025]
Abstract
Previous research suggests that the oxytocin (Oxt) system may play a role in the etiology of schizophrenia. To investigate, we used a subchronic phencyclidine (PCP) mouse model to test how disruption of Oxt or the Oxt receptor (Oxtr) affects schizophrenia-related behaviors. Specifically, we assessed how subchronic PCP impacted hyperlocomotion, sociability, and passive stress coping in male Oxt and Oxtr knockout (-/-) and wildtype (+/+) mice. Additionally, we evaluated immediate early gene activation in Oxtr -/- and +/+ mice to identify brain regions where the Oxt system might impact schizophrenia-associated behaviors. Lastly, we investigated cognitive flexibility in Oxtr -/- and +/+ mice. We found that subchronic PCP treatment decreased social interactions in Oxt -/- mice as compared to Oxt +/+ mice, with no genotypic differences in the Oxtr line of mice. Increased c-Fos expression was observed in Oxtr -/- mice relative to Oxtr +/+ controls in the medial amygdala and the paraventricular nucleus of the hypothalamus following a forced swim test. Finally, we found deficits in cognitive flexibility in Oxtr -/- mice treated with PCP, relative to Oxtr +/+ mice. These findings are consistent with the hypothesis that Oxt may buffer against some of the schizophrenia-associated symptoms induced by subchronic PCP treatment. Based on the data, we speculate that compensatory mechanisms may be able to accommodate the loss of the Oxt system, depending on the origin of the dysfunction and the behavioral endpoint in question. These findings also add support to data linking disruption of Oxt system signaling to schizophrenia.
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Affiliation(s)
- Coleman Sapp
- Laboratory of Neuroendocrinology and Behavior, Department of Biological Sciences, and the Brain Health Research Institute, Kent State University, Kent, OH, 44242, USA.
| | - Megan Rich
- Laboratory of Neuroendocrinology and Behavior, Department of Biological Sciences, and the Brain Health Research Institute, Kent State University, Kent, OH, 44242, USA; School of Biomedical Sciences, Kent State University, Kent, OH 44242, USA
| | - Karla Hess
- Laboratory of Neuroendocrinology and Behavior, Department of Biological Sciences, and the Brain Health Research Institute, Kent State University, Kent, OH, 44242, USA; School of Biomedical Sciences, Kent State University, Kent, OH 44242, USA
| | - Allison Losco
- Laboratory of Neuroendocrinology and Behavior, Department of Biological Sciences, and the Brain Health Research Institute, Kent State University, Kent, OH, 44242, USA
| | - Abigail Zupancic
- Laboratory of Neuroendocrinology and Behavior, Department of Biological Sciences, and the Brain Health Research Institute, Kent State University, Kent, OH, 44242, USA
| | - Heather K Caldwell
- Laboratory of Neuroendocrinology and Behavior, Department of Biological Sciences, and the Brain Health Research Institute, Kent State University, Kent, OH, 44242, USA; School of Biomedical Sciences, Kent State University, Kent, OH 44242, USA
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2
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Li X, Wang X, Xue L, Luo L, Hu L, Jiang W. RAGE/AP-1/OTR signaling pathway in rat hippocampus DG involved in CUS induced depressive-like behaviors. Behav Brain Res 2025; 485:115540. [PMID: 40090553 DOI: 10.1016/j.bbr.2025.115540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 03/10/2025] [Accepted: 03/11/2025] [Indexed: 03/18/2025]
Abstract
There has been a growing body of evidence indicating that the oxytocin (OT) system plays a significant role in the neurophysiology of chronic stress-related mood disorders in recent years. However, the precise alterations for the OT system in response to chronic stress and the underlying mechanism remains unclear. The present study demonstrated that chronic unpredictable stress (CUS) resulted in a reduction in the expression of RAGE and OTR, as well as an inhibition of AP-1 phosphorylation. RAGE knockdown in hippocampus DG induced depressive-like behaviors, down-regulated the OTR protein and mRNA levels, and reduced the AP-1 phosphorylation. The administration of OT via the nasal route reversed the depressive-like behaviors induced by RAGE knockdown, increased the levels of BDNF expression and AP-1 phosphorylation. On the other hand, RAGE over-expression in the hippocampus DG resisted the effects of CUS on depression-like behaviors, AP-1 phosphorylation, and OTR expression. These finding suggested that RAGE signaling pathway is involved in CUS induced depressive-like behaviors at least partially by regulating OTR expression.
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Affiliation(s)
- Xuemei Li
- Key Laboratory of Molecular and Biochemical Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing, China
| | - Xin Wang
- Key Laboratory of Molecular and Biochemical Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing, China
| | - Lifen Xue
- Key Laboratory of Molecular and Biochemical Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing, China
| | - Lan Luo
- Key Laboratory of Molecular and Biochemical Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing, China
| | - Lingxiao Hu
- Key Laboratory of Molecular and Biochemical Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing, China
| | - Wengao Jiang
- Key Laboratory of Molecular and Biochemical Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing, China.
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Steele SR, Ratuski AS, Hui EI, Mahoney BS, Geronimo JT, Huss MK, Parker KJ, Garner JP. Oxytocin administration rescues the negative impacts of social isolation on wound healing in mice. Horm Behav 2025; 171:105741. [PMID: 40239573 DOI: 10.1016/j.yhbeh.2025.105741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 03/28/2025] [Accepted: 04/08/2025] [Indexed: 04/18/2025]
Abstract
In humans and animals, social isolation leads to worsened health outcomes in many disease areas, including wound healing. Oxytocin, a prosocial hormone with anti-inflammatory properties, has been strongly implicated in the salutary benefits of social relationships. Oxytocin administration can mitigate the negative effects of social isolation on health outcomes, as demonstrated in rat and hamster wound healing models. However, little research has been conducted with mice, which are more common laboratory animal models, and which have markedly different social structures from these other rodent species. Moreover, the effects of social isolation and oxytocin administration on wound healing have not been investigated in mice within the same experiment, nor have they been compared between males and females. Here, we housed male and female C57BL/6 mice (n = 40) in social isolation or same-sex pairs. Mice received a subcutaneous biopsy punch wound and were subsequently administered IP oxytocin or placebo daily for 14 days. Socially isolated mice administered oxytocin, and pair-housed mice administered either oxytocin or placebo, showed a significantly faster decrease in wound area and more collagen fiber variance (i.e., less scar tissue) compared to socially isolated mice administered placebo. No sex differences were observed in any outcome measure. Thus, social housing and oxytocin administration each non-additively reduce the negative effects of social isolation on wound healing in mice. Oxytocin administration may be a promising pharmacological strategy by which to improve post-surgical healing in animals and humans, especially in those where limited social contact is necessary or in those with sparse social networks.
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Affiliation(s)
- Sydney R Steele
- Department of Comparative Medicine, Stanford University, California, USA
| | - Anna S Ratuski
- Department of Comparative Medicine, Stanford University, California, USA.
| | - Emily I Hui
- Department of Comparative Medicine, Stanford University, California, USA
| | - Brigette S Mahoney
- Department of Comparative Medicine, Stanford University, California, USA
| | - Jerome T Geronimo
- Department of Comparative Medicine, Stanford University, California, USA
| | - Monika K Huss
- Department of Comparative Medicine, Stanford University, California, USA
| | - Karen J Parker
- Department of Comparative Medicine, Stanford University, California, USA; Department of Psychiatry and Behavioral Sciences, Stanford University, California, USA
| | - Joseph P Garner
- Department of Comparative Medicine, Stanford University, California, USA; Department of Psychiatry and Behavioral Sciences, Stanford University, California, USA.
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Marroni SS, Santos VR, Castro OW, Tejada J, Santos J, Cortes de Oliveira JA, Garcia-Cairasco N. Epilepsy, compulsion and oxytocin: Insights from behavioral sequences, using neuroethology and complexity systems approaches. Epilepsy Behav 2025; 164:110273. [PMID: 39827679 DOI: 10.1016/j.yebeh.2025.110273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 10/23/2024] [Accepted: 01/14/2025] [Indexed: 01/22/2025]
Abstract
Epilepsies are complex neurological entities usually co-existing with neuropsychiatric comorbidities. We already demonstrated that microinjection of oxytocin (OT) into the central nucleus of amygdala (CeA) induces hypergrooming in Wistar rats, a model of compulsion. Furthermore, the Wistar Audiogenic Rat (WAR) strain is a genetic model of generalized tonic-clonic seizures. Here we quantified grooming behavior in WAR, with grooming scores, flowcharts and directed graphs of syntactic and non-syntactic grooming chains, after bilateral administration of OT or saline (SAL) into the CeA. Our current pioneer behavioral description considers that hypergrooming (compulsion) in WARs is a comorbidity because: (1) WARs have the highest grooming scores, when exposed only to novelty (2), WARs have better grooming scores than Wistars after CeA-SAL, (3) Epileptic WARs perform much better than Wistars in OT-CeA-dependent stereotyped behavioral sequences (flowcharts of syntactic/non-syntactic grooming chains). One additional observation is that the behavioral sequences here demonstrated can be modeled as reliable Markov chains. In conclusion we can drive hypergrooming in WARs, defined previously as a model of ritualistic motor behavior in Wistar rats, with OT from CeA, one of the principal amygdala complex outputs. As perspectives, ongoing cellular studies are on their way, to demonstrate the neural network, certainly incorporating cortico-striatal-thalamic-basal ganglia-cortical circuits, driven from CeA OT-dependent grooming pattern, a stereotyped, sequential and complex array of behaviors, and its association with seizure susceptibility.
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Affiliation(s)
- Simone S Marroni
- Physiology Department, Ribeirão Preto, School of Medicine, University of São Paulo, (USP), Ribeirão Preto, Brazil; Neuroscience and Behavioral Sciences Department, Ribeirão Preto, School of Medicine, University of São Paulo, (USP), Ribeirão Preto, Brazil
| | - Victor R Santos
- Physiology Department, Ribeirão Preto, School of Medicine, University of São Paulo, (USP), Ribeirão Preto, Brazil
| | - Olagide W Castro
- Physiology Department, Ribeirão Preto, School of Medicine, University of São Paulo, (USP), Ribeirão Preto, Brazil; Institute of Biological Sciences and Health, Federal University of Alagoas (UFAL), Maceio, Brazil
| | - Julian Tejada
- Psychology Department, Center of Education and Human Science, Federal University of Sergipe, (UFS), São Cristóvão, SE, Brazil
| | - Jessica Santos
- Physiology Department, Ribeirão Preto, School of Medicine, University of São Paulo, (USP), Ribeirão Preto, Brazil
| | | | - Norberto Garcia-Cairasco
- Physiology Department, Ribeirão Preto, School of Medicine, University of São Paulo, (USP), Ribeirão Preto, Brazil; Neuroscience and Behavioral Sciences Department, Ribeirão Preto, School of Medicine, University of São Paulo, (USP), Ribeirão Preto, Brazil.
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Constantino JL, van Dalfsen JH, Massetti S, Kamphuis J, Schoevers RA. Neurobiological mechanisms of antidepressant properties of psilocybin: A systematic review of blood biomarkers. Prog Neuropsychopharmacol Biol Psychiatry 2025; 136:111251. [PMID: 39788410 DOI: 10.1016/j.pnpbp.2025.111251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 01/05/2025] [Accepted: 01/05/2025] [Indexed: 01/12/2025]
Abstract
Psilocybin represents a novel therapeutic approach for individuals with major depressive disorder (MDD) who do not respond to conventional antidepressant treatment. Investigating the influence of psilocybin on the pathophysiological processes involved in MDD could enhance our neurobiological understanding of the presumed antidepressant action mechanism. This systematic review aims to summarize the results of human studies investigating changes in blood-based biomarkers of MDD to guide future research on potentially relevant analytes that could be monitored in clinical trials. A systematic search was performed in MEDLINE, Embase, and Web of Science to retrieve studies investigating changes in serum and plasma levels of neurotrophic, immunologic, neuroendocrine, and metabolic markers. Nine studies were included, describing findings on 15 biomarkers, exclusively in healthy participants. Studies consistently reported a decrease in interleukin-6, C-reactive protein, and eosinophils, and an increase in cortisol, prolactin, oxytocin, thyroid-stimulating hormone, adrenocorticotropic hormone, brain-derived neurotrophic factor, and free fatty acids following psilocybin administration. Less consistent effects were observed on interleukin-1β, interleukin-8, tumour necrosis factor-alpha, soluble urokinase plasminogen activator receptor, and growth hormone. The results are in line with preclinical studies and provide initial support from human studies that psilocybin potentially leads to beneficial effects on biomarkers of MDD. However, given the limited number of studies, findings should be approached with caution prior to replication. Further research should include larger samples, clinical populations, longer-term assessment, rigorous experimental designs, and account for the potential confounding of psychological stress related to the psychedelic experience.
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Affiliation(s)
| | - Jens H van Dalfsen
- Department of Psychiatry, University Medical Center Groningen, Groningen, the Netherlands
| | - Sara Massetti
- Department of Psychiatry, University Medical Center Groningen, Groningen, the Netherlands
| | - Jeanine Kamphuis
- Department of Psychiatry, University Medical Center Groningen, Groningen, the Netherlands
| | - Robert A Schoevers
- Department of Psychiatry, University Medical Center Groningen, Groningen, the Netherlands
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Petersson M, Uvnäs-Moberg K. Interactions of Oxytocin and Dopamine-Effects on Behavior in Health and Disease. Biomedicines 2024; 12:2440. [PMID: 39595007 PMCID: PMC11591571 DOI: 10.3390/biomedicines12112440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 10/14/2024] [Accepted: 10/19/2024] [Indexed: 11/28/2024] Open
Abstract
The hypothalamic neuropeptide and hormone oxytocin are of fundamental importance for maternal, social, and sexual behavior. Deviations in oxytocin levels have also been associated with anxiety, autism spectrum disorders (ASD), depression, ADHD (attention deficit hyperactivity disorder), and schizophrenia. Both oxytocin and dopamine are often considered reward- and feel-good hormones, and dopamine is associated with the above-mentioned behaviors and, and dopamine is also associated with the above-mentioned behaviors and disorders. Although being structurally totally different, oxytocin, a peptide, and dopamine, a monoamine, they have a number of similar effects. They are synthesized both in the brain and in the periphery, and they affect each other's release and receptors. In addition, oxytocin and dopamine are released in response to, for example, social interaction, sex, feeding, and massage. This review discusses interactions between oxytocin and dopamine with a specific focus on behavioral effects and possible roles of oxytocin and dopamine in various mental disorders and functional diversities.
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Affiliation(s)
- Maria Petersson
- Department of Endocrinology, Karolinska University Hospital, 171 76 Stockholm, Sweden
- Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 77 Stockholm, Sweden
| | - Kerstin Uvnäs-Moberg
- Department of Applied Animal Science and Welfare, Swedish University of Agricultural Sciences, 532 31 Skara, Sweden
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Bale R, Doshi G. Deciphering the role of siRNA in anxiety and depression. Eur J Pharmacol 2024; 981:176868. [PMID: 39128805 DOI: 10.1016/j.ejphar.2024.176868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 07/02/2024] [Accepted: 08/05/2024] [Indexed: 08/13/2024]
Abstract
Anxiety and depression are central nervous system illnesses that are among the most prevalent medical concerns of the twenty-first century. Patients with this condition and their families bear psychological, financial, and societal hardship. There are currently restrictions when utilizing the conventional course of treatment. RNA interference is expected to become an essential approach in anxiety and depression due to its potent and targeted gene silencing. Silencing of genes by post-transcriptional modification is the mechanism of action of small interfering RNA (siRNA). The suppression of genes linked to disease is typically accomplished by siRNA molecules in an efficient and targeted manner. Unfavourable immune responses, off-target effects, naked siRNA instability, nuclease vulnerability, and the requirement to create an appropriate delivery method are some of the challenges facing the clinical application of siRNA. This review focuses on the use of siRNA in the treatment of anxiety and depression.
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Affiliation(s)
- Rajeshwari Bale
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, V L M Road, Vile Parle (w), Mumbai, 400056, India
| | - Gaurav Doshi
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, V L M Road, Vile Parle (w), Mumbai, 400056, India.
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Petersson M, Höybye C. Is Oxytocin a Contributor to Behavioral and Metabolic Features in Prader-Willi Syndrome? Curr Issues Mol Biol 2024; 46:8767-8779. [PMID: 39194735 DOI: 10.3390/cimb46080518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Revised: 08/05/2024] [Accepted: 08/10/2024] [Indexed: 08/29/2024] Open
Abstract
Prader-Willi Syndrome (PWS) is a rare genetic disorder typically characterized by decreased social interaction, hyperphagia, poor behavioral control and temper tantrums, together with a high risk of morbid obesity unless food intake is controlled. The genetic defects that cause PWS include paternal 15q deletion (estimated in 60% of cases), chromosome 15 maternal uniparental disomy (UPD) (estimated in 35% of cases) and imprinting defects and translocations. Several studies indicate an oxytocin deficiency in PWS. Oxytocin is a hypothalamic nonapeptide with receptors located in the brain and in various other tissues in the body. It acts as a neuropeptide in several brain areas of great importance for behavioral and metabolic effects, as well as a neurohypophyseal hormone released into the circulation. Oxytocin in both rats and humans has strong and long-lasting behavioral and metabolic effects. Thus, an oxytocin deficiency might be involved in several of the behavioral and metabolic symptoms characterizing PWS. Treatment with oxytocin has, in some studies, shown improvement in psycho-social behavior and hyperphagia in individuals with PWS. This review focus on the behavioral and metabolic effects of oxytocin, the symptoms of a potential oxytocin deficiency in PWS and the effects of oxytocin treatment.
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Affiliation(s)
- Maria Petersson
- Department of Endocrinology, Karolinska University Hospital, 171 76 Stockholm, Sweden
- Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden
| | - Charlotte Höybye
- Department of Endocrinology, Karolinska University Hospital, 171 76 Stockholm, Sweden
- Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden
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Walia V, Wal P, Mishra S, Agrawal A, Kosey S, Dilipkumar Patil A. Potential role of oxytocin in the regulation of memories and treatment of memory disorders. Peptides 2024; 177:171222. [PMID: 38649032 DOI: 10.1016/j.peptides.2024.171222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 04/03/2024] [Accepted: 04/13/2024] [Indexed: 04/25/2024]
Abstract
Oxytocin (OXT) is an "affiliative" hormone or neurohormone or neuropeptide consists of nine amino acids, synthesized in magnocellular neurons of paraventricular (PVN) and supraoptic nuclei (SON) of hypothalamus. OXT receptors are widely distributed in various region of brain and OXT has been shown to regulate various social and nonsocial behavior. Hippocampus is the main region which regulates the learning and memory. Hippocampus particularly regulates the acquisition of new memories and retention of acquired memories. OXT has been shown to regulate the synaptic plasticity, neurogenesis, and consolidation of memories. Further, findings from both preclinical and clinical studies have suggested that the OXT treatment improves performance in memory related task. Various trials have suggested the positive impact of intranasal OXT in the dementia patients. However, these studies are limited in number. In the present study authors have highlighted the role of OXT in the formation and retrieval of memories. Further, the study demonstrated the outcome of OXT treatment in various memory and related disorders.
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Affiliation(s)
- Vaibhav Walia
- SGT College of Pharmacy, SGT University, Gurugram, Haryana, India.
| | - Pranay Wal
- PSIT-Pranveer Singh Institute of Technology (Pharmacy), Kanpur, UP 209305, India
| | - Shweta Mishra
- SGT College of Pharmacy, SGT University, Gurugram, Haryana, India
| | - Ankur Agrawal
- Jai Institute of Pharmaceutical Sciences and Research, Gwalior, MP, India
| | - Sourabh Kosey
- Department of Pharmacy Practice, ISF College of Pharmacy, Moga, Punjab, India
| | - Aditya Dilipkumar Patil
- Founder, Tech Hom Research Solutions (THRS), Plot no. 38, 1st floor, opposite to biroba mandir, near ST stand, Satara, Maharashtra 415110, India
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Jiang ST, Lian SY, Sun YH, Pan MB, Wang B, Wang H, Hua J, Wang YC, Wang QL, Dong YF. The oxytocin receptor is essential for the protective effect of pair housing on post-stroke depression in mice. Exp Gerontol 2024; 190:112432. [PMID: 38614224 DOI: 10.1016/j.exger.2024.112432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 04/04/2024] [Accepted: 04/10/2024] [Indexed: 04/15/2024]
Abstract
The beneficial effect of social interaction in mitigating the incidence of post-stroke depression (PSD) and ameliorating depressive symptoms has been consistently demonstrated through preclinical and clinical studies. However, the underlying relationship with oxytocin requires further investigation. In light of this, the present study aimed to explore the protective effect of pair housing on the development of PSD and the potential relationship with oxytocin receptors. The PSD model was induced by middle cerebral artery occlusion (MCAO) for 50 min, followed by 4-week isolated housing and restrained stress. Subsequently, each mouse in the pair-housing group (PH) was pair-housed with an isosexual healthy partner. Another group was continuously administrated fluoxetine (10 mg/Kg, i.p, once a day) for 3 weeks. To elucidate the potential role of oxytocin, we subjected pair-housed PSD mice to treatment with an oxytocin receptor (OXTR) antagonist (L368,889) (5 mg/Kg, i.p, once a day) for 3 weeks. At 31 to 32 days after MCAO, anxiety- and depressive-like behaviors were assessed using sucrose consumption, forced swim test, and tail-suspension test. The results showed that pair housing significantly improved post-stroke depression to an extent comparable to that of fluoxetine treatment. Furthermore, pair housing significantly decreased corticosterone in serum, increasing OXT mRNA expression in the hypothalamus. Treatment with L368,889 essentially reversed the effect of pair housing, with no discernible sex differences apart from changes in body weight. Pair housing increased hippocampal serotonin (5-HT), but treatment with L368,889 had no significant impact. Additionally, pair housing effectively reduced the number of reactive astrocytes and increased Nissl's body in the cortex and hippocampal CA3 regions. Correspondingly, treatment with L368,889 significantly reversed the changes in the Nissl's body and reactive astrocytes. Moreover, pair housing downregulated mRNA levels of TNF-α, IL-1β, and IL-6 in the cortex caused by PSD, which was also reversed by treatment with L368,889. In conclusion, pair housing protects against the development of PSD depending on OXT and OXTR in the brain, with no significant divergence based on sex. These findings provide valuable insights into the potential of social interaction and oxytocin as therapeutic targets for PSD. Further research into the underlying mechanisms of these effects may contribute to the development of novel treatments for PSD.
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Affiliation(s)
- Su-Ting Jiang
- Department of Medical Care, School of Nursing, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Shu-Ying Lian
- Department of Medical Care, School of Nursing, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Yao-Huan Sun
- Department of Medical Care, School of Nursing, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Mei-Bo Pan
- Department of Medical Care, School of Nursing, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Bin Wang
- Department of Medical Care, School of Nursing, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Hui Wang
- Department of Medical Care, School of Nursing, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Jun Hua
- Department of Neurology & Psychology, Shenzhen Traditional Chinese Medicine Hospital, Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Yi-Chen Wang
- Department of Medical Care, School of Nursing, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Qiu-Ling Wang
- Department of Medical Care, School of Nursing, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Yin-Feng Dong
- Department of Pathology and Pathophysiology, School of Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
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Cera N, Pinto J, Pignatelli D. The Role of Oxytocin in Polycystic Ovary Syndrome: A Systematic Review. Curr Issues Mol Biol 2024; 46:5223-5241. [PMID: 38920985 PMCID: PMC11201948 DOI: 10.3390/cimb46060313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 05/21/2024] [Accepted: 05/23/2024] [Indexed: 06/27/2024] Open
Abstract
Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder that affects women of reproductive age, representing the primary cause of anovulatory infertility. The nonapeptide oxytocin (OT) plays an important role in cognitive, emotional, and reproductive functions in human beings. Oxytocin receptors are expressed in several body parts, including the ovaries. Despite this, the possible role played by oxytocin in symptoms of PCOS is not clear. The present systematic review aimed at understanding the presence of possible oxytocin level alterations in PCOS, the connection between alterations of OT levels and the symptoms of PCOS, and the effect of oxytocin administration in PCOS. After a systematic search in the principal databases, eight studies, five human and three animal, were included. Four human studies and one animal study highlighted the role played by oxytocin in fertility issues related to PCOS. Three human and two animal studies investigated the role of body weight and OT levels. Studies that analyzed oxytocin basal levels in women agreed that PCOS is associated with a reduction in the serum level of oxytocin. Two human studies and one animal study agreed about lower levels of oxytocin, confirming a possible implication of the dysfunction of OT in the pathogenesis of PCOS.
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Affiliation(s)
- Nicoletta Cera
- Faculty of Psychology and Education Sciences, University of Porto, 4099-002 Porto, Portugal;
- Research Unit in Medical Imaging and Radiotherapy, Cross I&D Lisbon Research Centre, Escola Superior de Saúde da Cruz Vermelha Portuguesa, 1300-125 Lisbon, Portugal
| | - Joana Pinto
- Faculty of Psychology and Education Sciences, University of Porto, 4099-002 Porto, Portugal;
- Faculty of Medicine, University of Porto, 4099-002 Porto, Portugal;
| | - Duarte Pignatelli
- Faculty of Medicine, University of Porto, 4099-002 Porto, Portugal;
- Department of Endocrinology, Centro Hospitalar Universitário de São João, 4200-319 Porto, Portugal
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Tsukamoto H, Olesen ND, Petersen LG, Suga T, Sørensen H, Nielsen HB, Ogoh S, Secher NH, Hashimoto T. Circulating Plasma Oxytocin Level Is Elevated by High-Intensity Interval Exercise in Men. Med Sci Sports Exerc 2024; 56:927-932. [PMID: 38115226 DOI: 10.1249/mss.0000000000003360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2023]
Abstract
PURPOSE We evaluated whether repeated high-intensity interval exercise (HIIE) influences plasma oxytocin (OT) concentration in healthy men, and, given that OT is mainly synthesized in the hypothalamus, we assessed the concentration difference between the arterial (OT ART ) versus the internal jugular venous OT concentration (OT IJV ). Additionally, we hypothesized that an increase in cerebral OT release and the circulating concentration would be augmented by repeated HIIE. METHODS Fourteen healthy men (age = 24 ± 2 yr; mean ± SD) performed two identical bouts of HIIE. These HIIE bouts included a warm-up at 50%-60% maximal workload ( Wmax ) for 5 min followed by four bouts of exercise at 80%-90% Wmax for 4 min interspersed by exercise at 50%-60% Wmax for 3 min. The HIIE bouts were separated by 60 min of rest. OT was evaluated in blood through radial artery and internal jugular vein catheterization. RESULTS Both HIIE bouts increased both OT ART (median [IQR], from 3.9 [3.4-5.4] to 5.3 [4.4-6.3] ng·mL -1 in the first HIIE, P < 0.01) and OT IJV (from 4.6 [3.4-4.8] to 5.9 [4.3-8.2] ng·mL -1 , P < 0.01), but OT ART-IJV was unaffected (from -0.24 [-1.16 to 1.08] to 0.04 [-0.88 to 0.78] ng·mL -1 , P = 1.00). The increased OT levels were similar in the first and second HIIE bouts (OT ARTP = 0.25, OT IJVP = 0.36). CONCLUSIONS Despite no change in the cerebral OT release via the internal jugular vein, circulating OT increases during HIIE regardless of the accumulated exercise volume, indicating that OT may play role as one of the exerkines.
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Affiliation(s)
| | | | | | - Tadashi Suga
- Institute of Advanced Research for Sport and Health Science, Ritsumeikan University, Shiga, JAPAN
| | - Henrik Sørensen
- Department of Anesthesia, Rigshospitalet, Department of Clinical Medicine, University of Copenhagen, Copenhagen, DENMARK
| | | | - Shigehiko Ogoh
- Department of Biomedical Engineering, Toyo University, Saitama, JAPAN
| | - Niels H Secher
- Department of Anesthesia, Rigshospitalet, Department of Clinical Medicine, University of Copenhagen, Copenhagen, DENMARK
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13
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Zhang S, Zhang YD, Shi DD, Wang Z. Therapeutic uses of oxytocin in stress-related neuropsychiatric disorders. Cell Biosci 2023; 13:216. [PMID: 38017588 PMCID: PMC10683256 DOI: 10.1186/s13578-023-01173-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 11/18/2023] [Indexed: 11/30/2023] Open
Abstract
Oxytocin (OXT), produced and secreted in the paraventricular nucleus and supraoptic nucleus of magnocellular and parvocellular neurons. The diverse presence and activity of oxytocin suggests a potential for this neuropeptide in the pathogenesis and treatment of stress-related neuropsychiatric disorders (anxiety, depression and post-traumatic stress disorder (PTSD)). For a more comprehensive understanding of the mechanism of OXT's anti-stress action, the signaling cascade of OXT binding to targeting stress were summarized. Then the advance of OXT treatment in depression, anxiety, PTSD and the major projection region of OXT neuron were discussed. Further, the efficacy of endogenous and exogenous OXT in stress responses were highlighted in this review. To augment the level of OXT in stress-related neuropsychiatric disorders, current biological strategies were summarized to shed a light on the treatment of stress-induced psychiatric disorders. We also conclude some of the major puzzles in the therapeutic uses of OXT in stress-related neuropsychiatric disorders. Although some questions remain to be resolved, OXT has an enormous potential therapeutic use as a hormone that regulates stress responses.
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Affiliation(s)
- Sen Zhang
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, 600 Wan Ping Nan Road, Shanghai, 200030, China
- College of Physical Education and Health, East China Normal University, Shanghai, China
| | - Ying-Dan Zhang
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, 600 Wan Ping Nan Road, Shanghai, 200030, China
| | - Dong-Dong Shi
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, 600 Wan Ping Nan Road, Shanghai, 200030, China.
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Zhen Wang
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, 600 Wan Ping Nan Road, Shanghai, 200030, China.
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Institute of Psychological and Behavioral Science, Shanghai Jiao Tong University, Shanghai, China.
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14
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Ikeda N, Kawasaki M, Baba K, Nishimura H, Fujitani T, Suzuki H, Matsuura T, Ohnishi H, Shimizu M, Sanada K, Nishimura K, Yoshimura M, Maruyama T, Conway-Campbell BL, Onaka T, Teranishi H, Hanada R, Ueta Y, Sakai A. Chemogenetic Activation of Oxytocin Neurons Improves Pain in a Reserpine-induced Fibromyalgia Rat Model. Neuroscience 2023; 528:37-53. [PMID: 37532013 DOI: 10.1016/j.neuroscience.2023.07.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 07/20/2023] [Accepted: 07/25/2023] [Indexed: 08/04/2023]
Abstract
Fibromyalgia (FM) is a syndrome characterized by chronic pain with depression as a frequent comorbidity. However, efficient management of the pain and depressive symptoms of FM is lacking. Given that endogenous oxytocin (OXT) contributes to the regulation of pain and depressive disorders, herein, we investigated the role of OXT in an experimental reserpine-induced FM model. In FM model, OXT-monomeric red fluorescent protein 1 (OXT-mRFP1) transgenic rats exhibited increased depressive behavior and sensitivity in a mechanical nociceptive test, suggesting reduced pain tolerance. Additionally, the development of the FM-like phenotype in OXT-mRFP1 FM model rats was accompanied by a significant reduction in OXT mRNA expression in the magnocellular neurons of the paraventricular nucleus. OXT-mRFP1 FM model rats also had significantly fewer tryptophan hydroxylase (TPH)- and tyrosine hydroxylase (TH)-immunoreactive (ir) neurons as well as reduced serotonin and norepinephrine levels in the dorsal raphe and locus coeruleus. To investigate the effects of stimulating the endogenous OXT pathway, rats expressing OXT-human muscarinic acetylcholine receptor (hM3Dq)-mCherry designer receptors exclusively activated by designer drugs (DREADDs) were also assessed in the FM model. Treatment of these rats with clozapine-N-oxide (CNO), an hM3Dq-activating drug, significantly improved characteristic FM model-induced pathophysiological pain, but did not alter depressive-like behavior. The chemogenetically induced effects were reversed by pre-treatment with an OXT receptor antagonist, confirming the specificity of action via the OXT pathway. These results indicate that endogenous OXT may have analgesic effects in FM, and could be a potential target for effective pain management strategies for this disorder.
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Affiliation(s)
- Naofumi Ikeda
- Department of Orthopaedic Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Makoto Kawasaki
- Department of Orthopaedic Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
| | - Kazuhiko Baba
- Department of Orthopaedic Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Haruki Nishimura
- Department of Orthopaedic Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Teruaki Fujitani
- Department of Orthopaedic Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Hitoshi Suzuki
- Department of Orthopaedic Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Takanori Matsuura
- Department of Orthopaedic Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Hideo Ohnishi
- Department of Orthopaedic Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Makiko Shimizu
- Department of Physiology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Kenya Sanada
- Department of Physiology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Kazuaki Nishimura
- Department of Physiology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Mitsuhiro Yoshimura
- Department of Physiology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Takashi Maruyama
- Department of Physiology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | | | - Tatsushi Onaka
- Division of Brain and Neurophysiology, Department of Physiology, Jichi Medical University, Shimotsuke, Japan
| | - Hitoshi Teranishi
- Department of Neurophysiology, Faculty of Medicine, Oita University, Yufu, Japan
| | - Reiko Hanada
- Department of Neurophysiology, Faculty of Medicine, Oita University, Yufu, Japan
| | - Yoichi Ueta
- Department of Physiology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Akinori Sakai
- Department of Orthopaedic Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
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15
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Nisbett KE, Gonzalez LA, Teruel M, Carter CS, Vendruscolo LF, Ragozzino ME, Koob GF. Sex and hormonal status influence the anxiolytic-like effect of oxytocin in mice. Neurobiol Stress 2023; 26:100567. [PMID: 37706061 PMCID: PMC10495655 DOI: 10.1016/j.ynstr.2023.100567] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 08/15/2023] [Accepted: 08/22/2023] [Indexed: 09/15/2023] Open
Abstract
Anxiety and depression are highly prevalent psychiatric disorders, affecting approximately 18% of the United States population. Evidence indicates that central oxytocin mediates social cognition, social bonding, and social anxiety. Although it is well-established that oxytocin ameliorates social deficits, less is known about the therapeutic effects of oxytocin in non-social contexts. We hypothesized that positive effects of oxytocin in social contexts are attributable to intrinsic effects of oxytocin on neural systems that are related to emotion regulation. The present study investigated the effect of intracerebroventricular (ICV) oxytocin administration (i.e., central action) on anxiety- and depression-like behavior in C57Bl/6J mice using non-social tests. Male and female mice received an ICV infusion of vehicle or oxytocin (100, 200, or 500 ng), then were tested in the elevated zero maze (for anxiety-like behavior) and the tail suspension test (for depression-like behavior). Oxytocin dose-dependently increased open zone occupancy and entries in the elevated zero maze and reduced immobility duration in the tail suspension test in both sexes. Oxytocin decreased anxiety and depression-like behavior in male and female mice. The observed effect of oxytocin on anxiolytic-like behavior appeared to be driven by the males. Given the smaller anxiolytic-like effect of oxytocin in the female mice and the established interaction between oxytocin and reproductive hormones (estrogen and progesterone), we also explored whether oxytocin sensitivity in females varies across estrous cycle phases and in ovariectomized females that were or were not supplemented with estrogen or progesterone. Oxytocin reduced anxiety-like behavior in female mice in proestrus/estrus, ovariectomized females (supplemented or not with estrogen or progesterone), but not females in metestrus/diestrus. Additionally, oxytocin reduced depression-like behavior in all groups tested with slight differences across the various hormonal statuses. These results suggest that the effect of oxytocin in depression- and anxiety-like behavior in mice can be influenced by sex and hormonal status.
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Affiliation(s)
- Khalin E. Nisbett
- Graduate Program in Neuroscience, Graduate College, University of Illinois Chicago, Chicago, IL 60607, USA
- Neurobiology of Addiction Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA
- Stress and Addiction Neuroscience Unit, Integrative Neuroscience Research Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore, MD 21224, USA
- Department of Psychology, College of Liberal Arts and Sciences, University of Illinois Chicago, Chicago, IL 60607, USA
| | - Luis A. Gonzalez
- Neurobiology of Addiction Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA
| | - Marina Teruel
- Department of Psychology, College of Liberal Arts and Sciences, University of Illinois Chicago, Chicago, IL 60607, USA
| | - C. Sue Carter
- Department of Psychology, University of Virginia, Charlottesville, VA 22903, USA
- Kinsey Institute, Indiana University, Bloomington, IN 47405, USA
| | - Leandro F. Vendruscolo
- Neurobiology of Addiction Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA
| | - Michael E. Ragozzino
- Department of Psychology, College of Liberal Arts and Sciences, University of Illinois Chicago, Chicago, IL 60607, USA
| | - George F. Koob
- Neurobiology of Addiction Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA
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16
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Jiang J, Yang M, Tian M, Chen Z, Xiao L, Gong Y. Intertwined associations between oxytocin, immune system and major depressive disorder. Biomed Pharmacother 2023; 163:114852. [PMID: 37163778 PMCID: PMC10165244 DOI: 10.1016/j.biopha.2023.114852] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 04/28/2023] [Accepted: 05/04/2023] [Indexed: 05/12/2023] Open
Abstract
Major depressive disorder (MDD) is a prominent psychiatric disorder with a high prevalence rate. The recent COVID-19 pandemic has exacerbated the already high prevalence of MDD. Unfortunately, a significant proportion of patients are unresponsive to conventional treatments, necessitating the exploration of novel therapeutic strategies. Oxytocin, an endogenous neuropeptide, has emerged as a promising candidate with anxiolytic and antidepressant properties. Oxytocin has been shown to alleviate emotional disorders by modulating the hypothalamic-pituitary-adrenal (HPA) axis and the central immune system. The dysfunction of the immune system has been strongly linked to the onset and progression of depression. The central immune system is believed to be a key target of oxytocin in ameliorating emotional disorders. In this review, we examine the evidence regarding the interactions between oxytocin, the immune system, and depressive disorder. Moreover, we summarize and speculate on the potential roles of the intertwined association between oxytocin and the central immune system in treating emotional disorders.
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Affiliation(s)
- Junliang Jiang
- Department of Orthopedics and Traumatology, Affiliated Hospital of Yunnan University, Yunnan University, Kunming, China; Department of Critical Care Medicine and Neurosurgery of Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China
| | - Miaoxian Yang
- Department of Critical Care Medicine and Neurosurgery of Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China
| | - Mi Tian
- Department of Critical Care Medicine and Neurosurgery of Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China
| | - Zhong Chen
- Department of Orthopedics and Traumatology, Affiliated Hospital of Yunnan University, Yunnan University, Kunming, China.
| | - Lei Xiao
- Department of Critical Care Medicine and Neurosurgery of Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China.
| | - Ye Gong
- Department of Critical Care Medicine and Neurosurgery of Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China.
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17
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Azari AE, Peeri M, Masrour FF. The role of the oxytocinergic system in the antidepressant-like effect of swimming training in male mice. Behav Brain Res 2023; 449:114474. [PMID: 37148917 DOI: 10.1016/j.bbr.2023.114474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 03/12/2023] [Accepted: 03/20/2023] [Indexed: 05/08/2023]
Abstract
Increasing evidence shows that higher physical activity such as running and swimming exercises is associated with decreased depression-related symptoms. However, underlying mechanisms are not fully understood. This study aimed to investigate whether oxytocinergic system can mediate the antidepressant effect of swimming exercises in mice. First, male NMRI mice were subjected to swimming training for eight weeks, then animals intraperitoneally received oxytocin antagonist (L-368899) 1hour before behavioral tests. We assessed anhedonia and social behavior and behavioral despair using the sucrose preference test, social interaction test, and tail suspension test. Oxytocin levels in the brain and serum were also measured. The results showed that swimming training decreased anhedonia and behavioral despair, whereas it increased social behavior and oxytocin levels in male mice. On the other hand, a subthreshold dose of oxytocin antagonist treatment in exercised mice prevented the antidepressant effect of swimming exercise via increased anhedonia and behavioral despair and decreased social behavior compared to the swimming training group. However, the blockade of oxytocin receptors did not affect oxytocin levels in exercised mice. Overall, these findings suggest that oxytocinergic system can play a role in mediating the antidepressant-like effect of swimming training in mice.
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Affiliation(s)
- Amir Emad Azari
- Department of Exercise Physiology, Central Tehran Branch, Islamic Azad University, Tehran, Iran.
| | - Maghsoud Peeri
- Department of Exercise Physiology, Central Tehran Branch, Islamic Azad University, Tehran, Iran.
| | - Forouzan Fattahi Masrour
- Department of Exercise Physiology, Central Tehran Branch, Islamic Azad University, Tehran, Iran.
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18
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Isiguzo C, Mendez DD, Demirci JR, Youk A, Mendez G, Davis EM, Documet P. Stress, social support, and racial differences: Dominant drivers of exclusive breastfeeding. MATERNAL & CHILD NUTRITION 2023; 19:e13459. [PMID: 36411512 PMCID: PMC10019056 DOI: 10.1111/mcn.13459] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 10/21/2022] [Accepted: 10/24/2022] [Indexed: 11/23/2022]
Abstract
Exclusive breastfeeding is recommended for 6 months; however, many childbearing people wean their infants before 6 months. Psychosocial factors such as stress, social support and race are significant determinants of breastfeeding; however, few studies have longitudinally explored the effect of perceived stress and various forms of social support on exclusive breastfeeding. We used quantitative methodologies to examine exclusive breastfeeding, perceived stress and social support among 251 participants from the Postpartum Mothers Mobile Study. Participants between 18 and 44 years were recruited during pregnancy (irrespective of parity) and completed surveys in real-time via Ecological Momentary Assessment up to 12 months postpartum from December 2017 to August 2021. We measured perceived stress with the adapted Perceived Stress Scale and perceived social support with the Multi-dimensional Social Support Scale. Received social support was measured using a single question on breastfeeding support. We conducted a mixed-effects logistic regression to determine the effect of stress, race and social support on exclusive breastfeeding over 6 months. We examined the moderation effect of perceived social support and breastfeeding support in the relationship between perceived stress and exclusive breastfeeding. Black, compared with White, participants were less likely to breastfeed exclusively for 6 months. Participants who reported higher perceived stress were less likely to breastfeed exclusively for 6 months. Perceived social support moderated the relationship between perceived stress and exclusive breastfeeding (odds ratio: 0.01, 95% confidence interval: 0.001-0.072). However, breastfeeding support directly increased the likelihood of exclusive breastfeeding over 6 months. Perceived stress is negatively associated with exclusive breastfeeding. Birthing people who intend to breastfeed may benefit from perinatal support programs that include components to buffer stress.
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Affiliation(s)
- Chinwoke Isiguzo
- Behavioral and Community Health Sciences, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA
| | - Dara D Mendez
- Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA
| | - Jill R Demirci
- Department of Health Promotion and Development, School of Nursing, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Ada Youk
- Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Gabriella Mendez
- Behavioral and Community Health Sciences, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA
- Orthopedic Foot and Ankle Center, Worthington, Ohio, USA
| | - Esa M Davis
- Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Patricia Documet
- Behavioral and Community Health Sciences, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA
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19
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Hou W, Huang S, Li L, Guo X, He Z, Shang S, Jia Z, Zhang L, Qu Y, Huang C, Li Y, Li Y, Lv Z, Tai F. Oxytocin treatments or activation of the paraventricular nucleus-the shell of nucleus accumbens pathway reduce adverse effects of chronic social defeat stress on emotional and social behaviors in Mandarin voles. Neuropharmacology 2023; 230:109482. [PMID: 36893984 DOI: 10.1016/j.neuropharm.2023.109482] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 02/12/2023] [Accepted: 03/02/2023] [Indexed: 03/09/2023]
Abstract
Chronic social stress can cause psychological disease. Although oxytocin (OT) has been showed to modulate effects of chronic social defeat stress (CSDS) on emotional and social behaviors, however, how OT circuits mediate effects of CSDS on emotional and social abnormalities remains unclear. Here, we found that repeated intraperitoneal OT administration in the process of CSDS buffered adverse effects of CSDS on emotional and social behaviors in mandarin voles (Microtus mandarinus) of both sexes except no effect on depression-like behavior of males. Repeated OT treatments during CSDS prevented decrease of oxytocin receptors in nucleus accumbens (NAc) in females, but produced no effects on males. Furthermore, using designer receptors exclusively activated by designer drugs (DREADDs)-based chemogenetic tools, we determined that the activation of the paraventricular nucleus (PVN)-the shell of NAc (NAcs) projections before social defeat during CSDS process significantly prevented the increase of the anxiety-like behaviors and social avoidance induced by CSDS in both sexes, and reversed the depressive-like behaviors induced by CSDS only in females. Besides, optogenetic activation of PVN-NAcs projections after CSDS reduced anxiety-like behaviors and increased levels of sociality. Collectively, we suggest that PVN-NAcs projections modulate emotional and social behaviors during or after the process of CSDS sex-specifically, although AAV viruses did not specifically infect OT neurons. These findings offer potential targets for preventing or treating emotional and social disorders induced by chronic stress.
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Affiliation(s)
- Wenjuan Hou
- Institute of Brain and Behavioral Sciences, College of Life Sciences, Shaanxi Normal University, Xi'an, 710062, China
| | - Shuying Huang
- Institute of Brain and Behavioral Sciences, College of Life Sciences, Shaanxi Normal University, Xi'an, 710062, China
| | - Lu Li
- Institute of Brain and Behavioral Sciences, College of Life Sciences, Shaanxi Normal University, Xi'an, 710062, China
| | - Xing Guo
- Institute of Brain and Behavioral Sciences, College of Life Sciences, Shaanxi Normal University, Xi'an, 710062, China
| | - Zhixiong He
- Institute of Brain and Behavioral Sciences, College of Life Sciences, Shaanxi Normal University, Xi'an, 710062, China
| | - Shufeng Shang
- Institute of Brain and Behavioral Sciences, College of Life Sciences, Shaanxi Normal University, Xi'an, 710062, China; College of Bioscience and Engineering, Shaanxi University of Technology, Hanzhong, 723000, China
| | - Ziyan Jia
- Institute of Brain and Behavioral Sciences, College of Life Sciences, Shaanxi Normal University, Xi'an, 710062, China
| | - Lizi Zhang
- Institute of Brain and Behavioral Sciences, College of Life Sciences, Shaanxi Normal University, Xi'an, 710062, China
| | - Yishan Qu
- Institute of Brain and Behavioral Sciences, College of Life Sciences, Shaanxi Normal University, Xi'an, 710062, China
| | - Caihong Huang
- Institute of Brain and Behavioral Sciences, College of Life Sciences, Shaanxi Normal University, Xi'an, 710062, China
| | - Yin Li
- Institute of Brain and Behavioral Sciences, College of Life Sciences, Shaanxi Normal University, Xi'an, 710062, China
| | - Yitong Li
- Institute of Brain and Behavioral Sciences, College of Life Sciences, Shaanxi Normal University, Xi'an, 710062, China
| | - Zijian Lv
- Institute of Brain and Behavioral Sciences, College of Life Sciences, Shaanxi Normal University, Xi'an, 710062, China
| | - Fadao Tai
- Institute of Brain and Behavioral Sciences, College of Life Sciences, Shaanxi Normal University, Xi'an, 710062, China.
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20
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Marazziti D, Carter CS, Carmassi C, Della Vecchia A, Mucci F, Pagni G, Carbone MG, Baroni S, Giannaccini G, Palego L, Dell’Osso L. Sex matters: The impact of oxytocin on healthy conditions and psychiatric disorders. COMPREHENSIVE PSYCHONEUROENDOCRINOLOGY 2022; 13:100165. [PMID: 36590869 PMCID: PMC9800179 DOI: 10.1016/j.cpnec.2022.100165] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 12/12/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022] Open
Abstract
Oxytocin (OT) is involved in the regulation of physiological processes and emotional states, with increasing evidence for its beneficial actions being mediated by the autonomic and immune systems. Growing evidence suggests that OT plays a role in the pathophysiology of different psychiatric disorders. Given the limited information in humans the aim of this study was to retrospectively explore plasma OT levels in psychiatric patients, particularly focusing on sex-related differences, as compared with healthy controls. The patients studied here were divided into three groups diagnosed with obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD) or major depressive disorder (MDD). Plasma OT levels were significantly different between healthy men and women, with the latter showing higher values, while none of the three psychiatric groups showed sex-related differences in the parameters measured here. The intergroup analyses showed that the OT levels were significantly higher in OCD, lower in PTSD and even more reduced in MDD patients than in healthy subjects. These differences were also confirmed when gender was considered, with the exception of PTSD men, in whom OT levels were similar to those of healthy men. The present results indicated that OT levels were higher amongst healthy women than men, while a sex difference was less apparent or reversed in psychiatric patients. Reductions in sex differences in psychopathologies may be related to differential vulnerabilities in processes associated with basic adaptive and social functions.
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Affiliation(s)
- Donatella Marazziti
- Department of Clinical and Experimental Medicine, University of Pisa, Italy,Saint Camillus International University of Health and Medical Sciences – UniCamillus, Rome, Italy,Corresponding author. Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 57, 56100, Pisa, Italy.
| | - C. Sue Carter
- Kinsey Institute, Indiana University, Bloomington, IN, USA,Department of Psychology, University of Virginia, Charlottesville, VA, USA
| | - Claudia Carmassi
- Department of Clinical and Experimental Medicine, University of Pisa, Italy
| | | | - Federico Mucci
- Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Italy,Department of Psychiatry, North-Western Tuscany Region NHS Local Health Unit, Lucca Zone, Lucca, Italy
| | - Giovanni Pagni
- Department of Psychiatry, North-Western Tuscany Region NHS Local Health Unit, Lunigiana Zone, Aulla, Italy
| | - Manuel G. Carbone
- Department of Medicine and Surgery, Division of Psychiatry, University of Insubria, Varese, Italy
| | - Stefano Baroni
- Department of Clinical and Experimental Medicine, University of Pisa, Italy
| | | | | | - Liliana Dell’Osso
- Department of Clinical and Experimental Medicine, University of Pisa, Italy
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21
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Meng X, Grandjean J, Sbrini G, Schipper P, Hofwijks N, Stoop J, Calabrese F, Homberg J. Tryptophan Hydroxylase 2 Knockout Male Rats Exhibit a Strengthened Oxytocin System, Are Aggressive, and Are Less Anxious. ACS Chem Neurosci 2022; 13:2974-2981. [PMID: 36197033 PMCID: PMC9585586 DOI: 10.1021/acschemneuro.2c00448] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 09/23/2022] [Indexed: 01/20/2023] Open
Abstract
The central serotoninergic system is critical for stress responsivity and social behavior, and its dysregulations have been centrally implicated in virtually all neuropsychiatric disorders. Genetic serotonin depletion animal models could provide a tool to elucidate the causes and mechanisms of diseases and to develop new treatment approaches. Previously, mice lacking tryptophan hydroxylase 2 (Tph2) have been developed, showing altered behaviors and neurotransmission. However, the effect of congenital serotonin deficiency on emotional and social behavior in rats is still largely unknown, as are the underlying mechanisms. In this study, we used a Tph2 knockout (Tph2-/-) male rat model to study how the lack of serotonin in the rat brain affects anxiety-like and social behaviors. Since oxytocin is centrally implicated in these behaviors, we furthermore explored whether the effects of Tph2 knockout on behavior would relate to changes in the oxytocin system. We show that Tph2-/- rats display reduced anxiety-like behavior and a high level of aggression in social interactions. In addition, oxytocin receptor expression was increased in the infralimbic and prelimbic cortices, paraventricular nucleus, dorsal raphe nucleus, and some subregions of the hippocampus, which was paralleled by increased levels of oxytocin in the medial frontal cortex and paraventricular nucleus but not the dorsal raphe nucleus, central amygdala, and hippocampus. In conclusion, our study demonstrated reduced anxiety but exaggerated aggression in Tph2-/- male rats and reveals for the first time a potential involvement of altered oxytocin system function. Meanwhile, the research of oxytocin could be distinguished in almost any psychiatric disorder including anxiety and mental disorders. This research potentially proposes a new target for the treatment of such disorders, from a genetic serotonin deficiency aspect.
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Affiliation(s)
- Xianzong Meng
- Department
of Cognitive Neuroscience, Donders Institute for Brain, Cognition,
and Behaviour, Radboud University Medical
Centre, 6525 AJ Nijmegen, The Netherlands
| | - Joanes Grandjean
- Department
of Cognitive Neuroscience, Donders Institute for Brain, Cognition,
and Behaviour, Radboud University Medical
Centre, 6525 AJ Nijmegen, The Netherlands
- Department
of Medical Imaging, Radboud University Medical
Centre, 6525 GA Nijmegen, The Netherlands
| | - Giulia Sbrini
- Department
of Pharmacological and Biomolecular Sciences, Università Degli Studi Di Milano, Via Balzaretti 9, 20133 Milan, Italy
| | - Pieter Schipper
- Department
of Cognitive Neuroscience, Donders Institute for Brain, Cognition,
and Behaviour, Radboud University Medical
Centre, 6525 AJ Nijmegen, The Netherlands
| | - Nita Hofwijks
- Department
of Cognitive Neuroscience, Donders Institute for Brain, Cognition,
and Behaviour, Radboud University Medical
Centre, 6525 AJ Nijmegen, The Netherlands
| | - Jesse Stoop
- Department
of Cognitive Neuroscience, Donders Institute for Brain, Cognition,
and Behaviour, Radboud University Medical
Centre, 6525 AJ Nijmegen, The Netherlands
| | - Francesca Calabrese
- Department
of Pharmacological and Biomolecular Sciences, Università Degli Studi Di Milano, Via Balzaretti 9, 20133 Milan, Italy
| | - Judith Homberg
- Department
of Cognitive Neuroscience, Donders Institute for Brain, Cognition,
and Behaviour, Radboud University Medical
Centre, 6525 AJ Nijmegen, The Netherlands
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22
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Khodagholi F, Maleki A, Motamedi F, Mousavi MA, Rafiei S, Moslemi M. Oxytocin Prevents the Development of 3-NP-Induced Anxiety and Depression in Male and Female Rats: Possible Interaction of OXTR and mGluR2. Cell Mol Neurobiol 2022; 42:1105-1123. [PMID: 33201416 PMCID: PMC11441245 DOI: 10.1007/s10571-020-01003-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 11/07/2020] [Indexed: 01/01/2023]
Abstract
Huntington disease (HD) is a progressive neurological disorder with dominant motor symptoms. It also has psychiatric manifestations, like anxiety and depression, that can emerge themselves before motor symptoms and impose a major burden on patients. Oxytocin (OXT) is a newly emerged treatment for disorders like autism and schizophrenia and recently is using to alleviate depression and anxiety. In the current study, we investigated the behavioral and molecular effects of OXT on the development of anxiety and depression in 3-nitropropionic acid (3-NP)-induced model of HD. Anxiety- and depression-like behaviors as well as the levels of oxytocin receptor (OXTR), metabotropic glutamate receptor (mGluR) 2, mGluR5, and glutathione (GSH) were measured in striatum, hippocampus, prefrontal cortex, and amygdala. Also, we questioned if sex had any modulatory effect. We found that 3-NP increased anxiety and depression compared to controls. It also reduced the levels of OXTR and mGluR2, increased mGluR5, and reduced GSH in studied brain regions. Pretreatment with OXT before the injection of 3-NP ameliorated anxiety and depression. Additionally, it protected the brain from developing low levels of OXTR, mGluR2, and GSH and high levels of mGluR5 in studied regions. The protective effects of OXT were similar between male and female animals. These data suggest that OXTR, mGluR2, mGluR5, and GSH may contribute to psychiatric manifestations of HD. In addition, pretreatment with OXT could prevent the mood changes in male and female rats.
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Affiliation(s)
- Fariba Khodagholi
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Maleki
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fereshteh Motamedi
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Alsadat Mousavi
- Neurobiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shahrbanoo Rafiei
- Neurobiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehdi Moslemi
- Neurobiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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23
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Antidepressant-like effect of male mating behavior through oxytocin-induced CREB signaling. Neurosci Res 2022; 181:74-78. [DOI: 10.1016/j.neures.2022.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 04/02/2022] [Accepted: 04/05/2022] [Indexed: 11/19/2022]
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24
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Exploring the role of neuropeptides in depression and anxiety. Prog Neuropsychopharmacol Biol Psychiatry 2022; 114:110478. [PMID: 34801611 DOI: 10.1016/j.pnpbp.2021.110478] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 11/13/2021] [Accepted: 11/13/2021] [Indexed: 12/24/2022]
Abstract
Depression is one of the most prevalent forms of mental disorders and is the most common cause of disability in the Western world. Besides, the harmful effects of stress-related mood disorders on the patients themselves, they challenge the health care system with enormous social and economic impacts. Due to the high proportion of patients not responding to existing drugs, finding new treatment strategies has become an important topic in neurobiology, and there is much evidence that neuropeptides are not only involved in the physiology of stress but may also be clinically important. Based on preclinical trial data, new neuropharmaceutical candidates may target neuropeptides and their receptors and are expected to be essential and valuable tools in the treatment of psychiatric disorders. In the current article, we have summarized data obtained from animal models of depressive disorder and transgenic mouse models. We also focus on previously published research data of clinical studies on corticotropin-releasing hormone (CRH), galanin (GAL), neuropeptide Y (NPY), neuropeptide S (NPS), Oxytocin (OXT), vasopressin (VP), cholecystokinin (CCK), and melanin-concentrating hormone (MCH) stress research fields.
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25
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Mantas I, Saarinen M, Xu ZQD, Svenningsson P. Update on GPCR-based targets for the development of novel antidepressants. Mol Psychiatry 2022; 27:534-558. [PMID: 33589739 PMCID: PMC8960420 DOI: 10.1038/s41380-021-01040-1] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 01/22/2021] [Accepted: 01/25/2021] [Indexed: 01/31/2023]
Abstract
Traditional antidepressants largely interfere with monoaminergic transport or degradation systems, taking several weeks to have their therapeutic actions. Moreover, a large proportion of depressed patients are resistant to these therapies. Several atypical antidepressants have been developed which interact with G protein coupled receptors (GPCRs) instead, as direct targeting of receptors may achieve more efficacious and faster antidepressant actions. The focus of this review is to provide an update on how distinct GPCRs mediate antidepressant actions and discuss recent insights into how GPCRs regulate the pathophysiology of Major Depressive Disorder (MDD). We also discuss the therapeutic potential of novel GPCR targets, which are appealing due to their ligand selectivity, expression pattern, or pharmacological profiles. Finally, we highlight recent advances in understanding GPCR pharmacology and structure, and how they may provide new avenues for drug development.
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Affiliation(s)
- Ioannis Mantas
- Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden
| | - Marcus Saarinen
- Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden
| | - Zhi-Qing David Xu
- Department of Neurobiology, Beijing Key Laboratory of Neural Regeneration and Repair, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China
| | - Per Svenningsson
- Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
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26
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Ghazy AA, Soliman OA, Elbahnasi AI, Alawy AY, Mansour AM, Gowayed MA. Role of Oxytocin in Different Neuropsychiatric, Neurodegenerative, and Neurodevelopmental Disorders. Rev Physiol Biochem Pharmacol 2022; 186:95-134. [PMID: 36416982 DOI: 10.1007/112_2022_72] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Oxytocin has recently gained significant attention because of its role in the pathophysiology and management of dominant neuropsychiatric disorders. Oxytocin, a peptide hormone synthesized in the hypothalamus, is released into different brain regions, acting as a neurotransmitter. Receptors for oxytocin are present in many areas of the brain, including the hypothalamus, amygdala, and nucleus accumbens, which have been involved in the pathophysiology of depression, anxiety, schizophrenia, autism, Alzheimer's disease, Parkinson's disease, and attention deficit hyperactivity disorder. Animal studies have spotlighted the role of oxytocin in social, behavioral, pair bonding, and mother-infant bonding. Furthermore, oxytocin protects fetal neurons against injury during childbirth and affects various behaviors, assuming its possible neuroprotective characteristics. In this review, we discuss some of the concepts and mechanisms related to the role of oxytocin in the pathophysiology and management of some neuropsychiatric, neurodegenerative, and neurodevelopmental disorders.
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Affiliation(s)
- Aya A Ghazy
- Department of Clinical Pharmacy, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt
| | - Omar A Soliman
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria, Egypt
| | - Aya I Elbahnasi
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria, Egypt
| | - Aya Y Alawy
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria, Egypt
| | - Amira Ma Mansour
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria, Egypt
| | - Mennatallah A Gowayed
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria, Egypt.
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27
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Plessow F, Galbiati F, Eddy KT, Misra M, Miller KK, Klibanski A, Aulinas A, Lawson EA. Low oxytocin levels are broadly associated with more pronounced psychopathology in anorexia nervosa with primarily restricting but not binge/purge eating behavior. Front Endocrinol (Lausanne) 2022; 13:1049541. [PMID: 36798485 PMCID: PMC9927219 DOI: 10.3389/fendo.2022.1049541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 12/28/2022] [Indexed: 02/02/2023] Open
Abstract
OBJECTIVE Anorexia nervosa (AN) is commonly associated with depression, anxiety, and deficits in socioemotional functioning. Basal levels of oxytocin, a neurohormone with antidepressant, anxiolytic, and prosocial properties, are low in women with AN. However, the relationship between oxytocin and psychopathology of AN/atypical AN has not been examined in individuals with primarily food restriction (AN/AtypAN-R) or those with restriction plus binge/purge behaviors (AN/AtypAN-BP) alone, which is important to further elucidate the neurobiology of different AN presentations. We investigated whether oxytocin levels are related to eating, affective, and socioemotional psychopathology in women with AN/AtypAN-R and separately AN/AtypAN-BP. METHODS In a cross-sectional study of 53 women with low-weight AN or atypical AN based on DSM-5 (AN/AtypAN-R: n=21, AN/AtypAN-BP: n=32), we obtained fasting serum oxytocin levels and self-report measures of psychopathology, including the Eating Disorder Examination-Questionnaire (EDE-Q), Beck Depression Inventory-IA (BDI), State-Trait Anxiety Inventory (STAI), and Toronto Alexithymia Scale (TAS-20). RESULTS In individuals with AN/AtypAN-R, oxytocin levels were negatively associated with eating psychopathology (EDE-Q Global Score: r=-0.49, p=0.024), depressive and anxiety symptoms (BDI Total Score: r=-0.55, p=0.009; STAI Trait Score: r=-0.63, p=0.002), and socioemotional symptoms (TAS-20 Difficulty Identifying Feelings Score: r=-0.49, p=0.023). In contrast, in those with AN/AtypAN-BP oxytocin levels were negatively associated with depressive symptoms only (BDI Total Score: r=-0.52, p=0.049). CONCLUSIONS These findings support the notion that AN/AtypAN-R and AN/AtypAN-BP might have divergent underlying neurobiology. Understanding these differences is crucial to develop targeted treatments for a population with high levels of chronicity, for which no specific pharmacological treatments are currently available. CLINICAL TRIAL REGISTRATION https://clinicaltrials.gov, identifier: NCT01121211.
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Affiliation(s)
- Franziska Plessow
- Neuroendocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Francesca Galbiati
- Neuroendocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Kamryn T. Eddy
- Eating Disorders Clinical and Research Program, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Madhusmita Misra
- Neuroendocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
- Division of Pediatric Endocrinology, Massachusetts General Hospital for Children and Harvard Medical School, Boston, MA, United States
| | - Karen K. Miller
- Neuroendocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Anne Klibanski
- Neuroendocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Anna Aulinas
- Neuroendocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Elizabeth A. Lawson
- Neuroendocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
- *Correspondence: Elizabeth A. Lawson,
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28
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Mosaferi B, Jand Y, Salari AA. Gut microbiota depletion from early adolescence alters anxiety and depression-related behaviours in male mice with Alzheimer-like disease. Sci Rep 2021; 11:22941. [PMID: 34824332 PMCID: PMC8617202 DOI: 10.1038/s41598-021-02231-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Accepted: 11/12/2021] [Indexed: 12/13/2022] Open
Abstract
The gut-microbiota-brain axis plays an important role in stress-related disorders, and dysfunction of this complex bidirectional system is associated with Alzheimer's disease. This study aimed to assess the idea that whether gut microbiota depletion from early adolescence can alter anxiety- and depression-related behaviours in adult mice with or without Alzheimer-like disease. Male C57BL/6 mice were treated with an antibiotic cocktail from weaning to adulthood. Adult mice received an intracerebroventricular injection of amyloid-beta (Aβ)1-42, and were subjected to anxiety and depression tests. We measured, brain malondialdehyde and glutathione following anxiety tests, and assessed brain oxytocin and the hypothalamic-pituitary-adrenal (HPA) axis function by measuring adrenocorticotrophic hormone (ACTH) and corticosterone following depression tests. Healthy antibiotic-treated mice displayed significant decreases in anxiety-like behaviours, whereas they did not show any alterations in depression-like behaviours and HPA axis function. Antibiotic treatment from early adolescence prevented the development of anxiety- and depression-related behaviours, oxidative stress and HPA axis dysregulation in Alzheimer-induced mice. Antibiotic treatment increased oxytocin in the brain of healthy but not Alzheimer-induced mice. Taken together, these findings suggest that gut microbiota depletion following antibiotic treatment from early adolescence might profoundly affect anxiety- and depression-related behaviours, and HPA axis function in adult mice with Alzheimer-like disease.
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Affiliation(s)
- Belal Mosaferi
- Department of Basic Sciences, School of Nursing and Midwifery, Maragheh University of Medical Sciences, Maragheh, Iran
| | - Yahya Jand
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali-Akbar Salari
- Salari Institute of Cognitive and Behavioral Disorders (SICBD), P.O. Box 31396-45999, Karaj, Alborz, Iran.
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29
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Sasaki K, Ferdousi F, Fukumitsu S, Kuwata H, Isoda H. Antidepressant- and anxiolytic-like activities of Rosmarinus officinalis extract in rodent models: Involvement of oxytocinergic system. Biomed Pharmacother 2021; 144:112291. [PMID: 34653760 DOI: 10.1016/j.biopha.2021.112291] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 09/29/2021] [Accepted: 10/05/2021] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND Oxytocin (OXT), a neuropeptide involved in mammal reproductive and prosocial behaviors, has been reported to interact with various stressor-provoked neurobiological changes, including neuroendocrine, neurotransmitter, and inflammatory processes. In view of disturbances in psychosocial relationships due to social isolation and physical distancing measures amid the COVID-19 pandemic, being one of the triggering factors for the recent rise in depression and anxiety, OXT is a potential candidate for a new antidepressant. METHODS In this present study, we have aimed to investigate the effects of oral administration of Rosmarinus officinalis extract (RE), extracted from distillation residue of rosemary essential oil, on central OXT level in the context of other stress biomarkers and neurotransmitter levels in mice models. Tail suspension test (TST) and elevated plus maze test (EPMT) following LPS injection were employed to assess depressive- and anxiety-like behavior in mice, respectively. FINDINGS Pretreatment with RE for seven days significantly improved behavior in TST and EPMT. Whole-genome microarray analysis reveals that RE significantly reversed TST stress-induced alterations in gene expressions related to oxytocinergic and neurotransmitter pathways and inflammatory processes. In both models, RE significantly increased central Oxt and Oxtr expressions, as well as OXT protein levels. RE also significantly attenuated stress-induced changes in serum corticosterone, brain and serum BDNF levels, and brain neurotransmitters levels in both models. INTERPRETATION Altogether, our study is the first to report antidepressant- and anxiolytic-like activities of RE through modulating oxytocinergic system in mice brain and thus highlights the prospects of RE in the treatment of depressive disorders of psychosocial nature.
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Affiliation(s)
- Kazunori Sasaki
- Alliance for Research on the Mediterranean and North Africa (ARENA), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan; Open Innovation Laboratory for Food and Medicinal Resource Engineering, National Institute of Advanced Industrial Science and Technology (AIST) and University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan
| | - Farhana Ferdousi
- Alliance for Research on the Mediterranean and North Africa (ARENA), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan; Open Innovation Laboratory for Food and Medicinal Resource Engineering, National Institute of Advanced Industrial Science and Technology (AIST) and University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan; Faculty of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan
| | - Satoshi Fukumitsu
- Alliance for Research on the Mediterranean and North Africa (ARENA), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan; Tsukuba Life Science Innovation Program (T-LSI), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8577 Ibaraki, Japan
| | - Hidetoshi Kuwata
- Alliance for Research on the Mediterranean and North Africa (ARENA), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan
| | - Hiroko Isoda
- Alliance for Research on the Mediterranean and North Africa (ARENA), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan; Open Innovation Laboratory for Food and Medicinal Resource Engineering, National Institute of Advanced Industrial Science and Technology (AIST) and University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan; Faculty of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan; Tsukuba Life Science Innovation Program (T-LSI), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8577 Ibaraki, Japan.
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30
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Thornton JL, Everett NA, Webb P, Turner AJ, Cornish JL, Baracz SJ. Adolescent oxytocin administration reduces depression-like behaviour induced by early life stress in adult male and female rats. Prog Neuropsychopharmacol Biol Psychiatry 2021; 110:110279. [PMID: 33567331 DOI: 10.1016/j.pnpbp.2021.110279] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 01/29/2021] [Accepted: 02/05/2021] [Indexed: 01/06/2023]
Abstract
Early life stress (ELS) exposure alters brain development, increasing vulnerability for mental illness in adulthood, including depression. Despite this association, there are no approved pharmacotherapies to protect against the emergence of mental illness resulting from ELS. Recent preclinical work showed that oxytocin (OT) administration in adulthood reduced depressive-like behaviour in male rats with a history of ELS. However, the ability of an OT treatment regime in adolescence, a critical developmental window for the OT system, to prevent the expression of depressive-like behaviours following ELS has not been investigated. Therefore, the present study aimed to determine whether chronic OT administration can ameliorate the enduring effects of ELS on depressive-like behaviours in both male and female rats. Following birth, Long Evans rat pups (N = 107) underwent maternal separation (MS) for either 15 min (MS15) or 6 h (MS360) on postnatal days (PND) 1-21. During adolescence (PND 28-42), rats received a daily injection of either OT (1 mg/kg) or saline. During adulthood (PND 57 onwards), effort-related motivation was measured using a model of effortful choice (EC), while behavioural despair was measured using the forced swim test (FST). Lastly, body and organ weights were measured to examine the physiological impacts of ELS and chronic OT administration. Overall, in both sexes, MS360 increased behavioural despair yet had no impact on effort-related motivation. Importantly, adolescent OT administration prevented the MS360-induced increase in behavioural despair in both males and females. Additionally, MS360 resulted in persistent reductions in body weight in both sexes post-weaning and increased spleen weight in males and adrenal weight in females. OT treatment had no impact on body weight in either sex, but prevented the MS-induced increase in adrenal gland weight in females. Overall, these findings have important implications for using oxytocin as a preventative pharmacotherapy after ELS.
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Affiliation(s)
- Jade L Thornton
- Department of Psychology, Macquarie University, North Ryde, NSW 2109, Australia
| | - Nicholas A Everett
- School of Psychology, University of Sydney, Camperdown, NSW, 2050, Australia
| | - Paige Webb
- Department of Psychology, Macquarie University, North Ryde, NSW 2109, Australia
| | - Anita J Turner
- Department of Psychology, Macquarie University, North Ryde, NSW 2109, Australia
| | - Jennifer L Cornish
- Department of Psychology, Macquarie University, North Ryde, NSW 2109, Australia; Centre for Emotional Health, Macquarie University, North Ryde, NSW 2109, Australia
| | - Sarah J Baracz
- Department of Psychology, Macquarie University, North Ryde, NSW 2109, Australia; Centre for Emotional Health, Macquarie University, North Ryde, NSW 2109, Australia; School of Psychology, University of New South Wales, Randwick, NSW, 2052, Australia.
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31
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Abstract
Stress system dysfunction is a typical characteristic of acute depression and other mood disorders. The exact pattern of factors predisposing for stress-related mental disorders is yet to be unraveled. However, corticosteroid receptor function plays an important role for appropriate or dysfunctional neuroendocrine responses to stress exposure and hence in resilience or risk for the development and course of both, depression and anxiety disorders. Solid neuroscience data strongly support that both neuropeptides, corticotropin-releasing hormone (CRH) and vasopressin (AVP), are central in coordinating humoral and behavioral adaptation to stress. Other neuropeptides, including oxytocin, neuropeptide S, neuropeptide Y, and orexin, are also considered important contributors. Attempts to turn neuropeptide biology into treatments for stress-related disorders need to consider that neuropeptide receptors are specific drug targets for certain patient populations rather than universal targets for all patients, like biogenic amine systems. That is why most negative clinical trials testing neuropeptide receptor antagonists have been in fact failed trials by design, because no companion tests were used to identify which patients with depression are most likely to benefit from a specific neuropeptide receptor-targeting drug treatment. Therefore, the most important future research task is discovery and development of appropriate companion tests that will allow the successful transfer of the precious treasure of neuropeptide system-targeting drugs into clinics.
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Affiliation(s)
| | - Marcus Ising
- Max Planck Institute of Psychiatry, Munich, Germany
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32
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Amodeo G, Laurenzi PF, Santucci A, Cuomo A, Bolognesi S, Goracci A, Rossi R, Beccarini Crescenzi B, Neal SM, Fagiolini A. Advances in treatment for postpartum major depressive disorder. Expert Opin Pharmacother 2020; 21:1685-1698. [PMID: 32584616 DOI: 10.1080/14656566.2020.1779702] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Introduction: Postpartum depressive disorder (PPD) is a burdensome medical condition. To date, only one treatment (Brexanolone) has undergone registrational trials and is approved in the United States with an indication for the treatment of PPD. However, other treatments are prescribed and have been tested for this condition. Herein, the authors review the available scientific evidence pertaining to the somatic treatments of PPD. Areas covered: The authors evaluate the published open-label and randomized controlled trials (RCTs), examine the biological mechanisms of PPD treatments, and evaluate how the available data translates into information that may be useful for clinical practice. Expert opinion: Antidepressants have long been the mainstay of PPD treatment, despite the limited evidence from randomized clinical trials that supports this practice. Brexanolone improves treatment options for women with PPD. However, the relatively burdensome administration and monitoring protocol, along with the high cost of the medication, limit the possibility for an extensive use of this medication. Large, randomized, controlled trials of hormonal treatments in patients with PPD are warranted. Also, treatment with mood stabilizers and/or antipsychotics in women with major depressive disorder, who meet the DSM-5 mixed features specifiers in the post-partum period, should be tested in controlled clinical trials.
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Affiliation(s)
- Giovanni Amodeo
- Department of Molecular and Developmental Medicine, University of Siena School of Medicine
| | | | - Aurora Santucci
- Department of Molecular and Developmental Medicine, University of Siena School of Medicine
| | - Alessandro Cuomo
- Department of Molecular and Developmental Medicine, University of Siena School of Medicine
| | - Simone Bolognesi
- Department of Molecular and Developmental Medicine, University of Siena School of Medicine
| | - Arianna Goracci
- Department of Molecular and Developmental Medicine, University of Siena School of Medicine
| | - Rodolfo Rossi
- Department of System Medicine (RR), Tor Vergata University , Rome, Italy.,Department of Mental Health & Drug Abuse, AUSL Modena , Modena, Italy
| | | | - Stephen M Neal
- Department of Psychiatry, West Virginia School of Osteopathic Medicine , Lewisburg, WV, USA
| | - Andrea Fagiolini
- Department of Molecular and Developmental Medicine, University of Siena School of Medicine
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Panaro MA, Benameur T, Porro C. Hypothalamic Neuropeptide Brain Protection: Focus on Oxytocin. J Clin Med 2020; 9:jcm9051534. [PMID: 32438751 PMCID: PMC7290962 DOI: 10.3390/jcm9051534] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 05/06/2020] [Accepted: 05/14/2020] [Indexed: 02/06/2023] Open
Abstract
Oxytocin (OXT) is hypothalamic neuropeptide synthetized in the brain by magnocellular and parvo cellular neurons of the paraventricular (PVN), supraoptic (SON) and accessory nuclei (AN) of the hypothalamus. OXT acts in the central and peripheral nervous systems via G-protein-coupled receptors. The classical physiological functions of OXT are uterine contractions, the milk ejection reflex during lactation, penile erection and sexual arousal, but recent studies have demonstrated that OXT may have anti-inflammatory and anti-oxidant properties and regulate immune and anti-inflammatory responses. In the pathogenesis of various neurodegenerative diseases, microglia are present in an active form and release high levels of pro-inflammatory cytokines and chemokines that are implicated in the process of neural injury. A promising treatment for neurodegenerative diseases involves new therapeutic approaches targeting activated microglia. Recent studies have reported that OXT exerts neuroprotective effects through the inhibition of production of pro-inflammatory mediators, and in the development of correct neural circuitry. The focus of this review is to attribute a new important role of OXT in neuroprotection through the microglia–OXT interaction of immature and adult brains. In addition, we analyzed the strategies that could enhance the delivery of OXT in the brain and amplify its positive effects.
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Affiliation(s)
- Maria Antonietta Panaro
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70125 Bari, Italy;
| | - Tarek Benameur
- Department of Biomedical Sciences, College of Medicine, King Faisal University, 31982 Al-Ahsa, Saudi Arabia;
| | - Chiara Porro
- Department of Clinical and Experimental Medicine, University of Foggia, 71121 Foggia, Italy
- Correspondence:
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Lagunes-Merino O, Rodríguez-Landa JF, Caba M, Carro-Juárez M, García-Orduña F, Saavedra-Vélez M, Puga-Olguín A, de Jesús Rovirosa-Hernández M. Acute effect of an infusion of Montanoa tomentosa on despair-like behavior and activation of oxytocin hypothalamic cells in Wistar rats. J Tradit Complement Med 2020; 10:45-51. [PMID: 31956557 PMCID: PMC6957806 DOI: 10.1016/j.jtcme.2019.01.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Revised: 11/28/2018] [Accepted: 01/29/2019] [Indexed: 11/30/2022] Open
Abstract
Background and aim In Mexican traditional medicine, Montanoa tomentosa (Mt) has been used as a remedy for reproductive impairments and mood swings. In pre-clinical research, both the extract and some of its active metabolites have produced oxytocinergic-like effects on female reproductive organs; however, there are no detailed studies of its effects on mood swing and brain structures. The aim of this study, was to analyze the behavioral effects of acute administration of a Mt infusion on male rats, during the Open Field (OFT) and Forced Swim (FST) Tests, and their association with the activation of oxytocin (OXT) cells, indicated by Fos protein (Fos/OXT) in the paraventricular (PVN) and supraoptic nuclei (SON). Experimental procedure 52 adult male Wistar rats were assigned to two conditions; with FST (n = 8), or without (n = 5). Each integrated condition included four groups [Control, Vehicle, Fluoxetine (Flx; 10 mg/kg), and Mt (50 mg/kg), p.o.]. Results and conclusion Mt and Flx treatment produced an anti-despair-like effect on the FST, but no significant changes in locomotor activity. Also, the Mt infusion -but not Flx-significantly increased the number of Fos/OXT cells in the PVN and SON, regardless of the condition, compared to the control and vehicle groups. These results show that Mt, but not Flx, produces an anti-despair-like effect that could be associated with the activation of OXT cells in PVN and SON. This study thus contributes to our knowledge of the pharmacological activity of Mt infusions, which could be a natural antidepressant agent with future clinical relevance.
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Affiliation(s)
- Omar Lagunes-Merino
- Doctorado en Neuroetología, Universidad Veracruzana, Xalapa, Veracruz, 91190, Mexico
| | | | - Mario Caba
- Centro de Investigaciones Biomédicas, Universidad Veracruzana, Xalapa, Veracruz, 91190, Mexico
| | - Miguel Carro-Juárez
- Escuela de Medicina Veterinaria y Zootecnia, Universidad Autónoma de Tlaxcala, Tlaxcala, 90000, Mexico
| | | | | | - Abraham Puga-Olguín
- Doctorado en Neuroetología, Universidad Veracruzana, Xalapa, Veracruz, 91190, Mexico
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Gust K, Caccese C, Larosa A, Nguyen TV. Neuroendocrine Effects of Lactation and Hormone-Gene-Environment Interactions. Mol Neurobiol 2020; 57:2074-2084. [PMID: 31927723 DOI: 10.1007/s12035-019-01855-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Accepted: 12/11/2019] [Indexed: 12/12/2022]
Abstract
While correlational studies suggest that lactation may confer a certain level of protection from mental illness, this benefit is not uniformly expressed in all women who choose to breastfeed. We propose here that the neuroendocrine "resetting" induced by lactation may predispose toward positive affect states in a subset of hormone-sensitive mothers, with hormone-gene and hormone-environment interactions determining the ultimate psychological outcome. We find evidence to suggest that higher secretion of prolactin/oxytocin as well as lower secretion of vasopression/androgens in lactating mothers may protect against postpartum depression and anxiety, decrease levels of irritability, and optimize stress responses. On the other hand, while the abrupt withdrawal of estradiol/progesterone in the immediate postpartum period tends to be associated with adverse psychological outcomes, the chronic suppression of estrogens/progestogens induced by lactation may have antidepressant and anxiolytic effects over time. Finally, the hypo-cortisolemic state seen in lactating mothers appears to be associated with improved stress reactivity and circadian rhythms. We also discuss hormone-gene and hormone-environment interactions likely to modulate any potential psychological benefits related to lactation and focus on those factors that are either easy to screen for or known to be modifiable. In sum, neuroendocrine alterations induced by lactation may play a key role in determining reproductive psychiatric risk in a subset of hormone-sensitive women. Using these neuroendocrine factors as an individualized index of risk can help in devising targeted programs to support these women in pursuing lactation or, for those not able or willing, accessing psychological interventions in a timely manner.
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Affiliation(s)
- Kirsten Gust
- Reproductive Psychiatry Program, Departments of Psychiatry and Obstetrics-Gynecology, McGill University Health Centre, Montreal, QC, Canada
| | - Christina Caccese
- Department of Psychiatry, McGill University, 1001 Decarie Blvd., Montreal, QC, H4A 3J1, Canada
| | - Amanda Larosa
- Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada.,Neuroscience Division, Douglas Mental Health University Institute, Montreal, QC, Canada
| | - Tuong-Vi Nguyen
- Reproductive Psychiatry Program, Departments of Psychiatry and Obstetrics-Gynecology, McGill University Health Centre, Montreal, QC, Canada.
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Hayashi R, Kasahara Y, Hidema S, Fukumitsu S, Nakagawa K, Nishimori K. Oxytocin Ameliorates Impaired Behaviors of High Fat Diet-Induced Obese Mice. Front Endocrinol (Lausanne) 2020; 11:379. [PMID: 32719656 PMCID: PMC7347791 DOI: 10.3389/fendo.2020.00379] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Accepted: 05/12/2020] [Indexed: 12/18/2022] Open
Abstract
Excessive intake of fat is a major risk factor for lifestyle-related diseases such as heart disease and also affects brain function such as object recognition memory, social recognition, anxiety behavior, and depression-like behavior. Although oxytocin (OXT) has been reported to improve object recognition, social recognition, anxiety behavior, and depression-like behavior in specific conditions, previous studies did not explore the impact of OXT in high-fat diet (HFD)-fed mice. Furthermore, it remains unclear whether intake of HFD affects OXT/oxytocin receptor (OXTR) in the brain. Here, we demonstrated that peripheral OXT administration improves not only social recognition but also object recognition and depressive-like behavior in HFD-fed mice. In contrast, peripheral OXT administration to HFD-fed male mice increased fear and anxiety-related behavior. In addition, we observed that intake of HFD decreased OXTR and c-fos mRNA expression in the hippocampus, specifically. Furthermore, peripheral OXT administration increased OXT mRNA expression in the hypothalamus. Altogether, these findings suggest that OXT has the potential to improve various recognition memory processes via peripheral administration but also has side effects that increase fear-related behavior in males.
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Affiliation(s)
- Ryotaro Hayashi
- Laboratory of Molecular Biology, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
- Food and Biodynamic Chemistry Laboratory, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
- Nippon Flour Mills Co., Ltd., Innovation Center, Kanagawa, Japan
| | - Yoshiyuki Kasahara
- Department of Fetal Pathology, Graduate School of Medicine, Tohoku University, Sendai, Japan
| | - Shizu Hidema
- Laboratory of Molecular Biology, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
- Department of Bioregulation and Pharmacological Medicine, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Satoshi Fukumitsu
- Nippon Flour Mills Co., Ltd., Innovation Center, Kanagawa, Japan
- Collaborative Graduate School Program, University of Tsukuba, Tsukuba, Japan
- Alliance for Research on the Mediterranean and North Africa (ARENA), University of Tsukuba, Tsukuba, Japan
| | - Kiyotaka Nakagawa
- Food and Biodynamic Chemistry Laboratory, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Katsuhiko Nishimori
- Laboratory of Molecular Biology, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
- Department of Obesity and Inflammation Research, Fukushima Medical University School of Medicine, Fukushima, Japan
- *Correspondence: Katsuhiko Nishimori
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37
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Effects of intraperitoneal and intracerebroventricular injections of oxytocin on social and emotional behaviors in pubertal male mice. Physiol Behav 2019; 212:112701. [DOI: 10.1016/j.physbeh.2019.112701] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 09/27/2019] [Accepted: 10/04/2019] [Indexed: 12/20/2022]
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Cao C, Wang L, Wu J, Li G, Fang R, Liu P, Luo S, Elhai JD. Association between the OXTR rs53576 genotype and latent profiles of post-traumatic stress disorder and depression symptoms in a representative sample of earthquake survivors. ANXIETY STRESS AND COPING 2019; 33:140-147. [PMID: 31771350 DOI: 10.1080/10615806.2019.1695604] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Background and Objectives: Post-traumatic stress disorder (PTSD) and major depressive disorder are commonly experienced mental disorders among psychological trauma victims. Few studies have investigated the genetic basis for population heterogeneity of trauma-related psychopathology, including PTSD and depression. This study examined the main and interaction effects of the OXTR rs53576 genotype in distinguishing four subgroups identified by symptom profiles of PTSD and depression symptoms using latent profile analysis.Design: A cross-sectional design with a gene-environment interaction approach was adopted in the current study.Methods: This study was a secondary data analysis conducted on a sample of 1196 adult earthquake survivors. Participants completed assessments of earthquake exposure, PTSD symptoms, and depression symptoms. The rs53576 polymorphism of OXTR was genotyped using a custom-by-design 2×48-Plex SNPscanTMKit.Results: Multinomial logistic regression analyses revealed the main effects of the rs53576 genotype on symptom profiles. Specifically, G allele carriers were more likely in the combined PTSD-depression group than in the low symptom, predominantly depression, and predominantly PTSD groups. No significant interaction effects between this genotype and earthquake exposure on symptom profiles were found.Conclusions: Our findings support a genetic basis for trauma-related psychopathology heterogeneity. Furthermore, results provide preliminary evidence for the role of OXTR in PTSD/depression comorbidity.
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Affiliation(s)
- Chengqi Cao
- Center for Brain Disorder and Cognitive Science, Shenzhen University, Shenzhen, China.,Laboratory for Traumatic Stress Studies, CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, People's Republic of China.,Department of Psychology, University of Chinese Academy of Sciences, Beijing, People's Republic of China
| | - Li Wang
- Laboratory for Traumatic Stress Studies, CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, People's Republic of China.,Department of Psychology, University of Chinese Academy of Sciences, Beijing, People's Republic of China
| | - Jianhui Wu
- Center for Brain Disorder and Cognitive Science, Shenzhen University, Shenzhen, China
| | - Gen Li
- Laboratory for Traumatic Stress Studies, CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, People's Republic of China.,Department of Psychology, University of Chinese Academy of Sciences, Beijing, People's Republic of China
| | - Ruojiao Fang
- Laboratory for Traumatic Stress Studies, CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, People's Republic of China.,Department of Psychology, University of Chinese Academy of Sciences, Beijing, People's Republic of China
| | - Ping Liu
- People' s Hospital of Deyang City, Deyang, People's Republic of China
| | - Shu Luo
- People' s Hospital of Deyang City, Deyang, People's Republic of China
| | - Jon D Elhai
- Department of Psychology, University of Toledo, Toledo, OH, USA.,Department of Psychiatry, University of Toledo, Toledo, OH, USA
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Tsai TY, Tseng HH, Chi MH, Chang HH, Wu CK, Yang YK, Chen PS. The Interaction of Oxytocin and Social Support, Loneliness, and Cortisol Level in Major Depression. CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE 2019; 17:487-494. [PMID: 31671485 PMCID: PMC6852675 DOI: 10.9758/cpn.2019.17.4.487] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/26/2018] [Revised: 03/11/2019] [Accepted: 04/04/2019] [Indexed: 11/22/2022]
Abstract
Objective Loneliness is a specific risk factor for depressive symptoms and suicidal behavior. The present study examined whether the serum oxytocin level would interact with social support and buffers loneliness and hypothalamic-pituitary-adrenal (HPA)-axis activity in drug-naïve patients with major depressive disorder (MDD). Methods Twenty-six patients with MDD (male:female = 3:23; mean age, 45.54 ± 12.97 years) were recruited. The 17-item Hamilton Depression Rating Scale, UCLA Loneliness Scale and self-reported Measurement of Support Function Questionnaire were administered. Serum oxytocin and cortisol levels were assessed using a commercial immunoassay kits. Results In MDD patients, a negative association was found between degrees of social support and loneliness (β = −0.39, p = 0.04). The interaction between social support and serum oxytocin level was negatively associated with loneliness (β = −0.50, p = 0.017) and serum cortisol level (β = −0.55, p = 0.020) after adjusting for age. Follow-up analyses showed that the association between higher social support and lower loneliness was observed only in the higher-oxytocin group (r = −0.75, p = 0.003) but not in the lower group (r = −0.19, p = 0.53). The significance remained after further adjusting for sex and depression severity. Conclusion Low oxytocin level is a vulnerability factor for the buffering effect of social support for loneliness and aberrant HPA-axis activity in MDD patients.
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Affiliation(s)
- Tsung-Yu Tsai
- Departments of Psychiatry National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Taiwan
| | - Huai-Hsuan Tseng
- Departments of Psychiatry National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Taiwan.,Institute of Behavioral Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Mei Hung Chi
- Departments of Psychiatry National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Taiwan
| | - Hui Hua Chang
- Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,School of Pharmacy, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Pharmacy, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Taiwan.,Departments of Pharmacy National Cheng Kung University Hospital, Dou-Liou Branch, Yunlin, Taiwan
| | - Cheng-Kuan Wu
- Departments of Psychiatry National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Taiwan
| | - Yen Kuang Yang
- Departments of Psychiatry National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Taiwan.,Institute of Behavioral Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Po See Chen
- Departments of Psychiatry National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Taiwan.,Institute of Behavioral Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Addiction Research Center, National Cheng Kung University, Tainan, Taiwan
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40
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Abstract
The old classification of depression as reactive and endogenous, which are still observed in clinical practice, both cannot be accommodated under the current rubric of major depression. This is because psychiatric nosology under the Diagnostic and Statistical Manual of Mental Disorders (DSM) and its latest fifth edition (DSM-V) is still descriptive and not etiologic. The aim of this review was to revisit reactive and endogenous categories of depression from the perspective of today's understanding of etiological pathways. From an epigenetic perspective, the old dichotomy of reactive versus endogenous is interrelated through the impact of the environment (e.g., stress). This includes familial or prenatal depression, where the environmental impact is before birth, or childhood depression, where the early life stress is the precipitating factor to genetic susceptibility. In conclusion, searching for both environmental impact (e.g., stressors) and genetic predispositions in depression, even at a clinical level, could help clinicians with better therapeutic decisions.
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Doreste-Mendez R, Ríos-Ruiz EJ, Rivera-López LL, Gutierrez A, Torres-Reveron A. Effects of Environmental Enrichment in Maternally Separated Rats: Age and Sex-Specific Outcomes. Front Behav Neurosci 2019; 13:198. [PMID: 31555107 PMCID: PMC6727005 DOI: 10.3389/fnbeh.2019.00198] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Accepted: 08/13/2019] [Indexed: 01/10/2023] Open
Abstract
Maternal separation (MS) early in life is related to an increase in anxiety and depressive-like behaviors and neurobiological alterations mostly related to alterations in hypothalamic pituitary adrenal (HPA) axis reactivity. Environmental enrichment (EE) has been used to ameliorate the effects of MS. However, the outcomes of this intervention at different developmental periods after MS have not been studied. We subjected male and female Sprague–Dawley pups to MS and subsequently compared the effects of EE started either in the pre-pubertal period [postnatal day (PND) 22] or adulthood (PND 78). Anxiety and depressive-like behaviors as well as in hippocampal synaptic density and basal corticosterone, oxytocin, and vasopressin levels were measured. Our results support the beneficial effects of adulthood EE in decreasing anxiety in males as well as promoting synaptic density in ventral hippocampal CA3. Males displayed higher levels of vasopressin while females displayed higher oxytocin, with no changes in basal corticosterone for any group after EE.
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Affiliation(s)
- Raura Doreste-Mendez
- Department of Basic Sciences, Physiology and Pharmacology, Ponce Research Institute, Ponce Health Sciences University, Ponce, PR, United States.,School of Brain and Behavioral Sciences, Ponce Research Institute, Ponce Health Sciences University, Ponce, PR, United States
| | - Efraín J Ríos-Ruiz
- School of Brain and Behavioral Sciences, Ponce Research Institute, Ponce Health Sciences University, Ponce, PR, United States.,Institute of Translational Research in Behavioral Sciences, University of Puerto Rico-Ponce Campus, Ponce, PR, United States
| | - Leslie L Rivera-López
- Department of Neuroscience, University of Texas at Rio Grande Valley School of Medicine, Edinburg, TX, United States
| | - Alfredo Gutierrez
- Department of Community Health, School of Arts and Sciences, Tufts University, Medford, MA, United States
| | - Annelyn Torres-Reveron
- Department of Neuroscience, University of Texas at Rio Grande Valley School of Medicine, Edinburg, TX, United States.,Department of Human Genetics, University of Texas at Rio Grande Valley School of Medicine, Edinburg, TX, United States
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Matsushita H, Latt HM, Koga Y, Nishiki T, Matsui H. Oxytocin and Stress: Neural Mechanisms, Stress-Related Disorders, and Therapeutic Approaches. Neuroscience 2019; 417:1-10. [PMID: 31400490 DOI: 10.1016/j.neuroscience.2019.07.046] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 07/25/2019] [Accepted: 07/26/2019] [Indexed: 12/24/2022]
Abstract
Clinical reports show that oxytocin (OT) is related to stress-related disorders such as depression, anxiety disorder, and post-traumatic stress disorder. Two key structures in the brain should be paid special attention with regard to stress regulation, namely, the hypothalamus and the hippocampus. The former is the region for central command for most, if not all, of the major endocrine systems, and the latter takes a key position in the regulation of mood and anxiety. There are extensive neural projections between the two structures, and both are functionally intertwined. The hypothalamus projects OTergic neurons to the hippocampus, and the latter possesses high levels of OT receptors. The hippocampus also regulates the secretion of glucocorticoids, a major group of stress hormones. Excessive levels of glucocorticoids in chronic stress cause atrophy of the hippocampus, whereas OT has been shown to protect hippocampal neurons from the toxic effects of glucocorticoids. In this article, we discuss how neural and endocrine mechanisms interplay in stress regulation, with an emphasis on the role of OT, as well as its therapeutic potential in the treatment of stress-related disorders.
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Affiliation(s)
- Hiroaki Matsushita
- Department of Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
| | - Hein Min Latt
- Department of Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
| | - Yuuri Koga
- Department of Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Teiichi Nishiki
- Department of Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Hideki Matsui
- Department of Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
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Londono Tobon A, Newport DJ, Nemeroff CB. The Role of Oxytocin in Early Life Adversity and Later Psychopathology: a Review of Preclinical and Clinical Studies. ACTA ACUST UNITED AC 2018. [DOI: 10.1007/s40501-018-0158-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Jurek B, Neumann ID. The Oxytocin Receptor: From Intracellular Signaling to Behavior. Physiol Rev 2018; 98:1805-1908. [DOI: 10.1152/physrev.00031.2017] [Citation(s) in RCA: 601] [Impact Index Per Article: 85.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
The many facets of the oxytocin (OXT) system of the brain and periphery elicited nearly 25,000 publications since 1930 (see FIGURE 1 , as listed in PubMed), which revealed central roles for OXT and its receptor (OXTR) in reproduction, and social and emotional behaviors in animal and human studies focusing on mental and physical health and disease. In this review, we discuss the mechanisms of OXT expression and release, expression and binding of the OXTR in brain and periphery, OXTR-coupled signaling cascades, and their involvement in behavioral outcomes to assemble a comprehensive picture of the central and peripheral OXT system. Traditionally known for its role in milk let-down and uterine contraction during labor, OXT also has implications in physiological, and also behavioral, aspects of reproduction, such as sexual and maternal behaviors and pair bonding, but also anxiety, trust, sociability, food intake, or even drug abuse. The many facets of OXT are, on a molecular basis, brought about by a single receptor. The OXTR, a 7-transmembrane G protein-coupled receptor capable of binding to either Gαior Gαqproteins, activates a set of signaling cascades, such as the MAPK, PKC, PLC, or CaMK pathways, which converge on transcription factors like CREB or MEF-2. The cellular response to OXT includes regulation of neurite outgrowth, cellular viability, and increased survival. OXTergic projections in the brain represent anxiety and stress-regulating circuits connecting the paraventricular nucleus of the hypothalamus, amygdala, bed nucleus of the stria terminalis, or the medial prefrontal cortex. Which OXT-induced patterns finally alter the behavior of an animal or a human being is still poorly understood, and studying those OXTR-coupled signaling cascades is one initial step toward a better understanding of the molecular background of those behavioral effects.
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Affiliation(s)
- Benjamin Jurek
- Department of Behavioural and Molecular Neurobiology, Institute of Zoology, University of Regensburg, Regensburg, Germany
| | - Inga D. Neumann
- Department of Behavioural and Molecular Neurobiology, Institute of Zoology, University of Regensburg, Regensburg, Germany
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Latt HM, Matsushita H, Morino M, Koga Y, Michiue H, Nishiki T, Tomizawa K, Matsui H. Oxytocin Inhibits Corticosterone-induced Apoptosis in Primary Hippocampal Neurons. Neuroscience 2018; 379:383-389. [DOI: 10.1016/j.neuroscience.2018.03.025] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Revised: 02/20/2018] [Accepted: 03/16/2018] [Indexed: 12/17/2022]
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46
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Schindler EAD, Wallace RM, Sloshower JA, D'Souza DC. Neuroendocrine Associations Underlying the Persistent Therapeutic Effects of Classic Serotonergic Psychedelics. Front Pharmacol 2018; 9:177. [PMID: 29545753 PMCID: PMC5838010 DOI: 10.3389/fphar.2018.00177] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Accepted: 02/16/2018] [Indexed: 12/12/2022] Open
Abstract
Recent reports on the effects of psychedelic-assisted therapies for mood disorders and addiction, as well as the effects of psychedelics in the treatment of cluster headache, have demonstrated promising therapeutic results. In addition, the beneficial effects appear to persist well after limited exposure to the drugs, making them particularly appealing as treatments for chronic neuropsychiatric and headache disorders. Understanding the basis of the long-lasting effects, however, will be critical for the continued use and development of this drug class. Several mechanisms, including biological and psychological ones, have been suggested to explain the long-lasting effects of psychedelics. Actions on the neuroendocrine system are some such mechanisms that warrant further investigation in the study of persisting psychedelic effects. In this report, we review certain structural and functional neuroendocrinological pathologies associated with neuropsychiatric disorders and cluster headache. We then review the effects that psychedelic drugs have on those systems and provide preliminary support for potential long-term effects. The circadian biology of cluster headache is of particular relevance in this area. We also discuss methodologic considerations for future investigations of neuroendocrine system involvement in the therapeutic benefits of psychedelic drugs.
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Affiliation(s)
- Emmanuelle A D Schindler
- Department of Neurology, Yale School of Medicine, New Haven, CT, United States.,Department of Neurology, VA Connecticut Healthcare System, West Haven, CT, United States
| | - Ryan M Wallace
- Department of Psychiatry, Yale School of Medicine, New Haven, CT, United States
| | - Jordan A Sloshower
- Department of Psychiatry, Yale School of Medicine, New Haven, CT, United States.,Department of Psychiatry, VA Connecticut Healthcare System, West Haven, CT, United States
| | - Deepak C D'Souza
- Department of Psychiatry, Yale School of Medicine, New Haven, CT, United States.,Department of Psychiatry, VA Connecticut Healthcare System, West Haven, CT, United States
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47
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Abstract
Anxiety disorders are among the most prevalent psychiatric disorders in youth; however, progress in treatment for childhood anxiety has stalled over the past decade. The National Institute of Mental Health (NIMH) Research Domain Criteria (RDoC) project represents a shift toward a dimensional and interdisciplinary approach to psychiatric disorders; this shift can reframe developmental psychopathology for childhood anxiety and facilitate novel advances in its classification and treatment. Here we highlight constructs in the Systems for Social Processes and the Negative Valence System domains of RDoC, as they relate to childhood anxiety disorders. Childhood anxiety relates to both RDoC domains. In terms of social processes, through natural reliance on parents to reduce children's fear, attachment represents one particular social process, which plays a central role in anxiety among youth. In terms of negative valence, considerable research links threat conditioning to pediatric anxiety. Finally, fronto-amygdala circuitry relates to all three entities, as it has been shown to underly both attachment processes and threat learning, while it also has been consistently implicated in anxiety disorders across development. Through integrative and translational approaches, RDoC provides unique opportunities and simultaneous challenges for advancing the understanding and treatment of childhood anxiety disorders.
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48
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Abstract
There is growing interest in the use of oxytocin (OT) as a potential treatment for alcohol and other substance-use disorders. OT is a neuropeptide that modulates adaptive processes associated with addiction including reward, tolerance, associative learning, memory, and stress responses. OT exerts its effects through interactions with the hypothalamic-pituitary-adrenal axis and multiple neurotransmitter systems including the dopamine mesolimbic reward and corticotrophin-releasing factor stress systems. The effects of OT on stress systems are of high interest, given the strong link between stress, drug use and relapse, and known dysregulation of hypothalamic-pituitary-adrenal-axis activity associated with substance-use disorders. At the same time, the OT system is itself altered by acute or chronic drug exposure. This review summarizes the preclinical and clinical literature on the OT system and its relevance to drug and alcohol addiction. In addition, findings from recent clinical trials conducted in participants with cocaine, cannabis, or alcohol use disorder are included and evidence that OT may help to normalize blunted stress responses, and attenuate withdrawal-associated hypercortisolism, negative mood, and withdrawal symptoms is summarized.
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49
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Wang T, Shi C, Li X, Zhang P, Liu B, Wang H, Wang Y, Yang Y, Wu Y, Li H, Xu ZQD. Injection of oxytocin into paraventricular nucleus reverses depressive-like behaviors in the postpartum depression rat model. Behav Brain Res 2018; 336:236-243. [DOI: 10.1016/j.bbr.2017.09.012] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Revised: 08/28/2017] [Accepted: 09/04/2017] [Indexed: 01/07/2023]
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50
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Mitra S, Mucha M, Owen S, Bult-Ito A. Postpartum Lactation-Mediated Behavioral Outcomes and Drug Responses in a Spontaneous Mouse Model of Obsessive-Compulsive Disorder. ACS Chem Neurosci 2017; 8:2683-2697. [PMID: 28945961 DOI: 10.1021/acschemneuro.7b00231] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Using a spontaneous mouse model of obsessive-compulsive disorder (OCD), the current study evaluated the influence of postpartum lactation on the expression of compulsive-like behaviors, SSRI effectiveness, and the putative role of oxytocin and dopamine in mediating these lactation specific behavioral outcomes. Compulsive-like lactating mice were less compulsive-like in nest building and marble burying and showed enhanced responsiveness to fluoxetine (50 mg/kg) in comparison to compulsive-like nonlactating and nulliparous females. Lactating mice exhibited more anxiety-like behavior in the open field test compared to the nulliparous females, while chronic fluoxetine reduced anxiety-like behaviors. Blocking the oxytocin receptor with L368-899 (5 mg/kg) in the lactating mice exacerbated the compulsive-like and depression-like behaviors. The dopamine D2 receptor (D2R) agonist bromocriptine (10 mg/kg) suppressed marble burying, nest building, and central entries in the open field, but because it also suppressed overall locomotion in the open field, activation of the D2R receptor may have inhibited overall activity nonspecifically. Lactation- and fluoxetine-mediated behavioral outcomes in compulsive-like mice, therefore, appear to be partly regulated by oxytocinergic mechanisms. Serotonin immunoreactivity and serum levels were higher in lactating compulsive-like mice compared to nonlactating and nulliparous compulsive-like females. Together, these results suggest behavioral modulation, serotonergic alterations, and changes in SSRI effectiveness during lactation in compulsive-like mice. This warrants further investigation of postpartum events in OCD patients.
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Affiliation(s)
- Swarup Mitra
- Department
of Chemistry and Biochemistry, University of Alaska Fairbanks, Fairbanks, Alaska 99775, United States
- IDeA
Network of Biomedical Research Excellence (INBRE), University of Alaska Fairbanks, Fairbanks, Alaska 99775, United States
| | - McKenzie Mucha
- Department
of Chemistry and Biochemistry, University of Alaska Fairbanks, Fairbanks, Alaska 99775, United States
| | - Savanah Owen
- Department of Biology & Wildlife, University of Alaska Fairbanks, Fairbanks, Alaska 99775, United States
| | - Abel Bult-Ito
- Department of Biology & Wildlife, University of Alaska Fairbanks, Fairbanks, Alaska 99775, United States
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