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de la Salle S, Piche J, Duncan B, Choueiry J, Hyde M, Aidelbaum R, Baddeley A, Impey D, Rahmani N, Ilivitsky V, Knott V. Influence of GABA A and GABA B receptor activation on auditory sensory gating and its association with anxiety in healthy volunteers. J Psychopharmacol 2024; 38:532-540. [PMID: 38647196 DOI: 10.1177/02698811241246854] [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] [Indexed: 04/25/2024]
Abstract
BACKGROUND Dysfunctional sensory gating in anxiety disorders, indexed by the failure to inhibit the P50 event-related potential (ERP) to repeated stimuli, has been linked to deficits in the major inhibitory neurotransmitter γ-aminobutyric acid (GABA). AIMS/METHODS This study, conducted in 30 healthy volunteers, examined the acute effects of GABAA (lorazepam: 1 mg) and GABAB receptor (baclofen: 10 mg) agonists on P50 measures of auditory sensory gating within a paired-stimulus (S1-S2) paradigm and assessed changes in gating in relation to self-ratings of anxiety. RESULTS Compared to placebo, lorazepam reduced ERP indices of sensory gating by attenuating response to S1. Although not directly impacting P50 inhibition, baclofen-induced changes in gating (relative to placebo) were negatively correlated with trait but not state anxiety. CONCLUSIONS These preliminary findings support the involvement of GABA in sensory gating and tentatively suggest a role for GABAB receptor signaling in anxiety-associated gating dysregulation.
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Affiliation(s)
- Sara de la Salle
- The Royal's Institute of Mental Health Research at The Royal, Ottawa, ON, Canada
- School of Psychology, University of Ottawa, Ottawa, ON, Canada
| | - Justin Piche
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Brittany Duncan
- Department of Psychology, Carleton University, Ottawa, ON, Canada
| | - Joëlle Choueiry
- The Royal's Institute of Mental Health Research at The Royal, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Molly Hyde
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Robert Aidelbaum
- School of Psychology, University of Toronto, Toronto, ON, Canada
| | - Ashley Baddeley
- The Royal's Institute of Mental Health Research at The Royal, Ottawa, ON, Canada
| | - Danielle Impey
- School of Psychology, University of Ottawa, Ottawa, ON, Canada
| | - Noreen Rahmani
- School of Psychology, University of Ottawa, Ottawa, ON, Canada
| | | | - Verner Knott
- The Royal's Institute of Mental Health Research at The Royal, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
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Prefrontal cortical circuits in anxiety and fear: an overview. Front Med 2022; 16:518-539. [PMID: 35943704 DOI: 10.1007/s11684-022-0941-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 06/06/2022] [Indexed: 11/04/2022]
Abstract
Pathological anxiety is among the most difficult neuropsychiatric diseases to treat pharmacologically, and it represents a major societal problem. Studies have implicated structural changes within the prefrontal cortex (PFC) and functional changes in the communication of the PFC with distal brain structures in anxiety disorders. Treatments that affect the activity of the PFC, including cognitive therapies and transcranial magnetic stimulation, reverse anxiety- and fear-associated circuit abnormalities through mechanisms that remain largely unclear. While the subjective experience of a rodent cannot be precisely determined, rodent models hold great promise in dissecting well-conserved circuits. Newly developed genetic and viral tools and optogenetic and chemogenetic techniques have revealed the intricacies of neural circuits underlying anxiety and fear by allowing direct examination of hypotheses drawn from existing psychological concepts. This review focuses on studies that have used these circuit-based approaches to gain a more detailed, more comprehensive, and more integrated view on how the PFC governs anxiety and fear and orchestrates adaptive defensive behaviors to hopefully provide a roadmap for the future development of therapies for pathological anxiety.
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Neurocan regulates vulnerability to stress and the anti-depressant effect of ketamine in adolescent rats. Mol Psychiatry 2022; 27:2522-2532. [PMID: 35264728 DOI: 10.1038/s41380-022-01495-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 02/10/2022] [Accepted: 02/14/2022] [Indexed: 12/13/2022]
Abstract
Depression is more prevalent among adolescents than adults, but the underlying mechanisms remain largely unknown. Using a subthreshold chronic stress model, here we show that developmentally regulated expressions of the perineuronal nets (PNNs), and one of the components, Neurocan in the prelimbic cortex (PrL) are important for the vulnerability to stress and depressive-like behaviors in both adolescent and adult rats. Reduction of PNNs or Neurocan with pharmacological or viral methods to mimic the expression of PNNs in the PrL during adolescence compromised resilience to stress in adult rats, while virally mediated overexpression of Neurocan reversed vulnerability to stress in adolescent rats. Ketamine, a recent-approved drug for treatment-resistant depression rescued impaired function of Parvalbumin-positive neurons function, increased expression of PNNs in the PrL, and reversed depressive-like behaviors in adolescent rats. Furthermore, we show that Neurocan mediates the anti-depressant effect of ketamine, virally mediated reduction of Neurocan in the PrL abolished the anti-depressant effect of ketamine in adolescent rats. Our findings show an important role of Neurocan in depression in adolescence, and suggest a novel mechanism for the anti-depressant effect of ketamine.
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4
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Voiding and storage symptoms in depression/anxiety. Auton Neurosci 2021; 237:102927. [PMID: 34923228 DOI: 10.1016/j.autneu.2021.102927] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 09/27/2021] [Accepted: 12/05/2021] [Indexed: 12/11/2022]
Abstract
We here described the frequency and nature of voiding and storage bladder symptoms in depression/anxiety, for which we propose the name "bladder somatic symptom disorder (SSD)" because such symptoms most probably have brain mechanisms. SSD was formerly called as various terms including "somatoform disorder", "medically unexplained physical symptoms", "functional somatic syndrome" and "hysterical neurosis/hysteria". Bladder SSD has the following specific features that are distinguishable from "true" neurologic/organic bladder dysfunction: 1) situation-dependence (close association with life event in some), 2) urodynamically increased bladder sensation/hypersensitivity and 3) absence of neurologic/organic diseases, in addition to 4) other stress symptoms (insomnia, etc.), are key clues to the possibility of bladder SSD. Urodynamics in these patients showed, to a lesser extent, underactive bladder without post-void residual. These findings might reflect the biological changes of the depressive brain; e.g., decreases in serotonin and GABA, and possible increases in CRH. Treatment of bladder SSD can follow that of general depression/anxiety, with the potential addition of anticholinergic or selective beta3 bladder drugs.
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Chen L, Zhang X, Hu C, Zhang Y, Zhang L, Kan J, Li B, Du J. Regulation of GABA A and 5-HT Receptors Involved in Anxiolytic Mechanisms of Jujube Seed: A System Biology Study Assisted by UPLC-Q-TOF/MS and RT-qPCR Method. Front Pharmacol 2020; 11:01320. [PMID: 33178009 PMCID: PMC7593408 DOI: 10.3389/fphar.2020.01320] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 08/07/2020] [Indexed: 11/24/2022] Open
Abstract
The increase of the prevalence of anxiety greatly impacts the quality of life in China and globally. As the most popular traditional Chinese medicinal ingredient for nourishing health and tranquilizing mind, Jujube seed (Ziziphus jujuba Mill., Rhamnaceae) (SZJ) has been proved to exert anxiolytic effects in previous reports. In this study, a system biology method assisted by UPLC-Q-TOF/MS and RT-qPCR was developed to systematically demonstrate the anxiolytic mechanisms of SZJ. A total of 35 phytochemicals were identified from SZJ extract (Ziziphus jujuba Mill. var. spinosa [Bunge] Hu ex H.F. Chow), which interact with 71 anxiolytic targets. Protein-protein interaction, genes cluster, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis were subsequently conducted, and results demonstrated that regulation of serotonergic and GABAergic synapse pathways were dominantly involved in the anxiolytic mechanisms of SZJ extract. The effects of SZJ extract on mRNA expressions of multiple GABAA (gamma-aminobutyric acid type A) and 5-HT (serotonin) receptors subtypes were further validated in human neuroblastoma SH-SY5Y cells using RT-qPCR. Results showed that SZJ extract (250 μg/mL) significantly up-regulated the mRNA level of GABRA1 and GABRA3 as well as HTR1A, HTR2A, and HTR2B in non-H2O2 treated SH-SY5Y cells. However, it exerted an inhibitive effect on the overexpressed mRNA of GABRA1, GABRA2, HTR1A, and HTR2A in H2O2 treated SH-SY5Y cells. Taken together, our findings suggest that anxiolytic mechanisms of SZJ mostly involve the regulation of GABAergic and serotonergic synapse pathways, especially a two-way modulation of GABRA1, HTR1A, and HTR2A. Our current results provide potential direction for future investigation of SZJ as an anxiolytic agent.
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Affiliation(s)
- Liang Chen
- Nutrilite Health Institute, Amway (China) R&D Center, Shanghai, China
| | - Xue Zhang
- Nutrilite Health Institute, Amway (China) R&D Center, Shanghai, China
| | - Chun Hu
- Nutrilite Health Institute, Amway Innovation and Science, Buena Park, CA, United States
| | - Yi Zhang
- Nutrilite Health Institute, Amway (China) R&D Center, Shanghai, China
| | - Lu Zhang
- Nutrilite Health Institute, Amway (China) R&D Center, Shanghai, China
| | - Juntao Kan
- Nutrilite Health Institute, Amway (China) R&D Center, Shanghai, China
| | - Bo Li
- Nutrilite Health Institute, Amway (China) R&D Center, Shanghai, China
| | - Jun Du
- Nutrilite Health Institute, Amway (China) R&D Center, Shanghai, China
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Singh P, Walia V. Anxiolytic like effect of L-Carnitine in mice: Evidences for the involvement of NO-sGC-cGMP signaling pathway. Behav Brain Res 2020; 391:112689. [PMID: 32417275 DOI: 10.1016/j.bbr.2020.112689] [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] [Received: 04/03/2020] [Revised: 04/26/2020] [Accepted: 05/02/2020] [Indexed: 12/20/2022]
Abstract
L-Carnitine (LC) is an endogenous compound synthesized from the essential amino acids lysine and methionine. LC act as an antioxidant and modulates the levels of neurochemicals such as glutamate, GABA, NO etc. implicated in the regulation of anxiety and related behavior. However its exact role in the anxiety is not known. The present study was designed to investigate the anxiolytic like effect of LC in mice. LC (2.5, 5.0 and 10 mg/kg, i.p.) was administered to the mice and the anxiety related behavior was determined using light and dark box (LDB) and elevated plus maze (EPM) tests. The whole brain nitrite level was also determined. The results obtained demonstrated that LC (10 mg/kg, i.p.) exerted anxiolytic like effect in mice, accompanied by the reduction of whole brain nitrite level significantly as compared to control. Further, the influence of NO and GABA modulators pretreatments on the effect of subtherapeutic dose of LC was also determined. The results obtained demonstrated that NO donor/cGMP modulator counteracted while NO inhibitor potentiated the effect confers by the subtherapeutic dose of LC mice. Pretreatment of diazepam (1 mg/kg, i.p.) further potentiated the effect of subtherapeutic dose of LC (5 mg/kg, i.p.) in EPM and LDB tests and further reduced the brain nitrite level significantly as compared to LC (5 mg/kg, i.p.) alone treatment. Thus, LC exerted anxiolytic like effect in mice and NO-sGC-cGMP signaling pathway influences the anxiolytic like effect of LC in mice.
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Affiliation(s)
- Poonam Singh
- Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, 124001, Haryana, India.
| | - Vaibhav Walia
- Faculty of Pharmacy, DIT University, Dehradun, India.
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Luo ZY, Huang L, Lin S, Yin YN, Jie W, Hu NY, Hu YY, Guan YF, Liu JH, You QL, Chen YH, Luo ZC, Zhang SR, Li XW, Yang JM, Tao YM, Mei L, Gao TM. Erbin in Amygdala Parvalbumin-Positive Neurons Modulates Anxiety-like Behaviors. Biol Psychiatry 2020; 87:926-936. [PMID: 31889536 DOI: 10.1016/j.biopsych.2019.10.021] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 10/02/2019] [Accepted: 10/21/2019] [Indexed: 11/30/2022]
Abstract
BACKGROUND Anxiety disorders are the most common psychiatric diseases, affecting 28% of people worldwide within their lifetime. The excitation-inhibition imbalance in the amygdala is thought to be an underlying pathological mechanism; however, the cellular and molecular control of amygdala excitation-inhibition balance is largely unknown. METHODS By using mice expressing chemogenetic activator or inhibitor channel in amygdala parvalbumin (PV) neurons, Erbin mutant mice, and mice with Erbin specifically knocked down in amygdala PV neurons, we systematically investigated the role of amygdala PV neurons and Erbin expressed therein in the pathogenesis of anxiety disorders using the combined approaches of immunohistochemistry, electrophysiology, and behavior. RESULTS In naïve mice, chemogenetic inhibition of PV neurons produced anxiogenic effects, suggesting an essential role in the regulation of anxiety. In stressed mice with anxiety, excitatory postsynaptic responses on amygdala PV neurons were selectively diminished, accompanied by a decreased expression of Erbin specifically in amygdala PV neurons. Remarkably, both Erbin mutant mice and amygdala PV-specific Erbin knockdown mice exhibited impaired excitatory postsynaptic responses on amygdala PV neurons and increased anxiety-like behaviors. Furthermore, chemogenetic activation of amygdala PV neurons normalized anxiety behaviors in amygdala PV-specific Erbin knockdown mice and stressed mice. CONCLUSIONS Together, these results demonstrate that Erbin in PV neurons is critical for maintaining the excitation-inhibition balance in the amygdala and reveal a novel pathophysiological mechanism for anxiety disorders.
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Affiliation(s)
- Zheng-Yi Luo
- State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Lang Huang
- State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Song Lin
- State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Ya-Nan Yin
- State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Wei Jie
- State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Neng-Yuan Hu
- State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Yu-Ying Hu
- State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Yan-Fei Guan
- State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Ji-Hong Liu
- State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Qiang-Long You
- State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Yi-Hua Chen
- State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Zhou-Cai Luo
- State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Sheng-Rong Zhang
- State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Xiao-Wen Li
- State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Jian-Ming Yang
- State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Yan-Mei Tao
- Institute of Life Sciences, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, China
| | - Lin Mei
- Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio
| | - Tian-Ming Gao
- State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
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8
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Shaw JC, Crombie GK, Zakar T, Palliser HK, Hirst JJ. Perinatal compromise contributes to programming of GABAergic and glutamatergic systems leading to long-term effects on offspring behaviour. J Neuroendocrinol 2020; 32:e12814. [PMID: 31758712 DOI: 10.1111/jne.12814] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 10/30/2019] [Accepted: 11/20/2019] [Indexed: 01/01/2023]
Abstract
Extensive evidence now shows that adversity during the perinatal period is a significant risk factor for the development of neurodevelopmental disorders long after the causative event. Despite stemming from a variety of causes, perinatal compromise appears to have similar effects on the developing brain, thereby resulting in behavioural disorders of a similar nature. These behavioural disorders occur in a sex-dependent manner, with males affected more by externalising behaviours such as attention deficit hyperactivity disorder (ADHD) and females by internalising behaviours such as anxiety. Regardless of the causative event or the sex of the offspring, these disorders may begin in childhood or adolescence but extend into adulthood. A mechanism by which adverse events in the perinatal period impact later in life behaviour has been shown to be the changing epigenetic landscape. Methylation of the GAD1/GAD67 gene, which encodes the key glutamate-to-GABA-synthesising enzyme glutamate decarboxylase 1, resulting in increased levels of glutamate, is one epigenetic mechanism that may account for a tendency towards excitation in disorders such as ADHD. Exposure of the fetus or the neonate to high levels of cortisol may be the mediator between perinatal compromise and poor behavioural outcomes because evidence suggests that increased glucocorticoid exposure triggers widespread changes in the epigenetic landscape. This review summarises the current evidence and recent literature about the impact of various perinatal insults on the epigenome and the common mechanisms that may explain the similarity of behavioural outcomes occurring following diverse perinatal compromise.
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Affiliation(s)
- Julia C Shaw
- School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, Australia
- Mothers and Babies Research Centre, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Gabrielle K Crombie
- School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, Australia
- Mothers and Babies Research Centre, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Tamas Zakar
- Mothers and Babies Research Centre, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
- School of Medicine and Public Health, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, Australia
| | - Hannah K Palliser
- School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, Australia
- Mothers and Babies Research Centre, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Jonathan J Hirst
- School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, Australia
- Mothers and Babies Research Centre, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
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Walia V, Garg C, Garg M. Lithium potentiated, pyridoxine abolished and fluoxetine attenuated the anxiolytic effect of diazepam in mice. Brain Res Bull 2019; 150:343-353. [PMID: 31201833 DOI: 10.1016/j.brainresbull.2019.06.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Revised: 05/05/2019] [Accepted: 06/10/2019] [Indexed: 11/19/2022]
Abstract
In the present study, the anxiolytic effect of diazepam (1 and 2 mg/kg, i.p.) was determined alone and in combination with lithium (50 mg/kg, i.p.), pyridoxine (90 mg/kg, i.p.) and fluoxetine (10 mg/kg, i.p.) using elevated plus maze (EPM) and light/dark box (LDB) tests in experimental mice. The effect of various treatments on the brain GABA levels and glutamic acid decarboxylase (GAD) expression were also determined. The results obtained suggested that the diazepam (2 mg/kg, i.p.) exerted anxiolytic effect and significantly increased the brain GABA levels and GAD expression as compared to control group. Fluoxetine (10 mg/kg, i.p.) exerted anxiogenic effects, but did not affect the brain GABA levels and GAD activity significantly as compared to control. Pretreatments of pyridoxine (90 mg/kg, i.p.) abolished; lithium (50 mg/kg, i.p.) potentiated while fluoxetine (10 mg/kg, i.p.) attenuated the anxiolytic and neurochemical effects of diazepam (1 and 2 mg/kg, i.p.) treatment in mice. Therefore, the combined treatment of lithium and diazepam might be a promising treatment for anxiety.
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Affiliation(s)
- Vaibhav Walia
- Department of Pharmaceutical Sciences, M.D University Rohtak, Haryana, India
| | - Chanchal Garg
- Department of Pharmaceutical Sciences, M.D University Rohtak, Haryana, India
| | - Munish Garg
- Department of Pharmaceutical Sciences, M.D University Rohtak, Haryana, India.
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10
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Chen X, van Gerven J, Cohen A, Jacobs G. Human pharmacology of positive GABA-A subtype-selective receptor modulators for the treatment of anxiety. Acta Pharmacol Sin 2019; 40:571-582. [PMID: 30518829 DOI: 10.1038/s41401-018-0185-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2018] [Accepted: 10/10/2018] [Indexed: 12/11/2022]
Abstract
Anxiety disorders arise from disruptions among the highly interconnected circuits that normally serve to process the streams of potentially threatening stimuli. The resulting imbalance among these circuits can cause a fundamental misinterpretation of neural sensory information as threatening and can lead to the inappropriate emotional and behavioral responses observed in anxiety disorders. There is considerable preclinical evidence that the GABAergic system, in general, and its α2- and/or α5-subunit-containing GABA(A) receptor subtypes, in particular, are involved in the pathophysiology of anxiety disorders. However, the clinical efficacy of GABA-A α2-selective agonists for the treatment of anxiety disorders has not been unequivocally demonstrated. In this review, we present several human pharmacological studies that have been performed with the aim of identifying the pharmacologically active doses/exposure levels of several GABA-A subtype-selective novel compounds with potential anxiolytic effects. The pharmacological selectivity of novel α2-subtype-selective GABA(A) receptor partial agonists has been demonstrated by their distinct effect profiles on the neurophysiological and neuropsychological measurements that reflect the functions of multiple CNS domains compared with those of benzodiazepines, which are nonselective, full GABA(A) agonists. Normalizing the undesired pharmacodynamic side effects against the desired on-target effects on the saccadic peak velocity is a useful approach for presenting the pharmacological features of GABA(A)-ergic modulators. Moreover, combining the anxiogenic symptom provocation paradigm with validated neurophysiological and neuropsychological biomarkers may provide further construct validity for the clinical effects of novel anxiolytic agents. In addition, the observed drug effects on serum prolactin levels support the use of serum prolactin levels as a complementary neuroendocrine biomarker to further validate the pharmacodynamic measurements used during the clinical pharmacological study of novel anxiolytic agents.
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11
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Sheth C, Prescot AP, Legarreta M, Renshaw PF, McGlade E, Yurgelun-Todd D. Reduced gamma-amino butyric acid (GABA) and glutamine in the anterior cingulate cortex (ACC) of veterans exposed to trauma. J Affect Disord 2019; 248:166-174. [PMID: 30735853 DOI: 10.1016/j.jad.2019.01.037] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Revised: 01/01/2019] [Accepted: 01/22/2019] [Indexed: 01/04/2023]
Abstract
BACKGROUND Trauma-related diagnoses such as posttraumatic stress disorder (PTSD) are prevalent in veterans. The identification of mechanisms related to stress vulnerability and development of PTSD specifically in a veteran population may aid in the prevention of PTSD and identification of novel treatment targets. METHODS Veterans with PTSD (n = 27), trauma-exposed veterans with no PTSD (TEC, n = 18) and non-trauma-exposed controls (NTEC, n = 28) underwent single-voxel proton (1H) magnetic resonance spectroscopy (MRS) at 3 Tesla in the dorsal anterior cingulate cortex (dACC) using a two-dimensional (2D) J-resolved point spectroscopy sequence in addition to completing a clinical battery. RESULTS The PTSD and TEC groups demonstrated lower gamma-amino butyric acid (GABA)/H2O (p = 0.02) and glutamine (Gln)/H2O (p = 0.02) in the dACC as compared to the NTEC group. The PTSD group showed a trend towards higher Glu/GABA (p = 0.053) than the NTEC group. Further, GABA/H2O in the dACC correlated negatively with sleep symptoms in the PTSD group (p = 0.03) but not in the TEC and NTEC groups. LIMITATIONS Cross-sectional study design, concomitant medications, single voxel measurement as opposed to global changes, absence of measure of childhood or severity of trauma and objective sleep measures, female participants not matched for menstrual cycle phase. CONCLUSIONS Exposure to trauma in veterans may be associated with lower GABA/H2O and Gln/H2O in the dACC, suggesting disruption in the GABA-Gln-glutamate cycle. Further, altered Glu/GABA in the dACC in the PTSD group may indicate an excitatory-inhibitory imbalance. Further, lower GABA/H2O in the ACC was associated with poor sleep in the PTSD group. Treatments that restore GABAergic balance may be particularly effective in reducing sleep symptoms in PTSD.
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Affiliation(s)
- Chandni Sheth
- Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, UT, USA; Diagnostic Neuroimaging, University of Utah, Salt Lake City, UT, USA.
| | - Andrew P Prescot
- Department of Radiology, University of Utah School of Medicine, Salt Lake City, UT, USA.
| | - Margaret Legarreta
- Diagnostic Neuroimaging, University of Utah, Salt Lake City, UT, USA; George E. Wahlen Department of Veterans Affairs Medical Center, VA VISN 19 Mental Illness Research, Education and Clinical Center (MIRECC), Salt Lake City, UT, USA.
| | - Perry F Renshaw
- Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, UT, USA; Diagnostic Neuroimaging, University of Utah, Salt Lake City, UT, USA; George E. Wahlen Department of Veterans Affairs Medical Center, VA VISN 19 Mental Illness Research, Education and Clinical Center (MIRECC), Salt Lake City, UT, USA.
| | - Erin McGlade
- Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, UT, USA; Diagnostic Neuroimaging, University of Utah, Salt Lake City, UT, USA; George E. Wahlen Department of Veterans Affairs Medical Center, VA VISN 19 Mental Illness Research, Education and Clinical Center (MIRECC), Salt Lake City, UT, USA.
| | - Deborah Yurgelun-Todd
- Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, UT, USA; Diagnostic Neuroimaging, University of Utah, Salt Lake City, UT, USA; George E. Wahlen Department of Veterans Affairs Medical Center, VA VISN 19 Mental Illness Research, Education and Clinical Center (MIRECC), Salt Lake City, UT, USA.
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12
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Park SC, Kim YK. A Novel Bio-Psychosocial-Behavioral Treatment Model of Panic Disorder. Psychiatry Investig 2019; 16:4-15. [PMID: 30301303 PMCID: PMC6354044 DOI: 10.30773/pi.2018.08.21.1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Revised: 08/09/2018] [Accepted: 08/21/2018] [Indexed: 12/11/2022] Open
Abstract
To conceptualize a novel bio-psychosocial-behavioral treatment model of panic disorder (PD), it is necessary to completely integrate behavioral, psychophysiological, neurobiological, and genetic data. Molecular genetic research on PD is specifically focused on neurotransmitters, including serotonin, neuropeptides, glucocorticoids, and neurotrophins. Although pharmacological interventions for PD are currently available, the need for more effective, faster-acting, and more tolerable pharmacological interventions is unmet. Thus, glutamatergic receptor modulators, orexin receptor antagonists, corticotrophin-releasing factor 1 receptor antagonists, and other novel mechanism-based anti-panic therapeutics have been proposed. Research on the neural correlates of PD is focused on the dysfunctional "cross-talk" between emotional drive (limbic structure) and cognitive inhibition (prefrontal cortex) and the fear circuit, which includes the amygdala-hippocampus-prefrontal axis. The neural perspective regarding PD supports the idea that cognitive-behavioral therapy normalizes alterations in top-down cognitive processing, including increased threat expectancy and attention to threat. Consistent with the concept of "personalized medicine," it is speculated that Research Domain Criteria can enlighten further treatments targeting dysfunctions underlying PD more precisely and provide us with better definitions of moderators used to identify subgroups according to different responses to treatment. Structuring of the "negative valence systems" domain, which includes fear/anxiety, is required to define PD. Therefore, targeting glutamate- and orexin-related molecular mechanisms associated with the fear circuit, which includes the amygdala-hippocampus-prefrontal cortex axis, is required to define a novel bio-psychosocial-behavioral treatment model of PD.
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Affiliation(s)
- Seon-Cheol Park
- Department of Psychiatry, Inje University College of Medicine and Haeundae Paik Hospital, Busan, Republic of Korea
| | - Yong-Ku Kim
- Department of Psychiatry, College of Medicine, Korea University, Ansan Hospital, Ansan, Republic of Korea
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13
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Lai CH. Fear Network Model in Panic Disorder: The Past and the Future. Psychiatry Investig 2019; 16:16-26. [PMID: 30176707 PMCID: PMC6354036 DOI: 10.30773/pi.2018.05.04.2] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2018] [Accepted: 05/04/2018] [Indexed: 01/04/2023] Open
Abstract
The core concept for pathophysiology in panic disorder (PD) is the fear network model (FNM). The alterations in FNM might be linked with disturbances in the autonomic nervous system (ANS), which is a common phenomenon in PD. The traditional FNM included the frontal and limbic regions, which were dysregulated in the feedback mechanism for cognitive control of frontal lobe over the primitive response of limbic system. The exaggerated responses of limbic system are also associated with dysregulation in the neurotransmitter system. The neuroimaging studies also corresponded to FNM concept. However, more extended areas of FNM have been discovered in recent imaging studies, such as sensory regions of occipital, parietal cortex and temporal cortex and insula. The insula might integrate the filtered sensory information via thalamus from the visuospatial and other sensory modalities related to occipital, parietal and temporal lobes. In this review article, the traditional and advanced FNM would be discussed. I would also focus on the current evidences of insula, temporal, parietal and occipital lobes in the pathophysiology. In addition, the white matter and functional connectome studies would be reviewed to support the concept of advanced FNM. An emerging dysregulation model of fronto-limbic-insula and temporooccipito-parietal areas might be revealed according to the combined results of recent neuroimaging studies. The future delineation of advanced FNM model can be beneficial from more extensive and advanced studies focusing on the additional sensory regions of occipital, parietal and temporal cortex to confirm the role of advanced FNM in the pathophysiology of PD.
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Affiliation(s)
- Chien-Han Lai
- Institute of Biophotonics, National Yang-Ming University, Taipei, Taiwan.,PhD Psychiatry & Neuroscience Clinic, Taoyuan, Taiwan.,Department of Psychiatry, Yeezen General Hospital, Taoyuan, Taiwan
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14
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Sahoo S, S. B. Pharmacogenomic assessment of herbal drugs in affective disorders. Biomed Pharmacother 2019; 109:1148-1162. [DOI: 10.1016/j.biopha.2018.10.135] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 10/20/2018] [Accepted: 10/21/2018] [Indexed: 12/14/2022] Open
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15
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Walia V, Garg C, Garg M. Anxiolytic-like effect of pyridoxine in mice by elevated plus maze and light and dark box: Evidence for the involvement of GABAergic and NO-sGC-cGMP pathway. Pharmacol Biochem Behav 2018; 173:96-106. [PMID: 30040985 DOI: 10.1016/j.pbb.2018.06.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 04/21/2018] [Accepted: 06/11/2018] [Indexed: 10/28/2022]
Abstract
Present study was carried out to investigate the 'anxiolytic-like' effect of pyridoxine in mice. Pyridoxine (90, 180 and 360 mg/kg) was administered by intraperitoneal (i.p.) route to the experimental mice and anxiety-related behavior was evaluated by light and dark box (LDB) and elevated plus maze (EPM) models. Glutamate, GABA and nitrite levels were also determined in the isolated whole brain of mice. It was observed that pyridoxine (180 mg/kg, i.p.) exerted 'anxiolytic-like' effect in mice in EPM and LDB models. Also, there was a significant increase in the levels of GABA whereas; the levels of glutamate and nitrite were decreased as compared to the control group. Administration of pentamethylene tetrazole (PTZ; 20 mg/kg, i.p.) exerted anxiogenic effects in mice, but the combination of PTZ and pyridoxine (180 mg/kg, i.p.) abolished the 'anxiolytic-like' effect of pyridoxine, thereby, suggesting the possible role of GABA in the 'anxiolytic-like' effect of pyridoxine in mice. Further, the influence of NO-sGC-cGMP pathway was investigated by administering the sub-effective dose of pyridoxine in combination with sub-threshold doses of NO modulators i.e. l‑arginine (50 mg/kg, i.p.; NO donor); methylene blue (1 mg/kg, i.p.; NO and soluble guanylate cyclase inhibitor) and sildenafil (1 mg/kg, i.p.; phosphodiesterase inhibitor and cGMP modulator). It was observed that the 'anxiolytic-like' effect of pyridoxine in mice was counteracted by the NO donor and potentiated by the NO inhibitors. Thus, the present study confirmed the involvement of GABAergic and NO-sGC-cGMP pathway in the 'anxiolytic-like' effect of pyridoxine in mice.
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Affiliation(s)
- Vaibhav Walia
- Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak 124001, Haryana, India
| | - Chanchal Garg
- Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak 124001, Haryana, India
| | - Munish Garg
- Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak 124001, Haryana, India.
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Doron R, Sever A, Handelsman A, Toledano R, Franko M, Hirshler Y, Shamir A, Burstein O, Rehavi M. GABA A Receptor Density Is Not Altered by a Novel Herbal Anxiolytic Treatment. J Mol Neurosci 2018; 65:110-117. [PMID: 29737465 DOI: 10.1007/s12031-018-1078-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2017] [Accepted: 04/27/2018] [Indexed: 01/06/2023]
Abstract
Anxiety disorders are highly prevalent and considered a major public health concern worldwide. Current anxiolytics are of limited efficacy and associated with various side effects. Our novel herbal treatment (NHT), composed of four constituents, was shown to reduce anxiety-like behavior while precluding a common side effect caused by current anxiolytics, i.e., sexual dysfunction. Nevertheless, NHT's mechanism of action is yet to be determined. There is evidence that some medicinal herbs interact with the GABAergic system. Therefore, we aimed to examine whether NHT's anxiolytic-like effect is exerted by alterations in GABAA receptor density in the hippocampus, prefrontal cortex, and hypothalamus. The effects of 3-weeks treatment with NHT on anxiety-like behavior and locomotion were assessed using the elevated plus maze (EPM) and the open field test (OFT), respectively. Regional GABAA receptor levels were analyzed using [3H] RO15-1788 high-affinity binding assays. In stressed mice, NHT reduced anxiety-like behavior similarly to the benzodiazepine, clonazepam, while locomotion remained intact. Lack of changes or minor changes in regional GABAA receptor density in the brain were induced by NHT or clonazepam. In naive mice, performance in the EPM, locomotion and GABAA receptor densities were not altered by treatment with NHT or clonazepam. These findings support NHT as an efficacious and safe anxiolytic, although the GABAergic involvement remains to be further elucidated.
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Affiliation(s)
- Ravid Doron
- School of Behavioral Sciences, The Academic College Tel Aviv Yaffo, 6818211, Tel Aviv, Israel.
- Department of Education and Psychology, The Open University of Israel, 4353701, Ra'anana, Israel.
| | - Avital Sever
- Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, 6997801, Tel Aviv, Israel
| | - Assaf Handelsman
- School of Behavioral Sciences, The Academic College Tel Aviv Yaffo, 6818211, Tel Aviv, Israel
| | - Roni Toledano
- Department of Education and Psychology, The Open University of Israel, 4353701, Ra'anana, Israel
| | - Motty Franko
- School of Behavioral Sciences, The Academic College Tel Aviv Yaffo, 6818211, Tel Aviv, Israel
| | - Yafit Hirshler
- Department of Education and Psychology, The Open University of Israel, 4353701, Ra'anana, Israel
| | - Alon Shamir
- Faculty of Medicine, Technion - Israel Institute of Technology, 3200003, Haifa, Israel
- Mazor Mental Health Center, 2423314, Akko, Israel
| | - Or Burstein
- School of Behavioral Sciences, The Academic College Tel Aviv Yaffo, 6818211, Tel Aviv, Israel
| | - Moshe Rehavi
- Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, 6997801, Tel Aviv, Israel
- The Dr. Miriam and Sheldon G. Adelson Chair and Center for the Biology of Addictive Diseases, Tel Aviv University, 6997801, Tel Aviv, Israel
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17
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Hautzel H, Müller HW, Nikolaus S. Focus on GABAA receptor function. Nuklearmedizin 2018; 53:227-37. [DOI: 10.3413/nukmed-0647-14-03] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2014] [Accepted: 08/21/2014] [Indexed: 12/31/2022]
Abstract
SummaryImpairment of GABAA receptor function is increasingly recognized to play a major role in the pathophysiology of neuropsychiatric diseases including anxiety disorder (AD), major depressive disorder (MDD) and schizophrenia (SZ). Patients, method: We conducted a PUBMED search, which provided a total of 23 in vivo investigations with PET and SPECT, in which GABAA receptor binding in patients with the primary diagnosis of AD (n = 14, 160 patients, 172 controls), MDD (n = 2, 24 patients, 28 controls) or SZ (n = 6, 77 patients, 90 controls) was compared to healthy individuals. Results: A retrospective analysis revealed that AD, MDD and SZ differed as to both site(s) and extent(s) of GABAergic impairment. Additionally, it may be stated that, while the decline of GABAA receptor binding AD involved the whole mesolimbocortical system, in SZ it was confined to the frontal and temporal cortex. Conclusion: As GABA is known to inhibit dopamine and serotonin, GABAergic dysfunction may be associated with the disturbances of dopaminergic and serotonergic neurotransmission in neuropsychiatric disorders.
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18
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Maron E, Lan CC, Nutt D. Imaging and Genetic Approaches to Inform Biomarkers for Anxiety Disorders, Obsessive-Compulsive Disorders, and PSTD. Curr Top Behav Neurosci 2018; 40:219-292. [PMID: 29796838 DOI: 10.1007/7854_2018_49] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Anxiety disorders are the most common mental health problem in the world and also claim the highest health care cost among various neuropsychiatric disorders. Anxiety disorders have a chronic and recurrent course and cause significantly negative impacts on patients' social, personal, and occupational functioning as well as quality of life. Despite their high prevalence rates, anxiety disorders have often been under-diagnosed or misdiagnosed, and consequently under-treated. Even with the correct diagnosis, anxiety disorders are known to be difficult to treat successfully. In order to implement better strategies in diagnosis, prognosis, treatment decision, and early prevention for anxiety disorders, tremendous efforts have been put into studies using genetic and neuroimaging techniques to advance our understandings of the underlying biological mechanisms. In addition to anxiety disorders including panic disorder, generalised anxiety disorder (GAD), specific phobias, social anxiety disorders (SAD), due to overlapping symptom dimensions, obsessive-compulsive disorder (OCD), and post-traumatic stress disorder (PTSD) (which were removed from the anxiety disorder category in DSM-5 to become separate categories) are also included for review of relevant genetic and neuroimaging findings. Although the number of genetic or neuroimaging studies focusing on anxiety disorders is relatively small compare to other psychiatric disorders such as psychotic disorders or mood disorders, various structural abnormalities in the grey or white matter, functional alterations of activity during resting-state or task conditions, molecular changes of neurotransmitter receptors or transporters, and genetic associations have all been reported. With continuing effort, further genetic and neuroimaging research may potentially lead to clinically useful biomarkers for the prevention, diagnosis, and management of these disorders.
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Affiliation(s)
- Eduard Maron
- Neuropsychopharmacology Unit, Centre for Academic Psychiatry, Division of Brain Sciences, Imperial College London, London, UK.
- Department of Psychiatry, University of Tartu, Tartu, Estonia.
- Department of Psychiatry, North Estonia Medical Centre, Tallinn, Estonia.
| | - Chen-Chia Lan
- Neuropsychopharmacology Unit, Centre for Academic Psychiatry, Division of Brain Sciences, Imperial College London, London, UK
- Department of Psychiatry, Taichung Veterans General Hospital, Taichung, Taiwan
| | - David Nutt
- Neuropsychopharmacology Unit, Centre for Academic Psychiatry, Division of Brain Sciences, Imperial College London, London, UK
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Breit S, Kupferberg A, Rogler G, Hasler G. Vagus Nerve as Modulator of the Brain-Gut Axis in Psychiatric and Inflammatory Disorders. Front Psychiatry 2018; 9:44. [PMID: 29593576 PMCID: PMC5859128 DOI: 10.3389/fpsyt.2018.00044] [Citation(s) in RCA: 527] [Impact Index Per Article: 75.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Accepted: 02/01/2018] [Indexed: 12/13/2022] Open
Abstract
The vagus nerve represents the main component of the parasympathetic nervous system, which oversees a vast array of crucial bodily functions, including control of mood, immune response, digestion, and heart rate. It establishes one of the connections between the brain and the gastrointestinal tract and sends information about the state of the inner organs to the brain via afferent fibers. In this review article, we discuss various functions of the vagus nerve which make it an attractive target in treating psychiatric and gastrointestinal disorders. There is preliminary evidence that vagus nerve stimulation is a promising add-on treatment for treatment-refractory depression, posttraumatic stress disorder, and inflammatory bowel disease. Treatments that target the vagus nerve increase the vagal tone and inhibit cytokine production. Both are important mechanism of resiliency. The stimulation of vagal afferent fibers in the gut influences monoaminergic brain systems in the brain stem that play crucial roles in major psychiatric conditions, such as mood and anxiety disorders. In line, there is preliminary evidence for gut bacteria to have beneficial effect on mood and anxiety, partly by affecting the activity of the vagus nerve. Since, the vagal tone is correlated with capacity to regulate stress responses and can be influenced by breathing, its increase through meditation and yoga likely contribute to resilience and the mitigation of mood and anxiety symptoms.
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Affiliation(s)
- Sigrid Breit
- Division of Molecular Psychiatry, Translational Research Center, University Hospital of Psychiatry, University of Bern, Bern, Switzerland
| | - Aleksandra Kupferberg
- Division of Molecular Psychiatry, Translational Research Center, University Hospital of Psychiatry, University of Bern, Bern, Switzerland
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Gregor Hasler
- Division of Molecular Psychiatry, Translational Research Center, University Hospital of Psychiatry, University of Bern, Bern, Switzerland
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20
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Prescot A, Sheth C, Legarreta M, Renshaw PF, McGlade E, Yurgelun-Todd D. Altered Cortical GABA in Female Veterans with Suicidal Behavior: Sex Differences and Clinical Correlates. CHRONIC STRESS (THOUSAND OAKS, CALIF.) 2018; 2:2470547018768771. [PMID: 29756082 PMCID: PMC5947869 DOI: 10.1177/2470547018768771] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Accepted: 03/14/2018] [Indexed: 11/21/2022]
Abstract
Background Suicide is a public health concern in the civilian and veteran populations. Stressful life events are precipitating factors for suicide. The neurochemical underpinnings of the association between stress/trauma and suicide risk are unclear, especially in regards to sex differences. We hypothesized that gamma-amino butyric acid (GABA), the major inhibitory neurotransmitter may be a neurochemical candidate that is critical in the association between stress and suicide risk in veterans. Methods Proton magnetic resonance spectroscopy (1H MRS) at 3.0 Tesla was used to measure in vivo neurochemistry in the anterior cingulate cortex (ACC; predominantly the dorsal ACC) of 81 veterans (16 females), including 57 (11 females) who endorsed past suicidal ideation (SI) and/or suicide attempt (SA) and 24 (5 females) with no history of SI and/or SA. Suicidal behavior (SB) was defined as the presence of SI and/or SA. Results We observed no significant differences in GABA/ Creatine+phosphocreatine (Cr+PCr) between veterans with SB (SB+) and without SB (SB-). However, the female SB+ group showed significantly reduced GABA/Cr+PCr vs. the female SB- group. We observed a trend-level significant negative correlation between GABA/Cr+PCr and the defensive avoidance (DA) subscale on the Trauma Symptom Inventory (TSI) in the SB+ group. In contrast, the SB- group exhibited a positive relationship between the two variables. Furthermore, we found significant negative correlations between GABA/Cr+PCr and Hamilton Rating Scale for Depression (HAM-D) scores as well as between GABA/Cr+PCr and several subscales of the TSI in female veterans. Conclusions This study suggests that reduced GABA/Cr+ PCr ratio in the ACC, which may be related to altered inhibitory capacity, may underlie suicide risk in female veterans. Further, the negative association between GABA/Cr+PCr and stress symptomatology and depression scores suggests that MRS studies may shed light on intermediate phenotypes of SB.
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Affiliation(s)
- Andrew Prescot
- Department of Radiology, University of Utah School of
Medicine, Salt Lake City, UT, USA
| | - Chandni Sheth
- Department of Psychiatry, University of Utah School of
Medicine, Salt Lake City, UT, USA
- Diagnostic Neuroimaging, University of Utah, Salt Lake City, UT, USA
| | - Margaret Legarreta
- Diagnostic Neuroimaging, University of Utah, Salt Lake City, UT, USA
- George E. Wahlen Department of Veterans
Affairs Medical Center, VA VISN 19 Mental Illness Research, Education and Clinical
Center, Salt Lake City, UT, USA
| | - Perry F. Renshaw
- Department of Psychiatry, University of Utah School of
Medicine, Salt Lake City, UT, USA
- Diagnostic Neuroimaging, University of Utah, Salt Lake City, UT, USA
- George E. Wahlen Department of Veterans
Affairs Medical Center, VA VISN 19 Mental Illness Research, Education and Clinical
Center, Salt Lake City, UT, USA
| | - Erin McGlade
- Department of Psychiatry, University of Utah School of
Medicine, Salt Lake City, UT, USA
- Diagnostic Neuroimaging, University of Utah, Salt Lake City, UT, USA
- George E. Wahlen Department of Veterans
Affairs Medical Center, VA VISN 19 Mental Illness Research, Education and Clinical
Center, Salt Lake City, UT, USA
| | - Deborah Yurgelun-Todd
- Department of Psychiatry, University of Utah School of
Medicine, Salt Lake City, UT, USA
- Diagnostic Neuroimaging, University of Utah, Salt Lake City, UT, USA
- George E. Wahlen Department of Veterans
Affairs Medical Center, VA VISN 19 Mental Illness Research, Education and Clinical
Center, Salt Lake City, UT, USA
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Mick I, Ramos AC, Myers J, Stokes PR, Chandrasekera S, Erritzoe D, Mendez MA, Gunn RN, Rabiner EA, Searle GE, Galduróz JCF, Waldman AD, Bowden-Jones H, Clark L, Nutt DJ, Lingford-Hughes AR. Evidence for GABA-A receptor dysregulation in gambling disorder: correlation with impulsivity. Addict Biol 2017; 22:1601-1609. [PMID: 27739164 PMCID: PMC5697606 DOI: 10.1111/adb.12457] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Revised: 07/14/2016] [Accepted: 08/30/2016] [Indexed: 12/11/2022]
Abstract
As a behavioural addiction, gambling disorder (GD) provides an opportunity to characterize addictive processes without the potentially confounding effects of chronic excessive drug and alcohol exposure. Impulsivity is an established precursor to such addictive behaviours, and GD is associated with greater impulsivity. There is also evidence of GABAergic dysregulation in substance addiction and in impulsivity. This study therefore investigated GABAA receptor availability in 15 individuals with GD and 19 healthy volunteers (HV) using [11C]Ro15‐4513, a relatively selective α5 benzodiazepine receptor PET tracer and its relationship with impulsivity. We found significantly higher [11C]Ro15‐4513 total distribution volume (VT) in the right hippocampus in the GD group compared with HV. We found higher levels of the ‘Negative Urgency’ construct of impulsivity in GD, and these were positively associated with higher [11C]Ro15‐4513 VT in the amygdala in the GD group; no such significant correlations were evident in the HV group. These results contrast with reduced binding of GABAergic PET ligands described previously in alcohol and opiate addiction and add to growing evidence for distinctions in the neuropharmacology between substance and behavioural addictions. These results provide the first characterization of GABAA receptors in GD with [11C]Ro15‐4513 PET and show greater α5 receptor availability and positive correlations with trait impulsivity. This GABAergic dysregulation is potential target for treatment.
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Affiliation(s)
- Inge Mick
- Centre for Neuropsychopharmacology, Division of Brain Sciences, Faculty of Medicine; Imperial College London; UK
| | - Anna C. Ramos
- Centre for Neuropsychopharmacology, Division of Brain Sciences, Faculty of Medicine; Imperial College London; UK
- Department of Psychobiology; Universidade Federal de São Paulo; Brazil
| | - Jim Myers
- Centre for Neuropsychopharmacology, Division of Brain Sciences, Faculty of Medicine; Imperial College London; UK
| | - Paul R. Stokes
- Centre for Neuropsychopharmacology, Division of Brain Sciences, Faculty of Medicine; Imperial College London; UK
- Centre for Affective Disorders, Department of Psychological Medicine; Institute of Psychiatry, Psychology and Neuroscience, King's College London; UK
| | - Samantha Chandrasekera
- Centre for Neuropsychopharmacology, Division of Brain Sciences, Faculty of Medicine; Imperial College London; UK
| | - David Erritzoe
- Centre for Neuropsychopharmacology, Division of Brain Sciences, Faculty of Medicine; Imperial College London; UK
| | - Maria A. Mendez
- Forensic and Neurodevelopmental Sciences; Institute of Psychiatry, King's College; UK
| | - Roger N. Gunn
- Centre for Neuropsychopharmacology, Division of Brain Sciences, Faculty of Medicine; Imperial College London; UK
- Imanova Ltd.; Centre for Imaging Sciences; UK
| | - Eugenii A. Rabiner
- Imanova Ltd.; Centre for Imaging Sciences; UK
- Department of Neuroimaging; Institute of Psychiatry, King's College; UK
| | | | | | - Adam D. Waldman
- Department of Imaging, Division of Experimental Medicine, Department of Medicine; Imperial College; UK
| | - Henrietta Bowden-Jones
- National Problem Gambling Clinic, CNWL NHS Foundation Trust; Imperial College London; UK
| | - Luke Clark
- Centre for Gambling Research at UBC, Department of Psychology; University of British Columbia; Canada
| | - David J. Nutt
- Centre for Neuropsychopharmacology, Division of Brain Sciences, Faculty of Medicine; Imperial College London; UK
| | - Anne R. Lingford-Hughes
- Centre for Neuropsychopharmacology, Division of Brain Sciences, Faculty of Medicine; Imperial College London; UK
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Shaw JC, Palliser HK, Dyson RM, Berry MJ, Hirst JJ. Disruptions to the cerebellar GABAergic system in juvenile guinea pigs following preterm birth. Int J Dev Neurosci 2017; 65:1-10. [PMID: 29024720 DOI: 10.1016/j.ijdevneu.2017.10.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Revised: 10/05/2017] [Accepted: 10/06/2017] [Indexed: 10/18/2022] Open
Abstract
BACKGROUND Children that are born preterm are at an increased risk of developing cognitive problems and behavioural disorders, such as attention deficit hyperactivity disorder (ADHD). There is increasing interest in the role of the cerebellum in these processes and the potential involvement of GABAergic pathways in neurodevelopmental disorders. We propose that preterm birth, and the associated loss of the trophic intrauterine environment, alters the development of the cerebellum, contributing to ongoing neurobehavioral disorders. METHODS Guinea pigs were delivered preterm (GA62) or spontaneously at term (GA69), and tissues collected at corrected postnatal day (PND) 28. Neurodevelopmental and GABAergic markers myelin basic protein (MBP), neuronal nuclei (NeuN), calbindin (Purkinje cells), and GAD67 (GABA synthesis enzyme) were analysed in cerebellar lobules IX and X by immunohistochemistry. Protein expression of GAD67 and GAT1 (GABA transporter enzyme) were quantified by western blot, whilst neurosteroid-sensitive GABAA receptor subunits were measured by RT-PCR. RESULTS MBP immunostaining was increased in lobule IX of preterm males, and reduced in lobule X of preterm females when compared to their term counterparts. GAD67 staining was decreased in lobule IX and X of the preterm males, but only in lobule X of the preterm females compared to term cohorts for each sex. Internal granule cell layer width of lobule X was decreased in preterm cohorts of both sexes compared to terms. There were no differences between gestational age groups for NeuN staining, GAD67 and GAT1 protein expression as measured by western blotting, or GABAA receptor subunits as measured by RT-PCR between preterm and term for either sex. CONCLUSIONS The present findings suggest that components of the cerebellar GABAergic system of the ex-preterm cerebellum are disrupted. The higher expression of myelin in the preterm males may be due to a deficit in axonal pruning, whereas females have a deficit in myelination at 28 corrected days of age. Together these ongoing alterations may contribute to the neurodevelopmental and behavioural disorders observed in those born preterm.
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Affiliation(s)
- Julia C Shaw
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia; Mothers and Babies Research Centre, Hunter Medical Research Institute, Australia.
| | - Hannah K Palliser
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia; Mothers and Babies Research Centre, Hunter Medical Research Institute, Australia
| | - Rebecca M Dyson
- Department of Paediatrics and Child Health, University of Otago, Wellington, New Zealand; Centre for Translational Physiology, University of Otago, Wellington, New Zealand
| | - Mary J Berry
- Department of Paediatrics and Child Health, University of Otago, Wellington, New Zealand; Centre for Translational Physiology, University of Otago, Wellington, New Zealand
| | - Jonathan J Hirst
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia; Mothers and Babies Research Centre, Hunter Medical Research Institute, Australia
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Goddard AW. The Neurobiology of Panic: A Chronic Stress Disorder. CHRONIC STRESS (THOUSAND OAKS, CALIF.) 2017; 1:2470547017736038. [PMID: 32440580 PMCID: PMC7219873 DOI: 10.1177/2470547017736038] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/11/2017] [Revised: 09/05/2017] [Accepted: 09/15/2017] [Indexed: 12/20/2022]
Abstract
Panic disorder is an often chronic and impairing human anxiety syndrome, which frequently results in serious psychiatric and medical comorbidities. Although, to date, there have been many advances in the diagnosis and treatment of panic disorder, its pathophysiology still remains to be elucidated. In this review, recent evidence for a neurobiological basis of panic disorder is reviewed with particular attention to risk factors such as genetic vulnerability, chronic stress, and temperament. In addition, neuroimaging data are reviewed which provides support for the concept of panic disorder as a fear network disorder. The potential impact of the National Institute of Mental Health Research Domain Criteria constructs of acute and chronic threats responses and their implications for the neurobiology of panic disorder are also discussed.
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Affiliation(s)
- Andrew W. Goddard
- UCSF Fresno Medical Education and
Research Program, University of California, San Francisco, USA
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24
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Bandelow B, Baldwin D, Abelli M, Altamura C, Dell'Osso B, Domschke K, Fineberg NA, Grünblatt E, Jarema M, Maron E, Nutt D, Pini S, Vaghi MM, Wichniak A, Zai G, Riederer P. Biological markers for anxiety disorders, OCD and PTSD - a consensus statement. Part I: Neuroimaging and genetics. World J Biol Psychiatry 2016; 17:321-65. [PMID: 27403679 DOI: 10.1080/15622975.2016.1181783] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVES Biomarkers are defined as anatomical, biochemical or physiological traits that are specific to certain disorders or syndromes. The objective of this paper is to summarise the current knowledge of biomarkers for anxiety disorders, obsessive-compulsive disorder (OCD) and post-traumatic stress disorder (PTSD). METHODS Findings in biomarker research were reviewed by a task force of international experts in the field, consisting of members of the World Federation of Societies for Biological Psychiatry Task Force on Biological Markers and of the European College of Neuropsychopharmacology Anxiety Disorders Research Network. RESULTS The present article (Part I) summarises findings on potential biomarkers in neuroimaging studies, including structural brain morphology, functional magnetic resonance imaging and techniques for measuring metabolic changes, including positron emission tomography and others. Furthermore, this review reports on the clinical and molecular genetic findings of family, twin, linkage, association and genome-wide association studies. Part II of the review focuses on neurochemistry, neurophysiology and neurocognition. CONCLUSIONS Although at present, none of the putative biomarkers is sufficient and specific as a diagnostic tool, an abundance of high-quality research has accumulated that will improve our understanding of the neurobiological causes of anxiety disorders, OCD and PTSD.
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Affiliation(s)
- Borwin Bandelow
- a Department of Psychiatry and Psychotherapy , University of Göttingen , Germany
| | - David Baldwin
- b Faculty of Medicine , University of Southampton , Southampton , UK
| | - Marianna Abelli
- c Department of Clinical and Experimental Medicine , Section of Psychiatry, University of Pisa , Italy
| | - Carlo Altamura
- d Department of Psychiatry , University of Milan; Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico , Milan , Italy
| | - Bernardo Dell'Osso
- d Department of Psychiatry , University of Milan; Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico , Milan , Italy
| | - Katharina Domschke
- e Department of Psychiatry, Psychosomatics and Psychotherapy , University of Wuerzburg , Germany
| | - Naomi A Fineberg
- f Hertfordshire Partnership University NHS Foundation Trust and University of Hertfordshire , Rosanne House, Parkway , Welwyn Garden City , UK
| | - Edna Grünblatt
- e Department of Psychiatry, Psychosomatics and Psychotherapy , University of Wuerzburg , Germany ;,g Neuroscience Center Zurich , University of Zurich and the ETH Zurich , Zürich , Switzerland ;,h Department of Child and Adolescent Psychiatry and Psychotherapy , Psychiatric Hospital, University of Zurich , Zürich , Switzerland ;,i Zurich Center for Integrative Human Physiology , University of Zurich , Switzerland
| | - Marek Jarema
- j Third Department of Psychiatry , Institute of Psychiatry and Neurology , Warszawa , Poland
| | - Eduard Maron
- k North Estonia Medical Centre, Department of Psychiatry , Tallinn , Estonia ;,l Department of Psychiatry , University of Tartu , Estonia ;,m Faculty of Medicine, Department of Medicine, Centre for Neuropsychopharmacology, Division of Brain Sciences , Imperial College London , UK
| | - David Nutt
- m Faculty of Medicine, Department of Medicine, Centre for Neuropsychopharmacology, Division of Brain Sciences , Imperial College London , UK
| | - Stefano Pini
- c Department of Clinical and Experimental Medicine , Section of Psychiatry, University of Pisa , Italy
| | - Matilde M Vaghi
- n Department of Psychology and Behavioural and Clinical Neuroscience Institute , University of Cambridge , UK
| | - Adam Wichniak
- j Third Department of Psychiatry , Institute of Psychiatry and Neurology , Warszawa , Poland
| | - Gwyneth Zai
- n Department of Psychology and Behavioural and Clinical Neuroscience Institute , University of Cambridge , UK ;,o Neurogenetics Section, Centre for Addiction & Mental Health , Toronto , Canada ;,p Frederick W. Thompson Anxiety Disorders Centre, Department of Psychiatry, Sunnybrook Health Sciences Centre , Toronto , Canada ;,q Institute of Medical Science and Department of Psychiatry, University of Toronto , Toronto , Canada
| | - Peter Riederer
- e Department of Psychiatry, Psychosomatics and Psychotherapy , University of Wuerzburg , Germany ;,g Neuroscience Center Zurich , University of Zurich and the ETH Zurich , Zürich , Switzerland ;,h Department of Child and Adolescent Psychiatry and Psychotherapy , Psychiatric Hospital, University of Zurich , Zürich , Switzerland
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25
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Shaw JC, Palliser HK, Dyson RM, Hirst JJ, Berry MJ. Long-term effects of preterm birth on behavior and neurosteroid sensitivity in the guinea pig. Pediatr Res 2016; 80:275-83. [PMID: 27055188 DOI: 10.1038/pr.2016.63] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2015] [Accepted: 01/28/2016] [Indexed: 01/10/2023]
Abstract
BACKGROUND Ex-preterm children and adolescents are at risk of developing late-onset neurodevelopmental and behavioral disorders. The mechanisms by which this happens are poorly understood and relevant animal models are required. METHODS Ex-preterm (delivered at 62 d gestation) and term (spontaneously delivered) juvenile guinea pigs underwent behavioral testing at 25 d corrected postnatal age, with tissues collected at 28 d. Neurodevelopmental markers (myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP)) were analyzed in the hippocampus and subcortical white matter by immunohistochemistry. Gamma-aminobutyric acid A (GABAA) receptor subunit mRNA levels were quantified by reverse transcription polymerase chain reaction (RT-PCR), and salivary cortisol measured by enzyme-linked immunosorbent assay. RESULTS Preterm males travelled greater distances, were mobile for longer, spent more time investigating objects, and approached or interacted with familiar animals more than controls. Myelination and reactive astrocyte coverage was lower in the hippocampus and the subcortical white matter in preterm males. Hippocampal levels of the α5 subunit were also lower in the preterm male brain. Baseline salivary cortisol was higher for preterm males compared to controls. CONCLUSION We conclude that juvenile ex-preterm male guinea pigs exhibit a hyperactive phenotype and feature impaired neurodevelopment, making this a suitable model for future therapeutic studies.
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Affiliation(s)
- Julia C Shaw
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia.,Hunter Medical Research Institute, Mothers and Babies Research Centre, Newcastle, Australia
| | - Hannah K Palliser
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia.,Hunter Medical Research Institute, Mothers and Babies Research Centre, Newcastle, Australia
| | - Rebecca M Dyson
- Department of Paediatrics, Graduate School of Medicine and IHMRI, University of Wollongong, Wollongong, Australia
| | - Jonathan J Hirst
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia.,Hunter Medical Research Institute, Mothers and Babies Research Centre, Newcastle, Australia
| | - Mary J Berry
- Centre for Translational Physiology, University of Otago, Wellington, New Zealand.,Department of Paediatrics and Child Health, University of Otago, Wellington, New Zealand
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26
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Canetta S, Bolkan S, Padilla-Coreano N, Song L, Sahn R, Harrison N, Gordon JA, Brown A, Kellendonk C. Maternal immune activation leads to selective functional deficits in offspring parvalbumin interneurons. Mol Psychiatry 2016; 21:956-68. [PMID: 26830140 PMCID: PMC4914410 DOI: 10.1038/mp.2015.222] [Citation(s) in RCA: 159] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Revised: 12/04/2015] [Accepted: 12/15/2015] [Indexed: 12/26/2022]
Abstract
Abnormalities in prefrontal gamma aminobutyric acid (GABA)ergic transmission, particularly in fast-spiking interneurons that express parvalbumin (PV), are hypothesized to contribute to the pathophysiology of multiple psychiatric disorders, including schizophrenia, bipolar disorder, anxiety disorders and depression. While primarily histological abnormalities have been observed in patients and in animal models of psychiatric disease, evidence for abnormalities in functional neurotransmission at the level of specific interneuron populations has been lacking in animal models and is difficult to establish in human patients. Using an animal model of a psychiatric disease risk factor, prenatal maternal immune activation (MIA), we found reduced functional GABAergic transmission in the medial prefrontal cortex (mPFC) of adult MIA offspring. Decreased transmission was selective for interneurons expressing PV, resulted from a decrease in release probability and was not observed in calretinin-expressing neurons. This deficit in PV function in MIA offspring was associated with increased anxiety-like behavior and impairments in attentional set shifting, but did not affect working memory. Furthermore, cell-type specific optogenetic inhibition of mPFC PV interneurons was sufficient to impair attentional set shifting and enhance anxiety levels. Finally, we found that in vivo mPFC gamma oscillations, which are supported by PV interneuron function, were linearly correlated with the degree of anxiety displayed in adult mice, and that this correlation was disrupted in MIA offspring. These results demonstrate a selective functional vulnerability of PV interneurons to MIA, leading to affective and cognitive symptoms that have high relevance for schizophrenia and other psychiatric disorders.
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Affiliation(s)
- Sarah Canetta
- Department of Psychiatry, Mailman School of Public Health, Columbia University Medical Center, New York, NY 10032, USA
| | - Scott Bolkan
- Department of Psychiatry, Mailman School of Public Health, Columbia University Medical Center, New York, NY 10032, USA
| | - Nancy Padilla-Coreano
- Department of Psychiatry, Mailman School of Public Health, Columbia University Medical Center, New York, NY 10032, USA,Division of Integrative Neuroscience, New York State Psychiatric Institute, New York, NY 10032, USA
| | - LouJin Song
- Department of Pharmacology, Mailman School of Public Health, Columbia University Medical Center, New York, NY 10032, USA
| | | | - Neil Harrison
- Department of Pharmacology, Mailman School of Public Health, Columbia University Medical Center, New York, NY 10032, USA,Department of Anesthesiology, Mailman School of Public Health, Columbia University Medical Center, New York, NY 10032, USA
| | - Joshua A. Gordon
- Department of Psychiatry, Mailman School of Public Health, Columbia University Medical Center, New York, NY 10032, USA,Division of Integrative Neuroscience, New York State Psychiatric Institute, New York, NY 10032, USA
| | - Alan Brown
- Department of Psychiatry, Mailman School of Public Health, Columbia University Medical Center, New York, NY 10032, USA,Department of Epidemiology, Mailman School of Public Health, Columbia University Medical Center, New York, NY 10032, USA,Divison of Epidemiology, New York State Psychiatric Institute, New York, NY 10032, USA
| | - Christoph Kellendonk
- Department of Psychiatry, Mailman School of Public Health, Columbia University Medical Center, New York, NY 10032, USA,Department of Pharmacology, Mailman School of Public Health, Columbia University Medical Center, New York, NY 10032, USA,Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY 10032, USA
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Lai CH, Wu YT. The Explorative Analysis to Revise Fear Network Model for Panic Disorder: Functional Connectome Statistics. Medicine (Baltimore) 2016; 95:e3597. [PMID: 27149492 PMCID: PMC4863809 DOI: 10.1097/md.0000000000003597] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Functional connectome analysis in panic disorder (PDO) is a relatively new field for research. We tried to investigate the functional connectome alterations in PDO to re-examine the precision and role of fear network model for the pathophysiology of PDO.We enrolled 53 PDO patients and 54 controls with imaging data in this study. After preprocessing, we calculated the connectivity matrix of functional connectivity in whole brain for each subject. Then network-based statistics (The University of Melbourne and Melbourne Health, Australia) of connectome was used to perform group comparisons between patients and controls. The correlation between network measures of significant subnetwork and illness duration or severity of PDO was also performed.Within the 6 network models, only 1 network survived after multiple corrections. We found decreased functional connectivity in the edges between the following nodes: the left parahippocampal gyrus, bilateral precentral gyri, bilateral middle cingulate gyri, bilateral supramarginal gyri, bilateral calcarine fissures, and right lingual gyrus. The central hubs were the left parahippocampal gyrus and left precentral gyrus. The importance of limbic areas and connection with sensory and motor regions might shed light on the revision of fear network model for the pathophysiology of PDO.
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Affiliation(s)
- Chien-Han Lai
- From the Department of Psychiatry (C-HL), Cheng Hsin General Hospital, Taipei City; Department of Biomedical Imaging and Radiological Sciences (C-HL, Y-TW); Institute of Biophotonics (C-HL, Y-TW); and Brain Research Center (Y-TW), National Yang-Ming University, Taipei, Taiwan, ROC
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28
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Goddard AW. Cortical and subcortical gamma amino acid butyric acid deficits in anxiety and stress disorders: Clinical implications. World J Psychiatry 2016; 6:43-53. [PMID: 27014597 PMCID: PMC4804267 DOI: 10.5498/wjp.v6.i1.43] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Revised: 12/18/2015] [Accepted: 01/29/2016] [Indexed: 02/05/2023] Open
Abstract
Anxiety and stress disorders are a major public health issue. However, their pathophysiology is still unclear. The gamma amino acid butyric acid (GABA) neurochemical system has been strongly implicated in their pathogenesis and treatment by numerous preclinical and clinical studies, the most recent of which have been highlighted and critical review in this paper. Changes in cortical GABA appear related to normal personality styles and responses to stress. While there is accumulating animal and human neuroimaging evidence of cortical and subcortical GABA deficits across a number of anxiety conditions, a clear pattern of findings in specific brain regions for a given disorder is yet to emerge. Neuropsychiatric conditions with anxiety as a clinical feature may have GABA deficits as an underlying feature. Different classes of anxiolytic therapies support GABA function, and this may be an area in which newer GABA neuroimaging techniques could soon offer more personalized therapy. Novel GABAergic pharmacotherapies in development offer potential improvements over current therapies in reducing sedative and physiologic dependency effects, while offering rapid anxiolysis.
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29
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Ruland T, Domschke K, Schütte V, Zavorotnyy M, Kugel H, Notzon S, Vennewald N, Ohrmann P, Arolt V, Pfleiderer B, Zwanzger P. Neuropeptide S receptor gene variation modulates anterior cingulate cortex Glx levels during CCK-4 induced panic. Eur Neuropsychopharmacol 2015; 25:1677-82. [PMID: 26235955 DOI: 10.1016/j.euroneuro.2015.07.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Revised: 06/16/2015] [Accepted: 07/14/2015] [Indexed: 01/04/2023]
Abstract
An excitatory-inhibitory neurotransmitter dysbalance has been suggested in pathogenesis of panic disorder. The neuropeptide S (NPS) system has been implicated in modulating GABA and glutamate neurotransmission in animal models and to genetically drive altered fear circuit function and an increased risk of panic disorder in humans. Probing a multi-level imaging genetic risk model of panic, in the present magnetic resonance spectroscopy (MRS) study brain glutamate+glutamine (Glx) levels in the bilateral anterior cingulate cortex (ACC) during a pharmacological cholecystokinin tetrapeptide (CCK-4) panic challenge were assessed depending on the functional neuropeptide S receptor gene (NPSR1) rs324981 A/T variant in a final sample of 35 healthy male subjects. The subjective panic response (Panic Symptom Scale; PSS) as well as cortisol and ACTH levels were ascertained throughout the experiment. CCK-4 injection was followed by a strong panic response. A significant time×genotype interaction was detected (p=.008), with significantly lower ACC Glx/Cr levels in T allele carriers as compared to AA homozygotes 5min after injection (p=.003). CCK-4 induced significant HPA axis stimulation, but no effect of genotype was discerned. The present pilot data suggests NPSR1 gene variation to modulate Glx levels in the ACC during acute states of stress and anxiety, with blunted, i.e. possibly maladaptive ACC glutamatergic reactivity in T risk allele carriers. Our results underline the notion of a genetically driven rapid and dynamic response mechanism in the neural regulation of human anxiety and further strengthen the emerging role of the NPS system in anxiety.
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Affiliation(s)
- Tillmann Ruland
- Mood and Anxiety Disorders Research Unit, Department of Psychiatry and Psychotherapy, University of Muenster, Germany
| | - Katharina Domschke
- Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Germany
| | - Valerie Schütte
- Mood and Anxiety Disorders Research Unit, Department of Psychiatry and Psychotherapy, University of Muenster, Germany
| | - Maxim Zavorotnyy
- Mood and Anxiety Disorders Research Unit, Department of Psychiatry and Psychotherapy, University of Muenster, Germany; Department of Psychiatry and Psychotherapy, University of Marburg, Germany
| | - Harald Kugel
- Department of Clinical Radiology, University of Muenster, Germany
| | - Swantje Notzon
- Mood and Anxiety Disorders Research Unit, Department of Psychiatry and Psychotherapy, University of Muenster, Germany
| | - Nadja Vennewald
- Mood and Anxiety Disorders Research Unit, Department of Psychiatry and Psychotherapy, University of Muenster, Germany
| | - Patricia Ohrmann
- Mood and Anxiety Disorders Research Unit, Department of Psychiatry and Psychotherapy, University of Muenster, Germany
| | - Volker Arolt
- Mood and Anxiety Disorders Research Unit, Department of Psychiatry and Psychotherapy, University of Muenster, Germany
| | | | - Peter Zwanzger
- Mood and Anxiety Disorders Research Unit, Department of Psychiatry and Psychotherapy, University of Muenster, Germany; kbo-Inn-Salzach-Klinikum, Wasserburg am Inn, Germany; Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University of Munich, Munich, Germany.
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Spiacci A, Sergio TDO, da Silva GSF, Glass ML, Schenberg LC, Garcia-Cairasco N, Zangrossi H. Serotonin in the dorsal periaqueductal gray inhibits panic-like defensive behaviors in rats exposed to acute hypoxia. Neuroscience 2015; 307:191-8. [PMID: 26319117 DOI: 10.1016/j.neuroscience.2015.08.045] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2015] [Revised: 08/04/2015] [Accepted: 08/20/2015] [Indexed: 12/12/2022]
Abstract
It has been proposed that spontaneous panic attacks are the outcome of the misfiring of an evolved suffocation alarm system. Evidence gathered in the last years is suggestive that the dorsal periaqueductal gray (dPAG) in the midbrain harbors a hypoxia-sensitive suffocation alarm system. We here investigated whether facilitation of 5-HT-mediated neurotransmission within the dPAG changes panic-like defensive reactions expressed by male Wistar rats submitted to a hypoxia challenge (7% O2), as observed in other animal models of panic. Intra-dPAG injection of 5-HT (20 nmol), (±)-8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide (8-OH-DPAT) (8 nmol), a 5-HT1A receptor agonist, or (±)-2,5-dimethoxy-4-iodo amphetamine hydrochloride (DOI) (16 nmol), a preferential 5-HT2A agonist, reduced the number of upward jumps directed to the border of the experimental chamber during hypoxia, interpreted as escape attempts, without affecting the rats' locomotion. These effects were similar to those caused by chronic, but not acute, intraperitoneal administration of the antidepressant fluoxetine (5-15 mg/kg), or acute systemic administration of the benzodiazepine receptor agonist alprazolam (1-4 mg/kg), both drugs clinically used in the treatment of panic disorder. Our findings strengthen the view that the dPAG is a key encephalic area involved in the defensive behaviors triggered by activation of the suffocation alarm system. They also support the use of hypoxia-evoked escape as a model of respiratory-type panic attacks.
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Affiliation(s)
- A Spiacci
- Department of Pharmacology, School of Medicine of Ribeirao Preto, University of São Paulo, Avenue Bandeirantes, 3900, Ribeirão Preto CEP: 14049-900, Brazil
| | - T de Oliveira Sergio
- Department of Pharmacology, School of Medicine of Ribeirao Preto, University of São Paulo, Avenue Bandeirantes, 3900, Ribeirão Preto CEP: 14049-900, Brazil
| | - G S F da Silva
- Department of Physiology, School of Medicine of Ribeirao Preto, University of São Paulo, Ribeirão Preto, Brazil
| | - M L Glass
- Department of Physiology, School of Medicine of Ribeirao Preto, University of São Paulo, Ribeirão Preto, Brazil
| | - L C Schenberg
- Department of Physiological Sciences, Federal University of Espírito Santo, Vitória, Brazil
| | - N Garcia-Cairasco
- Department of Physiology, School of Medicine of Ribeirao Preto, University of São Paulo, Ribeirão Preto, Brazil
| | - H Zangrossi
- Department of Pharmacology, School of Medicine of Ribeirao Preto, University of São Paulo, Avenue Bandeirantes, 3900, Ribeirão Preto CEP: 14049-900, Brazil.
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31
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GABA and glutamate levels in occlusal splint-wearing males with possible bruxism. Arch Oral Biol 2015; 60:1021-9. [PMID: 25889171 DOI: 10.1016/j.archoralbio.2015.03.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2014] [Revised: 03/13/2015] [Accepted: 03/14/2015] [Indexed: 01/04/2023]
Abstract
OBJECTIVE The inhibitory neurotransmitter γ-aminobutyric acid (GABA) plays an important role in the pathophysiology of anxiety behavioural disorders such as panic disorder and post-traumatic stress disorder and is also implicated in the manifestation of tooth-grinding and clenching behaviours generally known as bruxism. In order to test whether the stress-related behaviours of tooth-grinding and clenching share similar underlying mechanisms involving GABA and other metabolites as do anxiety-related behavioural disorders, we performed a Magnetic Resonance Spectroscopy (MRS) study for accurate, in vivo metabolite quantification in anxiety-related brain regions. DESIGN MRS was performed in the right hippocampus and right thalamus involved in the hypothalamic-pituitary-adrenal axis system, together with a motor planning region (dorsal anterior cingulate cortex/pre-supplementary motor area) and right dorsolateral prefrontal cortex (DLPFC). Eight occlusal splint-wearing men (OCS) with possible tooth-grinding and clenching behaviours and nine male controls (CON) with no such behaviour were studied. RESULTS Repeated-measures ANOVA showed significant Group×Region interaction for GABA+ (p = 0.001) and glutamate (Glu) (p = 0.031). Between-group post hoc ANOVA showed significantly lower levels of GABA+ (p = 0.003) and higher levels of Glu (p = 0.002) in DLPFC of OCS subjects. These GABA+ and Glu group differences remained significant (GABA+, p = 0.049; Glu, p = 0.039) after the inclusion of anxiety as a covariate. Additionally, GABA and Glu levels in the DLPFC of all subjects were negatively related (Pearson's r = -0.75, p = 0.003). CONCLUSIONS These findings indicate that the oral behaviours of tooth-grinding and clenching, generally known as bruxism, may be associated with disturbances in brain GABAergic and glutamatergic systems.
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32
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Santos M, D'Amico D, Dierssen M. From neural to genetic substrates of panic disorder: Insights from human and mouse studies. Eur J Pharmacol 2015; 759:127-41. [PMID: 25818748 DOI: 10.1016/j.ejphar.2015.03.039] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2015] [Revised: 01/15/2015] [Accepted: 03/12/2015] [Indexed: 01/30/2023]
Abstract
Fear is an ancestral emotion, an intrinsic defensive response present in every organism. Although fear is an evolutionarily advantageous emotion, under certain pathologies such as panic disorder it might become exaggerated and non-adaptive. Clinical and preclinical work pinpoints that changes in cognitive processes, such as perception and interpretation of environmental stimuli that rely on brain regions responsible for high-level function, are essential for the development of fear-related disorders. This review focuses on the involvement of cognitive function to fear circuitry disorders. Moreover, we address how animal models are contributing to understand the involvement of human candidate genes to pathological fear and helping achieve progress in this field. Multidisciplinary approaches that integrate human genetic findings with state of the art genetic mouse models will allow to elucidate the mechanisms underlying pathology and to develop new strategies for therapeutic targeting.
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Affiliation(s)
- Mónica Santos
- Cellular & Systems Neurobiology, Systems Biology Program, Center for Genomic Regulation (CRG), E-08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), E-08003 Barcelona, Spain; CIBER de Enfermedades Raras (CIBERER), E-08003 Barcelona, Spain; Institute of Biology, Otto-von-Guericke University, 39120 Magdeburg, Germany.
| | - Davide D'Amico
- Cellular & Systems Neurobiology, Systems Biology Program, Center for Genomic Regulation (CRG), E-08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), E-08003 Barcelona, Spain; CIBER de Enfermedades Raras (CIBERER), E-08003 Barcelona, Spain; ZeClinics SL, E-08001 Barcelona, Spain.
| | - Mara Dierssen
- Cellular & Systems Neurobiology, Systems Biology Program, Center for Genomic Regulation (CRG), E-08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), E-08003 Barcelona, Spain; CIBER de Enfermedades Raras (CIBERER), E-08003 Barcelona, Spain.
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Nagamitsu S, Yamashita Y, Tanigawa H, Chiba H, Kaida H, Ishibashi M, Kakuma T, Croarkin PE, Matsuishi T. Upregulated GABA Inhibitory Function in ADHD Children with Child Behavior Checklist-Dysregulation Profile: 123I-Iomazenil SPECT Study. Front Psychiatry 2015; 6:84. [PMID: 26082729 PMCID: PMC4451796 DOI: 10.3389/fpsyt.2015.00084] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Accepted: 05/18/2015] [Indexed: 11/23/2022] Open
Abstract
The child behavior checklist-dysregulation profile (CBCL-DP) refers to a pattern of elevated scores on the attention problems, aggression, and anxiety/depression subscales of the child behavior checklist. The aim of the present study was to investigate the potential role of GABA inhibitory neurons in children with attention deficit/hyperactivity disorder (ADHD) and dysregulation assessed with a dimensional measure. Brain single photon emission computed tomography (SPECT) was performed in 35 children with ADHD using 123I-iomazenil, which binds with high affinity to benzodiazepine receptors. Iomazenil binding activities were assessed with respect to the presence or absence of a threshold CBCL-DP (a score ≥210 for the sum of the three subscales: Attention Problems, Aggression, and Anxiety/Depression). We then attempted to identify which CBCL-DP subscale explained the most variance with respect to SPECT data, using "age," "sex," and "history of maltreatment" as covariates. Significantly higher iomazenil binding activity was seen in the posterior cingulate cortex (PCC) of ADHD children with a significant CBCL-DP. The Anxiety/Depression subscale on the CBCL had significant effects on higher iomazenil binding activity in the left superior frontal, middle frontal, and temporal regions, as well as in the PCC. The present brain SPECT findings suggest that GABAergic inhibitory neurons may play an important role in the neurobiology of the CBCL-DP, in children with ADHD.
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Affiliation(s)
- Shinichiro Nagamitsu
- Department of Pediatrics and Child Health, Kurume University School of Medicine , Fukuoka , Japan
| | - Yushiro Yamashita
- Department of Pediatrics and Child Health, Kurume University School of Medicine , Fukuoka , Japan
| | - Hitoshi Tanigawa
- Department of Radiology, Kurume University School of Medicine , Fukuoka , Japan
| | - Hiromi Chiba
- Department of Psychiatry, Kurume University School of Medicine , Fukuoka , Japan
| | - Hayato Kaida
- Department of Radiology, Kurume University School of Medicine , Fukuoka , Japan
| | - Masatoshi Ishibashi
- Department of Radiology, Kurume University School of Medicine , Fukuoka , Japan
| | - Tatsuyuki Kakuma
- Biostatistics Center, Kurume University School of Medicine , Fukuoka , Japan
| | - Paul E Croarkin
- Department of Psychiatry and Psychology, Mayo Clinic, Rochester , MN , USA
| | - Toyojiro Matsuishi
- Department of Pediatrics and Child Health, Kurume University School of Medicine , Fukuoka , Japan
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Möhler H. The legacy of the benzodiazepine receptor: from flumazenil to enhancing cognition in Down syndrome and social interaction in autism. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2014; 72:1-36. [PMID: 25600365 DOI: 10.1016/bs.apha.2014.10.008] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The study of the psychopharmacology of benzodiazepines continues to provide new insights into diverse brain functions related to vigilance, anxiety, mood, epileptiform activity, schizophrenia, cognitive performance, and autism-related social behavior. In this endeavor, the discovery of the benzodiazepine receptor was a key event, as it supplied the primary benzodiazepine drug-target site, provided the molecular link to the allosteric modulation of GABAA receptors and, following the recognition of GABAA receptor subtypes, furnished the platform for future, more selective drug actions. This review has two parts. In a retrospective first part, it acknowledges the contributions to the field made by my collaborators over the years, initially at Hoffmann-La Roche in Basle and later, in academia, at the University and the ETH of Zurich. In the second part, the new frontier of GABA pharmacology, targeting GABAA receptor subtypes, is reviewed with special focus on nonsedative anxiolytics, antidepressants, analgesics, as well as enhancers of cognition in Down syndrome and attenuators of symptoms of autism spectrum disorders. It is encouraging that a clinical trial has been initiated with a partial inverse agonist acting on α5 GABAA receptors in an attempt to alleviate the cognitive deficits in Down syndrome.
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Affiliation(s)
- Hanns Möhler
- Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland; Department of Chemistry and Applied Biosciences, Federal Institute of Technology (ETH), Zurich, Switzerland.
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Farb DH, Ratner MH. Targeting the modulation of neural circuitry for the treatment of anxiety disorders. Pharmacol Rev 2014; 66:1002-32. [PMID: 25237115 DOI: 10.1124/pr.114.009126] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Anxiety disorders are a major public health concern. Here, we examine the familiar area of anxiolysis in the context of a systems-level understanding that will hopefully lead to revealing an underlying pharmacological connectome. The introduction of benzodiazepines nearly half a century ago markedly improved the treatment of anxiety disorders. These agents reduce anxiety rapidly by allosterically enhancing the postsynaptic actions of GABA at inhibitory type A GABA receptors but side effects limit their use in chronic anxiety disorders. Selective serotonin reuptake inhibitors and serotonin/norepinephrine reuptake inhibitors have emerged as an effective first-line alternative treatment of such anxiety disorders. However, many individuals are not responsive and side effects can be limiting. Research into a relatively new class of agents known as neurosteroids has revealed novel modulatory sites and mechanisms of action that are providing insights into the pathophysiology of certain anxiety disorders, potentially bridging the gap between the GABAergic and serotonergic circuits underlying anxiety. However, translating the pharmacological activity of compounds targeted to specific receptor subtypes in rodent models of anxiety to effective therapeutics in human anxiety has not been entirely successful. Since modulating any one of several broad classes of receptor targets can produce anxiolysis, we posit that a systems-level discovery platform combined with an individualized medicine approach based on noninvasive brain imaging would substantially advance the development of more effective therapeutics.
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Affiliation(s)
- David H Farb
- Laboratory of Molecular Neurobiology, Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts
| | - Marcia H Ratner
- Laboratory of Molecular Neurobiology, Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts
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Prenatal stress and inhibitory neuron systems: implications for neuropsychiatric disorders. Mol Psychiatry 2014; 19:641-51. [PMID: 24751963 PMCID: PMC4031286 DOI: 10.1038/mp.2014.35] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2013] [Revised: 03/03/2014] [Accepted: 03/10/2014] [Indexed: 01/09/2023]
Abstract
Prenatal stress is a risk factor for several psychiatric disorders in which inhibitory neuron pathology is implicated. A growing body of research demonstrates that inhibitory circuitry in the brain is directly and persistently affected by prenatal stress. This review synthesizes research that explores how this early developmental risk factor impacts inhibitory neurons and how these findings intersect with research on risk factors and inhibitory neuron pathophysiology in schizophrenia, anxiety, autism and Tourette syndrome. The specific impact of prenatal stress on inhibitory neurons, particularly developmental mechanisms, may elucidate further the pathophysiology of these disorders.
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Frontal white matter alterations in short-term medicated panic disorder patients without comorbid conditions: a diffusion tensor imaging study. PLoS One 2014; 9:e95279. [PMID: 24788587 PMCID: PMC4005735 DOI: 10.1371/journal.pone.0095279] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Accepted: 03/25/2014] [Indexed: 01/04/2023] Open
Abstract
The frontal cortex might play an important role in the fear network, and white matter (WM) integrity could be related to the pathophysiology of panic disorder (PD). A few studies have investigated alterations of WM integrity in PD. The aim of this study was to determine frontal WM integrity differences between patients with PD without comorbid conditions and healthy control (HC) subjects by using diffusion tensor imaging. Thirty-six patients with PD who had used medication within 1 week and 27 age- and sex-matched HC subjects participated in this study. Structural brain magnetic resonance imaging was performed on all participants. Panic Disorder Severity Scale and Beck Anxiety Inventory (BAI) scores were assessed. Tract-based spatial statistics (TBSS) was used for image analysis. TBSS analysis showed decreased fractional anisotropy (FA) in frontal WM and WM around the frontal lobe, including the corpus callosum of both hemispheres, in patients with PD compared to HC subjects. Moreover, voxel-wise correlation analysis revealed that the BAI scores for patients with PD were positively correlated with their FA values for regions showing group differences in the FA of frontal WM of both hemispheres. Altered integrity in frontal WM of patients with PD without comorbid conditions might represent the structural pathophysiology in these patients, and these changes could be related to clinical symptoms of PD.
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Tzanoulinou S, García-Mompó C, Castillo-Gómez E, Veenit V, Nacher J, Sandi C. Long-term behavioral programming induced by peripuberty stress in rats is accompanied by GABAergic-related alterations in the Amygdala. PLoS One 2014; 9:e94666. [PMID: 24736324 PMCID: PMC3988094 DOI: 10.1371/journal.pone.0094666] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Accepted: 03/19/2014] [Indexed: 12/25/2022] Open
Abstract
Stress during childhood and adolescence is a risk factor for psychopathology. Alterations in γ-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain, have been found following stress exposure and fear experiences and are often implicated in anxiety and mood disorders. Abnormal amygdala functioning has also been detected following stress exposure and is also implicated in anxiety and social disorders. However, the amygdala is not a unitary structure; it includes several nuclei with different functions and little is known on the potential differences the impact of early life stress may have on this system within different amygdaloid nuclei. We aimed here to evaluate potential regional differences in the expression of GABAergic-related markers across several amygdaloid nuclei in adult rats subjected to a peripuberty stress protocol that leads to enhanced basal amygdala activity and psychopathological behaviors. More specifically, we investigated the protein expression levels of glutamic acid decarboxylase (GAD; the principal synthesizing enzyme of GABA) and of GABA-A receptor subunits α2 and α3. We found reduced GAD and GABA-A α3, but not α2, subunit protein levels throughout all the amygdala nuclei examined (lateral, basolateral, basomedial, medial and central) and increased anxiety-like behaviors and reduced sociability in peripubertally stressed animals. Our results identify an enduring inhibition of the GABAergic system across the amygdala following exposure to early adversity. They also highlight the suitability of the peripuberty stress model to investigate the link between treatments targeting the dysfunctional GABAergic system in specific amygdala nuclei and recovery of specific stress-induced behavioral dysfunctions.
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Affiliation(s)
- Stamatina Tzanoulinou
- Laboratory of Behavioral Genetics, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Clara García-Mompó
- Neurobiology Unit and Program in Basic and Applied Neurosciences, Cell Biology Department, Universitat de València, Valencia, Spain
| | - Esther Castillo-Gómez
- Neurobiology Unit and Program in Basic and Applied Neurosciences, Cell Biology Department, Universitat de València, Valencia, Spain
| | - Vandana Veenit
- Laboratory of Behavioral Genetics, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Juan Nacher
- Neurobiology Unit and Program in Basic and Applied Neurosciences, Cell Biology Department, Universitat de València, Valencia, Spain
- CIBERSAM: Spanish National Network for Research in Mental Health, Madrid, Spain
- Fundacion Investigacion Hospital Clinico de Valencia, INCLIVA, Valencia, Spain
| | - Carmen Sandi
- Laboratory of Behavioral Genetics, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
- * E-mail:
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Zwanzger P, Zavorotnyy M, Gencheva E, Diemer J, Kugel H, Heindel W, Ruland T, Ohrmann P, Arolt V, Domschke K, Pfleiderer B. Acute shift in glutamate concentrations following experimentally induced panic with cholecystokinin tetrapeptide--a 3T-MRS study in healthy subjects. Neuropsychopharmacology 2013; 38:1648-54. [PMID: 23463151 PMCID: PMC3717541 DOI: 10.1038/npp.2013.61] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2012] [Revised: 02/05/2013] [Accepted: 02/08/2013] [Indexed: 01/04/2023]
Abstract
According to preclinical studies, glutamate has been implicated in the pathogenesis of anxiety. In order to elucidate the role of glutamate in anxiety and panic in humans, brain glutamate+glutamine (Glx) levels were measured during cholecystokinin-tetrapeptide (CCK-4)-induced panic using magnetic resonance spectroscopy (MRS). Eighteen healthy subjects underwent a CCK-4 challenge. MR spectra were obtained from the anterior cingulate cortex (ACC) using a single voxel point-resolved spectroscopy method and analyzed using LCModel. A combined fitting of Glx was performed. Panic was assessed using the Acute Panic Inventory (API) and Panic Symptom Scale (PSS) scores. Moreover, hypothalamic-pituitary-adrenal axis stimulation was monitored throughout the challenge. There was a significant panic response following CCK-4 as revealed by a marked increase in both the panic scores (API: F(1,17)=149.41; p<0.0001; PSS: F(1,17)=88.03; p<0.0001) and heart rate (HR: F(1,17)=72.79; p<0.0001). MRS measures showed a significant increase of brain Glx/creatine (Glx/Cr) levels peaking at 2-10 min after challenge (F(1,17)=15.94; p=0.001). There was also a significant increase in CCK-4-related cortisol release (F(6,11)=8.68; p=0.002). Finally, significant positive correlations were found between baseline Glx/Cr and both APImax (r=0.598; p=0.009) and maximum heart rate (HR(max)) during challenge (r=0.519; p=0.027). Our results suggest that CCK-4-induced panic is accompanied by a significant glutamate increase in the bilateral ACC. The results add to the hypothesis of a disturbance of the inhibitory-excitatory equilibrium and suggest that apart from static alterations rapid and dynamic neurochemical changes might also be relevant for the neural control of panic attacks.
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Affiliation(s)
- Peter Zwanzger
- Mood and Anxiety Disorders Research Unit, Department of Psychiatry and Psychotherapy, University of Muenster, Muenster, Germany.
| | - Maxim Zavorotnyy
- Mood and Anxiety Disorders Research Unit, Department of Psychiatry and Psychotherapy, University of Muenster, Muenster, Germany
| | - Elena Gencheva
- Mood and Anxiety Disorders Research Unit, Department of Psychiatry and Psychotherapy, University of Muenster, Muenster, Germany
| | - Julia Diemer
- Mood and Anxiety Disorders Research Unit, Department of Psychiatry and Psychotherapy, University of Muenster, Muenster, Germany
| | - Harald Kugel
- Department of Clinical Radiology, University of Muenster, Muenster, Germany
| | - Walter Heindel
- Department of Clinical Radiology, University of Muenster, Muenster, Germany
| | - Tillmann Ruland
- Mood and Anxiety Disorders Research Unit, Department of Psychiatry and Psychotherapy, University of Muenster, Muenster, Germany
| | - Patricia Ohrmann
- Mood and Anxiety Disorders Research Unit, Department of Psychiatry and Psychotherapy, University of Muenster, Muenster, Germany
| | - Volker Arolt
- Mood and Anxiety Disorders Research Unit, Department of Psychiatry and Psychotherapy, University of Muenster, Muenster, Germany
| | - Katharina Domschke
- Mood and Anxiety Disorders Research Unit, Department of Psychiatry and Psychotherapy, University of Muenster, Muenster, Germany,Department of Psychiatry, University of Wuerzburg, Wuerzburg, Germany
| | - Bettina Pfleiderer
- Department of Clinical Radiology, University of Muenster, Muenster, Germany
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40
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Long Z, Medlock C, Dzemidzic M, Shin YW, Goddard AW, Dydak U. Decreased GABA levels in anterior cingulate cortex/medial prefrontal cortex in panic disorder. Prog Neuropsychopharmacol Biol Psychiatry 2013; 44:131-5. [PMID: 23391588 PMCID: PMC3758115 DOI: 10.1016/j.pnpbp.2013.01.020] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2012] [Revised: 01/29/2013] [Accepted: 01/29/2013] [Indexed: 12/18/2022]
Abstract
Changes of various brain metabolites including γ-aminobutyric acid (GABA), measured by 1H-magnetic resonance spectroscopy (MRS), have been reported in panic disorder (PD). Deficits in GABA have been implicated in the pathophysiology of PD. Furthermore, it has been suggested that cortical metabolite changes in PD are familial. Eleven PD patients, including five with and six without a PD family history, and eight age- and gender-matched healthy controls without a family history of psychopathology were recruited. Each subject underwent MRS exams and behavioral assessments (resting visual analog anxiety level and the Panic Disorder Severity Scale). GABA was detected with a MEGA-PRESS J-editing sequence and fitted to minimize macromolecule contaminations. A significant decrease in GABA, expressed as the ratio of GABA over total creatine (GABA/tCr), was detected in the anterior cingulate cortex (ACC)/medial prefrontal cortex (mPFC) in PD patients (p<0.05), which tends to be pronounced in patients with a PD family history. No other patient/control differences in metabolites were noted in the ACC/mPFC or occipital cortex (OCC). Overall, our results indicate that deficits in GABA levels in PD patients vary by brain regions and possibly by family history status.
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Affiliation(s)
- Zaiyang Long
- School of Health Sciences, Purdue University, West Lafayette, IN, United States,Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Carla Medlock
- Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Mario Dzemidzic
- Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, United States,Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Yong-Wook Shin
- Department of Psychiatry, Ulsan University School of Medicine, Seoul, Republic of Korea
| | - Andrew W. Goddard
- Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, United States,Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Ulrike Dydak
- School of Health Sciences, Purdue University, West Lafayette, IN, United States,Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, United States,Corresponding author at: School of Health Sciences, Purdue University, 550 Stadium Mall Drive, West Lafayette, IN 47907, United States. Tel.: +1 765 494 0550, (U. Dydak)
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Koester C, Rudolph U, Haenggi T, Papilloud A, Fritschy JM, Crestani F. Dissecting the role of diazepam-sensitive γ-aminobutyric acid type A receptors in defensive behavioral reactivity to mild threat. Pharmacol Biochem Behav 2012; 103:541-9. [PMID: 23067879 DOI: 10.1016/j.pbb.2012.10.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2012] [Revised: 10/01/2012] [Accepted: 10/06/2012] [Indexed: 12/21/2022]
Abstract
Moderate reductions in synaptic γ-aminobutyric acid(A) receptors (GABA(A)Rs) have been associated with an enhanced defensive behavioral reactivity to mild threat, sensitive to diazepam. We here tested whether a deficit in α2 subunit-containing GABAergic synapses is sufficient to cause this anxiety-related phenotype and to prevent its attenuation by the benzodiazepine. Wild type (α2+/+), heterozygous (α2+/-) and homozygous (α2-/-) knock-out littermates were tested in the free-choice exploratory (FCE) and the light/dark choice (LDC) paradigms. α2-/- mice, double mutant α1H101Rα2-/- and α3H126Rα2-/- mice, which combine a lack of α2-GABA(A)Rs with point-mutated diazepam-insensitive either α1H101R or α3H126R-GABA(A)Rs, and double point-mutated α1H101Rα2H101R and α1H101Rα3H126R mice were used to uncover the GABA(A)R subtype(s) mediating the drug effects. Data show that in the FCE, α2-/- mice exhibited more retractions (i.e. risk assessment) and longer latencies to first occurrence into the novel compartment and less transitions and time spent inside it in comparison to α2+/- and α2+/+ mice. In the LDC, α2-/- mice visited and spent less time in the lit box and stayed longer in the tunnel than the other two groups. Minor differences were found between α2+/- and α2+/+ mice in the two paradigms. Diazepam (1.5mg/kg per os) normalized retractions and latencies in the FCE in α2-/- and α3H126Rα2-/- mice, but not in α1H101Rα2-/- mice. The same drug treatment failed to attenuate behavioral aversion in both paradigms in all mutants with impaired α2-GABA(A)R function. These results reveal α2-containing GABA(A)Rs as key molecular determinants in the regulation of anxiety-related responses elicited by exposure to relative novelty and mild threat. In the absence of these receptors, diazepam through activation of α1-GABA(A)Rs remains effective in reducing risk assessment, but not behavioral aversion.
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Affiliation(s)
- Christina Koester
- Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
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Abstract
Depression is a term that has been used to describe a variety of ailments, ranging from minor to incapacitating. Clinically significant depression, termed as major depression, is a serious condition characterized not only by depressed mood but also by a cluster of somatic, cognitive, and motivational symptoms. Significant research efforts are aimed to understand the neurobiological as well as psychiatric disorders, and the evaluation of treatment of these disorders is still based solely on the assessment of symptoms. In order to identify the biological markers for depression, we have focused on gathering information on different factors responsible for depression including stress, genetic variations, neurotransmitters, and cytokines and chemokines previously suggested to be involved in the pathophysiology of depression. The present review illustrates the potential of biomarker profiling for psychiatric disorders, when conducted in large collections. The review highlighted the biomarker signatures for depression, warranting further investigation.
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Affiliation(s)
- Anand Tamatam
- Biochemistry and Nutrition Discipline, Defence Food Research Laboratory, Siddarthanagar, Mysore, India
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Revise the revised? New dimensions of the neuroanatomical hypothesis of panic disorder. J Neural Transm (Vienna) 2012; 120:3-29. [PMID: 22692647 DOI: 10.1007/s00702-012-0811-1] [Citation(s) in RCA: 121] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2012] [Accepted: 04/16/2012] [Indexed: 12/14/2022]
Abstract
In 2000, Gorman et al. published a widely acknowledged revised version of their 1989 neuroanatomical hypothesis of panic disorder (PD). Herein, a 'fear network' was suggested to mediate fear- and anxiety-related responses: panic attacks result from a dysfunctional coordination of 'upstream' (cortical) and 'downstream' (brainstem) sensory information leading to heightened amygdala activity with subsequent behavioral, autonomic and neuroendocrine activation. Given the emergence of novel imaging methods such as fMRI and the publication of numerous neuroimaging studies regarding PD since 2000, a comprehensive literature search was performed regarding structural (CT, MRI), metabolic (PET, SPECT, MRS) and functional (fMRI, NIRS, EEG) studies on PD, which will be reviewed and critically discussed in relation to the neuroanatomical hypothesis of PD. Recent findings support structural and functional alterations in limbic and cortical structures in PD. Novel insights regarding structural volume increase or reduction, hyper- or hypoactivity, laterality and task-specificity of neural activation patterns emerged. The assumption of a generally hyperactive amygdala in PD seems to apply more to state than trait characteristics of PD, and involvement of further areas in the fear circuit, such as anterior cingulate and insula, is suggested. Furthermore, genetic risk variants have been proposed to partly drive fear network activity. Thus, the present state of knowledge generally supports limbic and cortical prefrontal involvement as originally proposed in the neuroanatomical hypothesis. Some modifications might be suggested regarding a potential extension of the fear circuit, genetic factors shaping neural network activity and neuroanatomically informed clinical subtypes of PD potentially guiding future treatment decisions.
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44
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Sinclair LI, Dineen PT, Malizia AL. Modulation of ion channels in clinical psychopharmacology: adults and younger people. Expert Rev Clin Pharmacol 2012; 3:397-416. [PMID: 22111619 DOI: 10.1586/ecp.10.21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
This review focuses on the use of Na(+), Ca(2+) and Cl(-) channel modulators in psychiatric disease. Drugs that modulate ion channels have been used in psychiatry for more than a century, and in this review we critically evaluate clinical research that reports the therapeutic effects of drugs acting on GABA(A), voltage-gated Na(+) and voltage-gated Ca(2+) channels in pediatric and adult patients. As in other fields, the evidence underpinning the use of medicines in younger people is far less robust than for adults. In addition, we discuss some current developments and highlight clinical disorders in which current molecules could be further tested. Notable success stories, such as benzodiazepines (in sleep and anxiety disorders) and antiepileptics (in bipolar disorder), have been the result of serendipitous discoveries or refinements of serendipitous discoveries, as in all other major treatments in psychiatry. Genomic, high-throughput screening and molecular pharmacology discoveries may, however, guide further developments in the future. This could include increased research in promising targets that have been perceived as commercially risky, such as selective α-subunit GABA(A) receptors.
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Affiliation(s)
- Lindsey I Sinclair
- Psychopharmacology Unit, Department of Community Based Medicine, University of Bristol, Bristol, UK
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45
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Maddock RJ, Buonocore MH. MR spectroscopic studies of the brain in psychiatric disorders. Curr Top Behav Neurosci 2012; 11:199-251. [PMID: 22294088 DOI: 10.1007/7854_2011_197] [Citation(s) in RCA: 154] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/15/2023]
Abstract
The measurement of brain metabolites with magnetic resonance spectroscopy (MRS) provides a unique perspective on the brain bases of neuropsychiatric disorders. As a context for interpreting MRS studies of neuropsychiatric disorders, we review the characteristic MRS signals, the metabolic dynamics,and the neurobiological significance of the major brain metabolites that can be measured using clinical MRS systems. These metabolites include N-acetylaspartate(NAA), creatine, choline-containing compounds, myo-inositol, glutamate and glutamine, lactate, and gamma-amino butyric acid (GABA). For the major adult neuropsychiatric disorders (schizophrenia, bipolar disorder, major depression, and the anxiety disorders), we highlight the most consistent MRS findings, with an emphasis on those with potential clinical or translational significance. Reduced NAA in specific brain regions in schizophrenia, bipolar disorder, post-traumatic stress disorder, and obsessive–compulsive disorder corroborate findings of reduced brain volumes in the same regions. Future MRS studies may help determine the extent to which the neuronal dysfunction suggested by these findings is reversible in these disorders. Elevated glutamate and glutamine (Glx) in patients with bipolar disorder and reduced Glx in patients with unipolar major depression support models of increased and decreased glutamatergic function, respectively, in those conditions. Reduced phosphomonoesters and intracellular pH in bipolar disorder and elevated dynamic lactate responses in panic disorder are consistent with metabolic models of pathogenesis in those disorders. Preliminary findings of an increased glutamine/glutamate ratio and decreased GABA in patients with schizophrenia are consistent with a model of NMDA hypofunction in that disorder. As MRS methods continue to improve, future studies may further advance our understanding of the natural history of psychiatric illnesses, improve our ability to test translational models of pathogenesis, clarify therapeutic mechanisms of action,and allow clinical monitoring of the effects of interventions on brain metabolicmarkers
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The GABA system in anxiety and depression and its therapeutic potential. Neuropharmacology 2012; 62:42-53. [DOI: 10.1016/j.neuropharm.2011.08.040] [Citation(s) in RCA: 348] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2011] [Accepted: 08/23/2011] [Indexed: 01/01/2023]
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Panic disorder. ACTA ACUST UNITED AC 2012; 106:363-74. [DOI: 10.1016/b978-0-444-52002-9.00020-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/07/2023]
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Lai CH, Wu YT. Duloxetine's modest short-term influences in subcortical structures of first episode drug-naïve patients with major depressive disorder and panic disorder. Psychiatry Res 2011; 194:157-62. [PMID: 21820879 DOI: 10.1016/j.pscychresns.2011.03.011] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2010] [Revised: 03/08/2011] [Accepted: 03/26/2011] [Indexed: 12/22/2022]
Abstract
We developed this study to follow up the hanges in subcortical structures after 6 weeks' treatment with therapy of duloxetine in first episode drug-naïve patients with major depressive disorder and panic disorder. Fifteen patients received duloxetine 60mg/d therapy for 6 weeks and achieved remission. They all underwent structural magnetic resonance imaging (MRI) of the brain at baseline and week 6. Fifteen healthy controls were also scanned twice at baseline and week 6 to exclude possible biases. Structural MRI data were preprocessed with FMRIB's Integrated Registration and Segmentation Tool function (FIRST version 1.2) of FSL (FMRIB Software Library; version 4.1.1) to perform subcortical segmentations of the brain using a shape and appearance model. Nonparametric corrections of these structural volumes in an F-test between pre- and post-treatment were used to identify the changes after duloxetine therapy. A false discovery correction of the F-test by FIRST was also performed. A paired t-test using SPSS was applied to confirm the changes in these structures. The patients had consistent changes of volumes in bilateral nucleus accumbens, left putamen, left hippocampus and brainstem after 6 weeks of treatment with duloxetine. There were no consistent changes in other subcortical structures. There were modest increases of the volumes of the above areas, which were not significant after false discovery correction by FIRST F-test comparisons. The volumetric increases were correlated with responses of clinical symptoms. The results suggested that duloxetine possibly contributed to modest increases in several subcortical areas of these patients with remission.
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Affiliation(s)
- Chien-Han Lai
- Department of Psychiatry, Buddhist Tzu-Chi General Hospital, Taipei Branch, Taipei, Taiwan.
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Maron E, Tõru I, Hirvonen J, Tuominen L, Lumme V, Vasar V, Shlik J, Nutt DJ, Helin S, Någren K, Tiihonen J, Hietala J. Gender differences in brain serotonin transporter availability in panic disorder. J Psychopharmacol 2011; 25:952-9. [PMID: 21148024 DOI: 10.1177/0269881110389207] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
The role of the serotonin (5-HT) system in the neurobiology and treatment of panic disorder (PD) remains unproven. Previously we detected lower brain 5-HT transporter (SERT) availability in PD, but the findings were preliminary and mainly limited to female patients. The aim of this study was to assess non-displaceable brain SERT binding potential (BP (ND)) in male and female patients with PD. The SERT BP (ND) was measured in groups of patients with PD (five males and six females) and matched healthy control subjects (12 males and 12 females) using positron emission tomography (PET) and [¹¹C]MADAM tracer. SERT BP (ND) were significantly higher in 13 of 20 studied brain regions, including several cortical and raphe areas, but lower in the hippocampus in males with PD as compared with healthy males. No significant differences in SERT BP (ND) were observed between female patients and controls. The results suggest gender-dependent regional differences in brain SERT availability and converge with previous PET findings of reduced 5-HT(1A) receptor binding in similar brain areas in PD. Distinctive functioning of the 5-HT system in males and females may underlie certain gender-dependent differences in expressions of PD.
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Affiliation(s)
- Eduard Maron
- Department of Neuropsychopharmacology and Molecular Imaging, Imperial College London, London, UK.
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