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1
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Gouda M, Ganesh CB. Food intake and the HPT axis in the cichlid fish: The implications of the gut-brain peptide cholecystokinin. Comp Biochem Physiol A Mol Integr Physiol 2025; 302:111813. [PMID: 39814128 DOI: 10.1016/j.cbpa.2025.111813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 12/28/2024] [Accepted: 01/12/2025] [Indexed: 01/18/2025]
Abstract
This work aimed to investigate the response of cholecystokinin (CCK) to starvation and its impact on food intake and the reproductive axis of the tilapia Oreochromis mossambicus. The fish subjected to 21 days of starvation showed a significant decrease in CCK immunoreactivity in the hypothalamus, pituitary gland, and intestine. The administration of injections of 0.5 and 5 μg of sulfated CCK-8 (CCK-8S) over 21 days resulted in a significant, dose-dependent decrease in food consumption. Administration of a high dose of CCK-8S (5 μg) caused a substantial decrease in the number of various spermatogenic cells, the intensity of androgen receptor immunoreactivity in the testis, and the percentage area of GnRH-immunoreactive fibres in the pars distalis of the pituitary gland (PPD), concurrent with a significant decline in serum levels of luteinizing hormone (LH) and 11-ketotestosterone (11-KT). Moreover, CCK-8S treatment markedly reduced the in vitro testicular 11-KT level. The findings indicate for the first time that CCK influences hypothalamic GnRH release into the pituitary gland, resulting in the inhibition of LH release from the pituitary and affecting testicular spermatogenesis, androgen receptor protein expression, and steroidogenesis in teleosts. In addition, CCK may also directly affect testicular steroidogenesis.
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Affiliation(s)
- Mallikarjun Gouda
- Neuroendocrinology Research Laboratory, Department of Studies in Zoology, Karnatak University, Dharwad 580 003, India
| | - C B Ganesh
- Neuroendocrinology Research Laboratory, Department of Studies in Zoology, Karnatak University, Dharwad 580 003, India.
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2
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Grieco SF, Johnston KG, Gao P, Garduño BM, Tang B, Yi E, Sun Y, Horwitz GD, Yu Z, Holmes TC, Xu X. Anatomical and molecular characterization of parvalbumin-cholecystokinin co-expressing inhibitory interneurons: implications for neuropsychiatric conditions. Mol Psychiatry 2023; 28:5293-5308. [PMID: 37443194 DOI: 10.1038/s41380-023-02153-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 05/15/2023] [Accepted: 06/19/2023] [Indexed: 07/15/2023]
Abstract
Inhibitory interneurons are crucial to brain function and their dysfunction is implicated in neuropsychiatric conditions. Emerging evidence indicates that cholecystokinin (CCK)-expressing interneurons (CCK+) are highly heterogenous. We find that a large subset of parvalbumin-expressing (PV+) interneurons express CCK strongly; between 40 and 56% of PV+ interneurons in mouse hippocampal CA1 express CCK. Primate interneurons also exhibit substantial PV/CCK co-expression. Mouse PV+/CCK+ and PV+/CCK- cells show distinguishable electrophysiological and molecular characteristics. Analysis of single nuclei RNA-seq and ATAC-seq data shows that PV+/CCK+ cells are a subset of PV+ cells, not of synuclein gamma positive (SNCG+) cells, and that they strongly express oxidative phosphorylation (OXPHOS) genes. We find that mitochondrial complex I and IV-associated OXPHOS gene expression is strongly correlated with CCK expression in PV+ interneurons at both the transcriptomic and protein levels. Both PV+ interneurons and dysregulation of OXPHOS processes are implicated in neuropsychiatric conditions, including autism spectrum (ASD) disorder and schizophrenia (SCZ). Analysis of human brain samples from patients with these conditions shows alterations in OXPHOS gene expression. Together these data reveal important molecular characteristics of PV-CCK co-expressing interneurons and support their implication in neuropsychiatric conditions.
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Affiliation(s)
- Steven F Grieco
- Department of Anatomy and Neurobiology, School of Medicine, University of California, Irvine, CA, 92697, USA
- Center for Neural Circuit Mapping, University of California, Irvine, CA, 92697, USA
| | - Kevin G Johnston
- Department of Anatomy and Neurobiology, School of Medicine, University of California, Irvine, CA, 92697, USA
- Department of Mathematics, School of Physical Sciences, University of California, Irvine, CA, 92697, USA
| | - Pan Gao
- Department of Anatomy and Neurobiology, School of Medicine, University of California, Irvine, CA, 92697, USA
| | - B Maximiliano Garduño
- Department of Anatomy and Neurobiology, School of Medicine, University of California, Irvine, CA, 92697, USA
| | - Bryan Tang
- Department of Anatomy and Neurobiology, School of Medicine, University of California, Irvine, CA, 92697, USA
| | - Elsie Yi
- Department of Anatomy and Neurobiology, School of Medicine, University of California, Irvine, CA, 92697, USA
| | - Yanjun Sun
- Department of Anatomy and Neurobiology, School of Medicine, University of California, Irvine, CA, 92697, USA
| | - Gregory D Horwitz
- Center for Neural Circuit Mapping, University of California, Irvine, CA, 92697, USA
- Department of Physiology and Biophysics, University of Washington, Seattle, WA, 98195, USA
| | - Zhaoxia Yu
- Center for Neural Circuit Mapping, University of California, Irvine, CA, 92697, USA
- Department of Statistics, Donald Bren School of Information and Computer Sciences, University of California, Irvine, CA, 92697, USA
| | - Todd C Holmes
- Center for Neural Circuit Mapping, University of California, Irvine, CA, 92697, USA
- Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, CA, 92697, USA
| | - Xiangmin Xu
- Department of Anatomy and Neurobiology, School of Medicine, University of California, Irvine, CA, 92697, USA.
- Center for Neural Circuit Mapping, University of California, Irvine, CA, 92697, USA.
- Department of Microbiology and Molecular Genetics, University of California, Irvine, CA, 92697, USA.
- Department of Biomedical Engineering, University of California, Irvine, CA, 92697, USA.
- Department of Computer Science, University of California, Irvine, CA, 92697, USA.
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3
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CCK2 receptors in chronic pain. NEUROBIOLOGY OF PAIN 2022; 11:100092. [PMID: 35571964 PMCID: PMC9097710 DOI: 10.1016/j.ynpai.2022.100092] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 04/22/2022] [Accepted: 05/02/2022] [Indexed: 11/21/2022]
Abstract
CCK2R is a historic target for pain management that has shown limited success. We review CCK2Rs and their role in peripheral and central circuits in chronic pain. We discuss the interactions between CCK2Rs and opioids. We highlight recent drug discovery efforts targeting CCK2R for chronic pain. The cholecystokinin receptor system, specifically cholecystokinin 2 receptor (CCK2R) is a historic target for pain management that has shown limited success. However, new approaches to target CCK2R have incited fresh enthusiasm for this target. In this mini-review, we discuss what is known about CCK2R in peripheral and central circuits under naïve physiological conditions and under conditions of chronic pain, the interactions of CCK2Rs with opioids and briefly, recent efforts to develop new treatments targeting CCK2R for chronic pain.
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4
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The Cholecystokinin Type 2 Receptor, a Pharmacological Target for Pain Management. Pharmaceuticals (Basel) 2021; 14:ph14111185. [PMID: 34832967 PMCID: PMC8618735 DOI: 10.3390/ph14111185] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 11/16/2021] [Accepted: 11/18/2021] [Indexed: 02/06/2023] Open
Abstract
Over the past decades, accumulating evidence has demonstrated a pivotal role of cholecystokinin type 2 receptor (CCK2R) in pain modulation. The established role of CCK2R activation in directly facilitating nociception has led to the development of several CCK2R antagonists, which have been shown to successfully alleviate pain in several rodent models of pain. However, the outcomes of clinical trials are more modest since they have not demonstrated the expected biological effect obtained in animals. Such discordances of results between preclinical and clinical studies suggest reconsidering our knowledge about the molecular basis of the pharmacology and functioning of CCK2R. This review focuses on the cellular localization of CCK2R specifically in the sensory nervous system and discusses in further detail the molecular mechanisms and signal transduction pathways involved in controlling pain perception. We then provide a comprehensive overview of the most successful compounds targeting CCK2R and report recent advances in pharmacological strategies used to achieve CCK2R modulation. We purposely distinguish between CCK2R benefits obtained in preclinical models and outcomes in clinical trials with different pain etiologies. Lastly, we emphasize the biological and clinical relevance of CCK2R as a promising target for the development of new treatments for pain management.
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Rehfeld JF. Cholecystokinin and Panic Disorder: Reflections on the History and Some Unsolved Questions. Molecules 2021; 26:5657. [PMID: 34577128 PMCID: PMC8469898 DOI: 10.3390/molecules26185657] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 09/08/2021] [Accepted: 09/14/2021] [Indexed: 12/12/2022] Open
Abstract
The classic gut hormone cholecystokinin (CCK) and its CCK2-receptor are expressed in almost all regions of the brain. This widespread expression makes CCK by far the most abundant peptidergic transmitter system in the brain. This CNS-ubiquity has, however, complicated the delineation of the roles of CCK peptides in normal brain functions and neuropsychiatric diseases. Nevertheless, the common panic disorder disease is apparently associated with CCK in the brain. Thus, the C-terminal tetrapeptide fragment of CCK (CCK-4) induces, by intravenous administration in a dose-related manner, panic attacks that are similar to the endogenous attacks in panic disorder patients. This review describes the history behind the discovery of the panicogenic effect of CCK-4. Subsequently, the review discusses three unsettled questions about the involvement of cerebral CCK in the pathogenesis of anxiety and panic disorder, including therapeutic attempts with CCK2-receptor antagonists.
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Affiliation(s)
- Jens F Rehfeld
- Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark
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6
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Huang Z, Tatti R, Loeven AM, Landi Conde DR, Fadool DA. Modulation of Neural Microcircuits That Control Complex Dynamics in Olfactory Networks. Front Cell Neurosci 2021; 15:662184. [PMID: 34239417 PMCID: PMC8259627 DOI: 10.3389/fncel.2021.662184] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 05/10/2021] [Indexed: 11/13/2022] Open
Abstract
Neuromodulation influences neuronal processing, conferring neuronal circuits the flexibility to integrate sensory inputs with behavioral states and the ability to adapt to a continuously changing environment. In this original research report, we broadly discuss the basis of neuromodulation that is known to regulate intrinsic firing activity, synaptic communication, and voltage-dependent channels in the olfactory bulb. Because the olfactory system is positioned to integrate sensory inputs with information regarding the internal chemical and behavioral state of an animal, how olfactory information is modulated provides flexibility in coding and behavioral output. Herein we discuss how neuronal microcircuits control complex dynamics of the olfactory networks by homing in on a special class of local interneurons as an example. While receptors for neuromodulation and metabolic peptides are widely expressed in the olfactory circuitry, centrifugal serotonergic and cholinergic inputs modulate glomerular activity and are involved in odor investigation and odor-dependent learning. Little is known about how metabolic peptides and neuromodulators control specific neuronal subpopulations. There is a microcircuit between mitral cells and interneurons that is comprised of deep-short-axon cells in the granule cell layer. These local interneurons express pre-pro-glucagon (PPG) and regulate mitral cell activity, but it is unknown what initiates this type of regulation. Our study investigates the means by which PPG neurons could be recruited by classical neuromodulators and hormonal peptides. We found that two gut hormones, leptin and cholecystokinin, differentially modulate PPG neurons. Cholecystokinin reduces or increases spike frequency, suggesting a heterogeneous signaling pathway in different PPG neurons, while leptin does not affect PPG neuronal firing. Acetylcholine modulates PPG neurons by increasing the spike frequency and eliciting bursts of action potentials, while serotonin does not affect PPG neuron excitability. The mechanisms behind this diverse modulation are not known, however, these results clearly indicate a complex interplay of metabolic signaling molecules and neuromodulators that may fine-tune neuronal microcircuits.
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Affiliation(s)
- Zhenbo Huang
- Program in Neuroscience, Florida State University, Tallahassee, FL, United States
| | - Roberta Tatti
- Program in Neuroscience, Florida State University, Tallahassee, FL, United States
| | - Ashley M Loeven
- Cell and Molecular Biology Program, Department of Biological Science, Florida State University, Tallahassee, FL, United States
| | - Daniel R Landi Conde
- Program in Neuroscience, Florida State University, Tallahassee, FL, United States
| | - Debra Ann Fadool
- Program in Neuroscience, Florida State University, Tallahassee, FL, United States.,Cell and Molecular Biology Program, Department of Biological Science, Florida State University, Tallahassee, FL, United States.,Institute of Molecular Biophysics, Florida State University, Tallahassee, FL, United States
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7
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Abstract
The birth certificate for endocrinology was Bayliss' and Starling's demonstration in 1902 that regulation of bodily functions is not only neuronal but also due to blood-borne messengers. Starling named these messengers hormones. Since then transport via blood has defined hormones. This definition, however, may be too narrow. Thus, today we know that several peptide hormones are not only produced and released to blood from endocrine cells but also released from neurons, myocytes, immune cells, endothelial cells, spermatogenic cells, fat cells, etc. And they are often secreted in cell-specific molecular forms with more or less different spectra of activity. The present review depicts this development with the story about cholecystokinin which was discovered in 1928 as a hormone and still in 1976 was conceived as a single blood-borne peptide. Today's multifaceted picture of cholecystokinin suggests that time may be ripe for expansion of the hormone concept to all messenger molecules, which activate their target cells - irrespective of their road to the target (endocrine, neurocrine, neuronal, paracrine, autocrine, etc.) and irrespective of their kind of activity as classical hormone, growth factor, neurotransmitter, adipokine, cytokine, myokine, or fertility factor.
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Affiliation(s)
- Jens F Rehfeld
- Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- Correspondence should be addressed to J F Rehfeld:
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8
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Schade R, Hlinak A, Marburger A, Henklein P, Morgenstern R, Blankenstein P, Gerl M, Zott A, Pfister C, Erhard M. Advantages of Using Egg Yolk Antibodies in the Life Sciences: The Results of Five Studies. Altern Lab Anim 2020. [DOI: 10.1177/026119299702500512] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
It has been known for over a century that specific antibodies can be extracted from the eggs of immunised chickens. However, it was only when animal welfare became a subject of public debate that the chicken was considered as an alternative source of antibodies due to the possibility of non-invasive antibody sampling. Unfortunately, the welfare of animals alone is not sufficient to attract the interest of scientists; it is therefore important to demonstrate to potential users that avian antibodies can be used successfully in a variety of scientific investigations. The particular specificity of avian antibodies would appear to be due to the phylogenetic difference between Mammalia and Aves as well as to differences between the molecular structures of avian immunoglobulin (IgY) and mammalian immunoglobulin (IgG). The use of avian antibodies has additional advantages, as a considerable quantity of antibodies can be obtained from one chicken, and because the specificity of avian antibodies often markedly differs from that of comparable mammalian antibodies. This paper aims to demonstrate the advantages of using avian antibodies by presenting the results of five separate studies. In the first study, coordinated by Rüdiger Schade, the visualisation of cholecystokinin-like immuno-reactivity in the substantia nigra of rats by using anti-cholecystokinin antibody, without the pre-treatment of colchicine, is described. The second study, headed by Albrecht Zott, describes the use of avian antibodies in the identification of modern acellular pertussis vaccines by using rocket immunoelectrophoresis. The identification of unknown vaccine batches and the comparison with reference vaccines is a prerequisite for reducing the number of animal experiments necessary for vaccine control. The third study, coordinated by Martin Gerl, investigates the specificity of antibodies directed against the N-terminal propeptide of procollagen type III (PIIINP). Among the antibodies originating from different species (rabbit, mouse and chicken), only the chicken antibody was able to respond to the PIIINP in both human and rat sera. Thus, a direct comparison between human serum samples (alcoholic liver) and serum samples derived from corresponding animal models was possible. The fourth study, coordinated by Michael Erhard, shows that egg yolk antibodies can be successfully used to manage infectious diarrhoea in young agricultural animals. The final study, led by Andreas Hlinak, describes the successful production of anti-bovine leukaemia virus antibody. This antibody could be used in several diagnostic systems (for example, enzyme immunoassays and cytology). The five studies demonstrate that avian antibodies are an attractive alternative to mammalian antibodies, not only with respect to the welfare of animals, but also with respect to scientific and economic considerations.
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Affiliation(s)
- Rüdiger Schade
- Institute of Pharmacology and Toxicology, Department of Medicine (Charité), Humboldt University, Dorotheenstrasse 94, 10117 Berlin, Germany
| | - Andreas Hlinak
- Institute of Virology, Department of Veterinary Medicine, Free University, Luisenstrasse 56, 10117 Berlin, Germany
| | - Andrea Marburger
- Institute of Pharmacology and Toxicology, Department of Medicine (Charité), Humboldt University, Dorotheenstrasse 94, 10117 Berlin, Germany
| | - Peter Henklein
- Institute of Biochemistry, Department of Medicine (Charité), Humboldt University, Dorotheenstrasse 94, 10117 Berlin, Germany
| | - Rudolf Morgenstern
- Institute of Pharmacology and Toxicology, Department of Medicine (Charité), Humboldt University, Dorotheenstrasse 94, 10117 Berlin, Germany
| | - Petra Blankenstein
- Institute of Virology, Department of Veterinary Medicine, Free University, Luisenstrasse 56, 10117 Berlin, Germany
| | - Martin Gerl
- Hoechst AG, TD Metabolism, H821, Postfach 800320, 65926 Frankfurt am Main, Germany
| | - Albrecht Zott
- Paul Ehrlich Institute, Paul Ehrlich Strasse 51–59, 63225 Langen, Germany
| | - Claus Pfister
- German Institute of Human Nutrition, Bergholz-Rehbrücke
| | - Michael Erhard
- Institute of Physiology, Physiological Chemistry and Animal Nutrition, Department of Veterinary Medicine, Ludwig Maximilians University, Veterinärstrasse 13, 80539 Munich, Germany
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9
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Abstract
SummaryThe role of the neuropeptide cholecystokinin in schizophrenia has been widely explored because of its modulating action on midbrain dopamine neurons. The recent discovery of more specific receptor subtype cholecystokinin antagonists should be considered as potential treatment for schizophrenia with fewer side effects. This paper reviews cholecystokinin/dopamine interactions in animal and human studies. Clinical trials with cholecystokinin agonists and antagonists in schizophrenia are updated.
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10
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Sheng N, Zheng H, Li M, Li M, Wang Z, Peng Y, Yu H, Zhang J. 4,5 caffeoylquinic acid and scutellarin, identified by integrated metabolomics and proteomics approach as the active ingredients of Dengzhan Shengmai, act against chronic cerebral hypoperfusion by regulating glutamatergic and GABAergic synapses. Pharmacol Res 2020; 152:104636. [PMID: 31926275 DOI: 10.1016/j.phrs.2020.104636] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 12/06/2019] [Accepted: 01/07/2020] [Indexed: 02/06/2023]
Abstract
Dengzhan Shengmai (DZSM) is a proprietary Chinese medicine for remarkable curative effect as a treatment of cerebrovascular diseases, such as chronic cerebral hypoperfusion (CCH) and dementia based on evidence-based medicine, which have been widely used in the recovery period of ischemic cerebrovascular diseases. The purpose of this study was to investigate the active substances and mechanism of DZSM against CCH. Integrative metabolomic and proteomic studies were performed to investigate the neuroprotective effect of DZSM based on CCH model rats. The exposed components of DZSM in target brain tissue were analysed by a high-sensitivity HPLC-MS/MS method, and the exposed components were tested on a glutamate-induced neuronal excitatory damage cell model for the verification of active ingredients and mechanism of DZSM. Upon proteomic and metabolomic analysis, we observed a significant response in DZSM therapy from the interconnected neurotransmitter transport pathways including glutamatergic and GABAergic synapses. Additionally, DZSM had a significant regulatory effect on glutamate and GABA-related proteins including vGluT1 and vIAAT, suggested that DZSM could be involved in the vesicle transport of excitatory and inhibitory neurotransmitters in the pre-synaptic membrane. DZSM could also regulated the metabolism of arachidonic acid (AA), phospholipids, lysophospholipids and the expression of phospholipase A2 in post-synaptic membrane. The results of glutamate-induced neuronal excitatory injury cell model experiment for verification of active ingredients and mechanism of DZSM showed that there are five active ingredients, and among them, 4,5 caffeoylquinic acid (4,5-CQA) and scutellarin (SG) could simultaneously affect the GABAergic and glutamatergic synaptic metabolism as well as the related receptors, the NR2b subunit of NMDA and the α1 subunit of GABAA. The active ingredients of DZSM could regulate the over-expression of the NMDA receptor, enhance the expression of the GABAA receptor, resist glutamate-induced neuronal excitatory damage, and finally maintain the balance of excitatory and inhibitory synaptic metabolism dominated by glutamate and GABA. Furtherly, we compared the efficacy of DZSM, 4,5-CQA, SG and the synergistic effect of 4,5-CQA and SG, and the results showed that all the groups significantly improved cell viability compared with the model group (p < 0.001). The western blot results showed that DZSM, 4,5-CQA, SG and 4,5-CQA/SG co-administration groups could significantly regulate the expression of receptors (GABAA α1 and NR2b subunit of NMDA) and synaptic-related proteins, such as Sv2a, Syp, Slc17a7, bin1 and Prkca, respectively. These results proved DZSM and its active ingredients (4,5-CQA and SG) had the effect of regulating glutamatergic and GABAergic synapses. Finally, membrane potential FLIPR assay of 4,5-CQA and SG was used for GABRA1 activity test, and it was found that the two compounds could increase GABA-induced activation of GABRA1 receptor (GABA 10 μM) in a dose-dependent manner with EC50 value of 48.74 μM and 29.77 μM, respectively. Manual patch clamp method was used to record NMDA NR1/NR2B subtype currents, and scutellarin could cause around 10 % blockade at 10 μM (p＜0.05 compared with the control group). These studies provided definitive clues of the mechanism for the neuroprotective effect of DZSM for CCH treatment and the active compounds regulating glutamatergic and GABAergic synapses. Additionally, 4,5-CQA and SG might be potential drugs for the treatment of neurodegenerative disease related to CCH.
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Affiliation(s)
- Ning Sheng
- Institute: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China
| | - Hao Zheng
- Institute: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China
| | - Min Li
- Institute: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China
| | - Menglin Li
- Institute: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China
| | - Zhe Wang
- Institute: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China
| | - Ying Peng
- Institute: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China
| | - Haibo Yu
- Institute: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China.
| | - Jinlan Zhang
- Institute: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, PR China.
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11
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Umschweif G, Greengard P, Sagi Y. The dentate gyrus in depression. Eur J Neurosci 2019; 53:39-64. [DOI: 10.1111/ejn.14640] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Revised: 11/05/2019] [Accepted: 11/28/2019] [Indexed: 12/19/2022]
Affiliation(s)
- Gali Umschweif
- Laboratory for Molecular and Cellular Neuroscience Rockefeller University New York NY USA
| | - Paul Greengard
- Laboratory for Molecular and Cellular Neuroscience Rockefeller University New York NY USA
| | - Yotam Sagi
- Laboratory for Molecular and Cellular Neuroscience Rockefeller University New York NY USA
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12
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Comeras LB, Herzog H, Tasan RO. Neuropeptides at the crossroad of fear and hunger: a special focus on neuropeptide Y. Ann N Y Acad Sci 2019; 1455:59-80. [PMID: 31271235 PMCID: PMC6899945 DOI: 10.1111/nyas.14179] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 05/15/2019] [Accepted: 06/03/2019] [Indexed: 12/11/2022]
Abstract
Survival in a natural environment forces an individual into constantly adapting purposive behavior. Specified interoceptive neurons monitor metabolic and physiological balance and activate dedicated brain circuits to satisfy essential needs, such as hunger, thirst, thermoregulation, fear, or anxiety. Neuropeptides are multifaceted, central components within such life‐sustaining programs. For instance, nutritional depletion results in a drop in glucose levels, release of hormones, and activation of hypothalamic and brainstem neurons. These neurons, in turn, release several neuropeptides that increase food‐seeking behavior and promote food intake. Similarly, internal and external threats activate neuronal pathways of avoidance and defensive behavior. Interestingly, specific nuclei of the hypothalamus and extended amygdala are activated by both hunger and fear. Here, we introduce the relevant neuropeptides and describe their function in feeding and emotional‐affective behaviors. We further highlight specific pathways and microcircuits, where neuropeptides may interact to identify prevailing homeostatic needs and direct respective compensatory behaviors. A specific focus will be on neuropeptide Y, since it is known for its pivotal role in metabolic and emotional pathways. We hypothesize that the orexigenic and anorexigenic properties of specific neuropeptides are related to their ability to inhibit fear and anxiety.
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Affiliation(s)
- Lucas B Comeras
- Department of Pharmacology, Medical University Innsbruck, Innsbruck, Austria
| | - Herbert Herzog
- Neuroscience Division, Garvan Institute of Medical Research, Sydney, New South Wales, Australia
| | - Ramon O Tasan
- Department of Pharmacology, Medical University Innsbruck, Innsbruck, Austria
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13
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Kong L, Berg FJ. Identification of cholecystokinin tetrapeptide amide metabolites in liver microsomes of human, Rhesus Monkey, Sprague-Dawley rat and CD1 mouse using ultra-high performance liquid chromatography coupled to high resolution mass spectrometer. J Chromatogr B Analyt Technol Biomed Life Sci 2018; 1096:80-87. [PMID: 30149298 DOI: 10.1016/j.jchromb.2018.08.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Revised: 08/13/2018] [Accepted: 08/17/2018] [Indexed: 11/30/2022]
Abstract
Endogenous cholecystokinin tetrapeptide (CCK-4, Trp-Met-Asp-Phe-NH2) is a fragment derived from a larger peptide hormone, cholecystokinin (or gastrin). As a panicogenic agent, CCK-4 is commonly used in clinic settings to induce panic attacks for the study of new anxiolytic drugs. However, few studies on CCK-4 metabolism have been published to date. In the present study, we investigate the metabolism of CCK-4 in liver microsomes of human (HLM), Rhesus Monkey (RMLM), Sprague-Dawley rat (RLM) and CD1 mouse (MLM) using ultra-high performance liquid chromatography coupled to a high resolution mass spetrometer. Ten metabolites, inlcuding tryptophan (M1), tryptophan amide (M2), hydroxy metabolites (M3-M5), truncated peptides (M6-M9), and CCK-4 acid (M10), were identified and 8 of them were reported for the first time. The metabolic pattern of CCK-4 in HLM was distinctly different from these in RMLM, RLM, and MLM. M2 and M9 were the major metabolites in HLM and accounted for 19.8% and 13.4% of initial CCK-4, respectively. In contrast, M2 was the major metabolite in RMLM and accounted for 41.4%, whereas M6 was the major metabolite in RLM and account for 39.1%. Three major metabolites M2, M7 and M8 in MLM accounted for 22.6%, 17.9% and 17.8% of initial CCK-4, respectively. Chemical inhibition experiment showed that aminopeptidase and/or endopeptidase hydrolysis were the major metabolic pathways in human to generate these metabolites. We further showed that cytochrome P450 were also involved in the metabolism of CCK-4 via hydroxylation, but to a less extend. These findings provide valuable information for the metabolic processes of CCK-4 among various species and an important reference basis for its safety evaluation and rational clinical application.
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Affiliation(s)
- Li Kong
- Research and Technology Directorate, U. S. Army, Edgewood Chemical Biological Center (ECBC), Aberdeen Proving Ground, MD 21010-5424, United States.
| | - Frederic J Berg
- Research and Technology Directorate, U. S. Army, Edgewood Chemical Biological Center (ECBC), Aberdeen Proving Ground, MD 21010-5424, United States
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Adriaenssens AE, Reimann F, Gribble FM. Distribution and Stimulus Secretion Coupling of Enteroendocrine Cells along the Intestinal Tract. Compr Physiol 2018; 8:1603-1638. [DOI: 10.1002/cphy.c170047] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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15
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Kim EJ, Kim YK. Panic disorders: The role of genetics and epigenetics. AIMS GENETICS 2018; 5:177-190. [PMID: 31435520 PMCID: PMC6690230 DOI: 10.3934/genet.2018.3.177] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Accepted: 07/02/2018] [Indexed: 01/04/2023]
Abstract
Panic disorder is characterized by symptoms with abrupt surges of fear with palpitations, sweating, trembling, heat sensations. Considering its disease burden on each individual and on society, understanding its etiology is important. Though no one specific etiology has been known, like other psychiatric disorders, multiple factors such as genetic, environmental, neurobiological, psychopathological factors have been suggested. In this article, we reviewed currently known etiologies and related study results, regarding especially genetic and epigenetic aspects of the panic disorder. Early studies, including twin studies, family studies, adoption studies suggested highly familial trait of panic disorder. Linkage studies, either, found panic disorder is not a single gene disorder but confirmed existence of multiple related genes. Chromosome and candidate gene studies found few related genes, NPY, ADORA2A, COMT, IKBKE. Newer method, genome-wide association studies (GWAS) have been searching for newer genes. No genome-wide significant genes, however, were detected, confirming previously known candidate genes, NPY5R on 4q31.3-32, BDKRB2 on 14q32, instead. Epigenetic modification has also been studied on many different psychiatric disorders. Monoamine oxidase A (MAOA) hypomethylation, taken together with negative life events, showed relation with panic disorder. Glutamate decarbodylases 1 (GAD1) hypomethylation was also specific on panic disorder patients. Relation with noradrenaline transporter (NET) gene SLC6a2 promoter methylation has also been studied. In conclusion, no specific gene or epigenetic pattern can fully explain etiology of panic disorder. Few genes and epigenetic patterns, however, showed strong association with panic disorder compared to healthy controls. Considering its multivariable background, further studies with larger populations can confirm current results and clarify etiologies of panic disorder.
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Affiliation(s)
- Eun Jeong Kim
- Department of Psychiatry, Korea University Ansan Hospital, Ansan, Republic of Korea
| | - Yong-Ku Kim
- Department of Psychiatry, Korea University Ansan Hospital, Ansan, Republic of Korea
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16
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Abstract
PURPOSE OF REVIEW Opioid use and abuse has led to a worldwide opioid epidemic. And while opioids are clinically useful when appropriately indicated, they are associated with a wide range of dangerous side effects and whether they are effective at treating or eliminating chronic pain is controversial. There has long been a need for the development of nonopioid alternative treatments for patients that live in pain, and until recently, only a few effective treatments were available. Today, there are a wide range of nonopioid treatments available including NSAIDs, acetaminophen, corticosteroids, nerve blocks, SSRIs, neurostimulators, and anticonvulsants. However, these treatments are still not entirely effective at treating pain, which has sparked a new exploration of novel nonopioid pharmacotherapies. RECENT FINDINGS This manuscript will outline the most recent trends in novel nonopioid pharmacotherapy development including tramadol/dexketoprofen, TrkA inhibitors, tapentadol, opioid agonists, Nektar 181, TRV 130, ßarrestin2, bisphosphonates, antibodies, sodium channel blockers, NMDA antagonists, TRP receptors, transdermal vitamin D, AAK1 kinase inhibition, calcitonin gene-related peptide (CGRP), TRPV4 antagonists, cholecystokinin, delta opioid receptor, neurokinin, and gene therapy. The pharmacotherapies discussed in this manuscript outline promising opioid alternatives which can change the future of chronic pain treatment.
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17
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Menon N, Prabhavalkar KS, Bhatt LK. Neuropeptides: A promising target for treating seizures. Neuropeptides 2017; 65:63-70. [PMID: 28559061 DOI: 10.1016/j.npep.2017.05.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Revised: 05/16/2017] [Accepted: 05/21/2017] [Indexed: 11/28/2022]
Abstract
Seizures are serious neurological disorders affecting nearly 50 million people worldwide. Seizures are characterized by abnormal, repetitive and synchronised firing of the neurons which is produced as a result of imbalance in the levels of the excitatory and inhibitory neurotransmitters. Neuropeptides are found to regulate seizures by rectifying this imbalance. These neuropeptides are stored in the dense core synaptic vesicles, and are released on excitation. This review focuses on certain neuropeptides which can alleviate both, the effects of seizures as well as epileptogenesis. Thus making it an attractive target for the management of seizures.
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Affiliation(s)
- Neethi Menon
- SVKM's Dr Bhanuben Nanavati College of Pharmacy, Vile Parle (W), Mumbai-56, India
| | - Kedar S Prabhavalkar
- SVKM's Dr Bhanuben Nanavati College of Pharmacy, Vile Parle (W), Mumbai-56, India.
| | - Lokesh K Bhatt
- SVKM's Dr Bhanuben Nanavati College of Pharmacy, Vile Parle (W), Mumbai-56, India
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18
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Kozyrev N, Coolen LM. Activation of galanin and cholecystokinin receptors in the lumbosacral spinal cord is required for ejaculation in male rats. Eur J Neurosci 2017; 45:846-858. [DOI: 10.1111/ejn.13515] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Revised: 12/15/2016] [Accepted: 12/17/2016] [Indexed: 01/23/2023]
Affiliation(s)
- Natalie Kozyrev
- Department of Anatomy and Cell Biology; Western University; London ON Canada
- Department of Physiology; University of Michigan; Ann Arbor MI USA
| | - Lique M. Coolen
- Department of Anatomy and Cell Biology; Western University; London ON Canada
- Department of Physiology; University of Michigan; Ann Arbor MI USA
- Department of Neurobiology and Anatomical Sciences; University of Mississippi Medical Center; Jackson MS USA
- Department of Physiology and Biophysics; University of Mississippi Medical Center; 2500 North State Street Jackson MS 39216 USA
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19
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Skrabanek P, Cannon D, Kirrane J, Legge D, Powell D. Circulating immunoreactive substance P in man. Ir J Med Sci 2016; 145:399. [PMID: 27517263 DOI: 10.1007/bf02938979] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Immunoreactive substance P (iSP) has been measured in plasma in 77 normal subjects and in 125 hospital patients. Factors affectingin-vitro degradation of iSP were studied.In vivo, iSP is degraded in the liver and its level in the circulation is independent of kidney excretory function.During insulin-induced hypoglycaemic stress and also during glucose-tolerance test, iSP in plasma decreased transiently. No circadian rhythm of iSP was observed, but in a study in sleeping volunteers episodic secretory bursts were seen, separated by one- to two-hour intervals, the first peak appearing about 90 minutes after the subjects fell asleep.In a patient with carcinoid metastases in the liver, an elevated level of iSP was found in the general circulation with a marked gradient at the hepatic venous effluent.
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Affiliation(s)
- P Skrabanek
- Department of Endocrinology, Mater Misericordiae Hospital, Dublin.,Department of Immunology, Mater Misericordiae Hospital, Dublin.,Department of Radiology, Mater Misericordiae Hospital, Dublin
| | - D Cannon
- Department of Endocrinology, Mater Misericordiae Hospital, Dublin.,Department of Immunology, Mater Misericordiae Hospital, Dublin.,Department of Radiology, Mater Misericordiae Hospital, Dublin
| | - J Kirrane
- Department of Endocrinology, Mater Misericordiae Hospital, Dublin.,Department of Immunology, Mater Misericordiae Hospital, Dublin.,Department of Radiology, Mater Misericordiae Hospital, Dublin
| | - D Legge
- Department of Endocrinology, Mater Misericordiae Hospital, Dublin.,Department of Immunology, Mater Misericordiae Hospital, Dublin.,Department of Radiology, Mater Misericordiae Hospital, Dublin
| | - D Powell
- Department of Endocrinology, Mater Misericordiae Hospital, Dublin.,Department of Immunology, Mater Misericordiae Hospital, Dublin.,Department of Radiology, Mater Misericordiae Hospital, Dublin
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20
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Oxidative Stress Implications in the Affective Disorders: Main Biomarkers, Animal Models Relevance, Genetic Perspectives, and Antioxidant Approaches. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2016; 2016:3975101. [PMID: 27563374 PMCID: PMC4983669 DOI: 10.1155/2016/3975101] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Revised: 06/30/2016] [Accepted: 07/05/2016] [Indexed: 01/12/2023]
Abstract
The correlation between the affective disorders and the almost ubiquitous pathological oxidative stress can be described in a multifactorial way, as an important mechanism of central nervous system impairment. Whether the obvious changes which occur in oxidative balance of the affective disorders are a part of the constitutive mechanism or a collateral effect yet remains as an interesting question. However it is now clear that oxidative stress is a component of these disorders, being characterized by different aspects in a disease-dependent manner. Still, there are a lot of controversies regarding the relevance of the oxidative stress status in most of the affective disorders and despite the fact that most of the studies are showing that the affective disorders development can be correlated to increased oxidative levels, there are various studies stating that oxidative stress is not linked with the mood changing tendencies. Thus, in this minireview we decided to describe the way in which oxidative stress is involved in the affective disorders development, by focusing on the main oxidative stress markers that could be used mechanistically and therapeutically in these deficiencies, the genetic perspectives, some antioxidant approaches, and the relevance of some animal models studies in this context.
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Functional synergy between cholecystokinin receptors CCKAR and CCKBR in mammalian brain development. PLoS One 2015; 10:e0124295. [PMID: 25875176 PMCID: PMC4398320 DOI: 10.1371/journal.pone.0124295] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2014] [Accepted: 03/11/2015] [Indexed: 12/11/2022] Open
Abstract
Cholecystokinin (CCK), a peptide hormone and one of the most abundant neuropeptides in vertebrate brain, mediates its actions via two G-protein coupled receptors, CCKAR and CCKBR, respectively active in peripheral organs and the central nervous system. Here, we demonstrate that the CCK receptors have a dynamic and largely reciprocal expression in embryonic and postnatal brain. Using compound homozygous mutant mice lacking the activity of both CCK receptors, we uncover their additive, functionally synergistic effects in brain development and demonstrate that CCK receptor loss leads to abnormalities of cortical development, including defects in the formation of the midline and corpus callosum, and cortical interneuron migration. Using comparative transcriptome analysis of embryonic neocortex, we define the molecular mechanisms underlying these defects. Thus we demonstrate a developmental, hitherto unappreciated, role of the two CCK receptors in mammalian neocortical development.
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Bowers ME, Ressler KJ. Interaction between the cholecystokinin and endogenous cannabinoid systems in cued fear expression and extinction retention. Neuropsychopharmacology 2015; 40:688-700. [PMID: 25176168 PMCID: PMC4289957 DOI: 10.1038/npp.2014.225] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2014] [Revised: 07/10/2014] [Accepted: 08/02/2014] [Indexed: 01/29/2023]
Abstract
Post-traumatic stress disorder (PTSD) is thought to develop, in part, from improper inhibition of fear. Accordingly, one of the most effective treatment strategies for PTSD is exposure-based psychotherapy. Ideally, neuroscience would inform adjunct therapies that target the neurotransmitter systems involved in extinction processes. Separate studies have implicated the cholecystokinin (CCK) and endocannabinoid systems in fear; however, there is a high degree of anatomical colocalization between the cannabinoid 1 receptor (Cnr1) and CCK in the basolateral amygdala (BLA), a brain region critical for emotion regulation. Although most research has focused on GABA and GABAergic plasticity as the mechanism by which Cnr1 mediates fear inhibition, we hypothesize that a functional interaction between Cnr1 and CCKB receptor (CCKBR) is critical for fear extinction processes. In this study, systemic pharmacological manipulation of the cannabinoid system modulated cued fear expression in C57BL/6J mice after consolidation of auditory fear conditioning. Knockout of the CCKBR, however, had no effect on fear- or anxiety-like behaviors. Nonetheless, administration of a Cnr1 antagonist increased freezing behavior during a cued fear expression test in wild-type subjects, but had no effect on freezing behavior in CCKBR knockout littermates. In addition, we found that Cnr1-positive fibers form perisomatic clusters around CCKBR-positive cell bodies in the BLA. These CCKBR-positive cells comprise a molecularly heterogenous population of excitatory and inhibitory neurons. These findings provide novel evidence that Cnr1 contributes to cued fear expression via an interaction with the CCK system. Dysfunctional Cnr1-CCKBR interactions might contribute to the etiology of, or result from, fear-related psychiatric disease.
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Affiliation(s)
- Mallory E Bowers
- Behavioral Neuroscience, Department of Psychiatry and Behavioral Sciences, Howard Hughes Medical Institute, Emory University, Yerkes Research Center, Atlanta, GA, USA
| | - Kerry J Ressler
- Behavioral Neuroscience, Department of Psychiatry and Behavioral Sciences, Howard Hughes Medical Institute, Emory University, Yerkes Research Center, Atlanta, GA, USA,Howard Hughes Medical Institute, Emory University, Atlanta, GA, USA,Behavioral Neuroscience, Department of Psychiatry and Behavioral Sciences, Howard Hughes Medical Institute, Emory University, Yerkes Research Center, 954 Gatewood Dr, NE Atlanta, GA 30329, USA, Tel: +1 404 727 7739, Fax: +1 404 727 8070, E-mail:
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23
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Ji X, Li D, Li H. Preparation and application of a novel molecularly imprinted solid-phase microextraction monolith for selective enrichment of cholecystokinin neuropeptides in human cerebrospinal fluid. Biomed Chromatogr 2015; 29:1280-9. [DOI: 10.1002/bmc.3418] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Revised: 11/15/2014] [Accepted: 11/28/2014] [Indexed: 11/10/2022]
Affiliation(s)
- Xiang Ji
- College of Chemistry and Molecular Sciences; Wuhan University; Wuhan 430072 China
| | - Dan Li
- College of Chemistry and Molecular Sciences; Wuhan University; Wuhan 430072 China
| | - Hua Li
- College of Chemistry and Molecular Sciences; Wuhan University; Wuhan 430072 China
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Thomas J, Mustafa S, Johnson J, Nicotra L, Hutchinson M. The relationship between opioids and immune signalling in the spinal cord. Handb Exp Pharmacol 2015; 227:207-238. [PMID: 25846621 DOI: 10.1007/978-3-662-46450-2_11] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Opioids are considered the gold standard for the treatment of moderate to severe pain. However, heterogeneity in analgesic efficacy, poor potency and side effects are associated with opioid use, resulting in dose limitations and suboptimal pain management. Traditionally thought to exhibit their analgesic actions via the activation of the neuronal G-protein-coupled opioid receptors, it is now widely accepted that neuronal activity of opioids cannot fully explain the initiation and maintenance of opioid tolerance, hyperalgesia and allodynia. In this review we will highlight the evidence supporting the role of non-neuronal mechanisms in opioid signalling, paying particular attention to the relationship of opioids and immune signalling.
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Affiliation(s)
- Jacob Thomas
- Discipline of Pharmacology, School of Medical Sciences, University of Adelaide, Adelaide, Australia,
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25
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Thomas J, Hutchinson MR. Exploring neuroinflammation as a potential avenue to improve the clinical efficacy of opioids. Expert Rev Neurother 2014; 12:1311-24. [DOI: 10.1586/ern.12.125] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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26
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Griebel G, Holmes A. 50 years of hurdles and hope in anxiolytic drug discovery. Nat Rev Drug Discov 2013; 12:667-87. [PMID: 23989795 DOI: 10.1038/nrd4075] [Citation(s) in RCA: 307] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Anxiety disorders are the most prevalent group of psychiatric diseases, and have high personal and societal costs. The search for novel pharmacological treatments for these conditions is driven by the growing medical need to improve on the effectiveness and the side effect profile of existing drugs. A huge volume of data has been generated by anxiolytic drug discovery studies, which has led to the progression of numerous new molecules into clinical trials. However, the clinical outcome of these efforts has been disappointing, as promising results with novel agents in rodent studies have very rarely translated into effectiveness in humans. Here, we analyse the major trends from preclinical studies over the past 50 years conducted in the search for new drugs beyond those that target the prototypical anxiety-associated GABA (γ-aminobutyric acid)-benzodiazepine system, which have focused most intensively on the serotonin, neuropeptide, glutamate and endocannabinoid systems. We highlight various key issues that may have hampered progress in the field, and offer recommendations for how anxiolytic drug discovery can be more effective in the future.
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Affiliation(s)
- Guy Griebel
- Sanofi, Exploratory Unit, Chilly-Mazarin 91385, France
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Sears C, Wilson J, Fitches A. Investigating the role of BDNF and CCK system genes in suicidality in a familial bipolar cohort. J Affect Disord 2013; 151:611-617. [PMID: 23890582 DOI: 10.1016/j.jad.2013.07.006] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2013] [Revised: 07/04/2013] [Accepted: 07/04/2013] [Indexed: 11/26/2022]
Abstract
BACKGROUND Suicidal behaviour is a phenotype widely associated with psychiatric disorders such as major depressive disorder and bipolar disorder. However, recent evidence indicates that part of the heritability of suicidal behaviour is independent of the heritability of individual psychiatric disorders. This allows investigation into genetic risk factors for suicidal behaviour within a disorder using a candidate gene association approach. METHODS We used family-based association testing in a cohort of 130 multiplex bipolar pedigrees, comprising 795 individuals, to look for associations between suicidal behaviour and 32 single nucleotide polymorphisms (SNPs) from across the genes brain-derived neurotrophic factor (BDNF), cholecystokinin (CCK) and the cholecystokinin beta-receptor (CCKBR). RESULTS We found associations (p≤0.05) between suicide attempt and 12 SNPs of CCKBR and five SNPs of BDNF. After correction for multiple testing, seven SNPs of CCKBR remained significantly associated. No association was found between CCK and suicidal behaviour. LIMITATIONS The study relied on retrospective self-reporting by individuals to determine phenotype, and the sample size was relatively small. CONCLUSIONS The results of the study support the hypothesis that some CCKBR polymorphisms may contribute to an underlying predisposition towards suicidal behaviour in bipolar disorder.
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Affiliation(s)
- Catherine Sears
- Department of Pathology, Dunedin School of Medicine, University of Otago, P.O. Box 913, Dunedin 9054, New Zealand
| | - Julia Wilson
- Department of Pathology, Dunedin School of Medicine, University of Otago, P.O. Box 913, Dunedin 9054, New Zealand
| | - Alison Fitches
- Department of Pathology, Dunedin School of Medicine, University of Otago, P.O. Box 913, Dunedin 9054, New Zealand.
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Cholecystokinin: an excitatory modulator of mitral/tufted cells in the mouse olfactory bulb. PLoS One 2013; 8:e64170. [PMID: 23691163 PMCID: PMC3655022 DOI: 10.1371/journal.pone.0064170] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2012] [Accepted: 04/12/2013] [Indexed: 12/02/2022] Open
Abstract
Cholecystokinin (CCK) is widely distributed in the brain as a sulfated octapeptide (CCK-8S). In the olfactory bulb, CCK-8S is concentrated in two laminae: an infraglomerular band in the external plexiform layer, and an inframitral band in the internal plexiform layer (IPL), corresponding to somata and terminals of superficial tufted cells with intrabulbar projections linking duplicate glomerular maps of olfactory receptors. The physiological role of CCK in this circuit is unknown. We made patch clamp recordings of CCK effects on mitral cell spike activity in mouse olfactory bulb slices, and applied immunohistochemistry to localize CCKB receptors. In cell-attached recordings, mitral cells responded to 300 nM –1 µM CCK-8S by spike excitation, suppression, or mixed excitation-suppression. Antagonists of GABAA and ionotropic glutamate receptors blocked suppression, but excitation persisted. Whole-cell recordings revealed that excitation was mediated by a slow inward current, and suppression by spike inactivation or inhibitory synaptic input. Similar responses were elicited by the CCKB receptor-selective agonist CCK-4 (1 µM). Excitation was less frequent but still occurred when CCKB receptors were blocked by LY225910, or disrupted in CCKB knockout mice, and was also observed in CCKA knockouts. CCKB receptor immunoreactivity was detected on mitral and superficial tufted cells, colocalized with Tbx21, and was absent from granule cells and the IPL. Our data indicate that CCK excites mitral cells postsynaptically, via both CCKA and CCKB receptors. We hypothesize that extrasynaptic CCK released from tufted cell terminals in the IPL may diffuse to and directly excite mitral cell bodies, creating a positive feedback loop that can amplify output from pairs of glomeruli receiving sensory inputs encoded by the same olfactory receptor. Dynamic plasticity of intrabulbar projections suggests that this could be an experience-dependent amplification mechanism for tuning and optimizing olfactory bulb signal processing in different odor environments.
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Dunn IC, Meddle SL, Wilson PW, Wardle CA, Law AS, Bishop VR, Hindar C, Robertson GW, Burt DW, Ellison SJH, Morrice DM, Hocking PM. Decreased expression of the satiety signal receptor CCKAR is responsible for increased growth and body weight during the domestication of chickens. Am J Physiol Endocrinol Metab 2013; 304:E909-21. [PMID: 23443924 PMCID: PMC3651647 DOI: 10.1152/ajpendo.00580.2012] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2012] [Accepted: 02/22/2013] [Indexed: 12/05/2022]
Abstract
Animal domestication has resulted in changes in growth and size. It has been suggested that this may have involved selection for differences in appetite. Divergent growth between chickens selected for egg laying or meat production is one such example. The neurons expressing AGRP and POMC in the basal hypothalamus are important components of appetite regulation, as are the satiety feedback pathways that carry information from the intestine, including CCK and its receptor CCKAR (CCK1 receptor). Using 16 generations of a cross between a fast and a relatively slow growing strain of chicken has identified a region on chromosome 4 downstream of the CCKAR gene, which is responsible for up to a 19% difference in body weight at 12 wk of age. Animals possessing the high-growth haplotype at the locus have lower expression of mRNA and immunoreactive CCKAR in the brain, intestine, and exocrine organs, which is correlated with increased levels of orexigenic AGRP in the hypothalamus. Animals with the high-growth haplotype are resistant to the anorectic effect of exogenously administered CCK, suggesting that their satiety set point has been altered. Comparison with traditional breeds shows that the high-growth haplotype has been present in the founders of modern meat-type strains and may have been selected early in domestication. This is the first dissection of the physiological consequences of a genetic locus for a quantitative trait that alters appetite and gives us an insight into the domestication of animals. This will allow elucidation of how differences in appetite occur in birds and also mammals.
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Affiliation(s)
- Ian C Dunn
- University of Edinburgh, Roslin Institute and Royal (Dick) School of Veterinary Studies, Easter Bush, United Kingdom
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Sui Y, Vermeulen R, Hökfelt T, Horne MK, Stanić D. Female mice lacking cholecystokinin 1 receptors have compromised neurogenesis, and fewer dopaminergic cells in the olfactory bulb. Front Cell Neurosci 2013; 7:13. [PMID: 23459364 PMCID: PMC3584826 DOI: 10.3389/fncel.2013.00013] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2012] [Accepted: 02/03/2013] [Indexed: 12/17/2022] Open
Abstract
Neurogenesis in the adult rodent brain is largely restricted to the subependymal zone (SVZ) of the lateral ventricle and subgranular zone (SGZ) of the dentate gyrus (DG). We examined whether cholecystokinin (CCK) through actions mediated by CCK1 receptors (CCK1R) is involved in regulating neurogenesis. Proliferating cells in the SVZ, measured by 5-bromo-2-deoxyuridine (BrdU) injected 2 h prior to death or by immunoreactivity against Ki67, were reduced by 37 and 42%, respectively, in female (but not male) mice lacking CCK1Rs (CCK1R(-/-)) compared to wild-type (WT). Generation of neuroblasts in the SVZ and rostral migratory stream (RMS) was also affected, since the number of doublecortin (DCX)-immunoreactive (ir) neuroblasts in these regions decreased by 29%. In the SGZ of female CCK1R(-/-) mice, BrdU-positive (+), and Ki67-ir cells were reduced by 38 and 56%, respectively, while DCX-ir neuroblasts were down 80%. Subsequently, the effect of reduced SVZ/SGZ proliferation on the generation and survival of mature adult-born cells in female CCK1R(-/-) mice was examined. In the OB granule cell layer (GCL), the number of neuronal nuclei (NeuN)-ir and calretinin-ir cells was stable compared to WT, and 42 days after BrdU injections, the number of BrdU+ cells co-expressing GABA- or NeuN-like immunoreactivity (LI) was similar. Compared to WT, the granule cell layer of the DG in female CCK1R(-/-) mice had a similar number of calbindin-ir cells and BrdU+ cells co-expressing calbindin-LI 42 days after BrdU injections. However, the OB glomerular layer (GL) of CCK1R(-/-) female mice had 11% fewer NeuN-ir cells, 23% less TH-ir cells, and a 38% and 29% reduction in BrdU+ cells that co-expressed TH-LI or GABA-LI, respectively. We conclude that CCK, via CCK1Rs, is involved in regulating the generation of proliferating cells and neuroblasts in the adult female mouse brain, and mechanisms are in place to maintain steady neuronal populations in the OB and DG when the rate of proliferation is altered.
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Affiliation(s)
- Yi Sui
- Neurodegeneration Division, Florey Institute of Neuroscience and Mental Health, University of Melbourne Parkville, VIC, Australia ; Department of Neurology, Shenyang First People's Hospital Shenyang, China
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Ozaki T, Mohammad S, Morioka E, Takiguchi S, Ikeda M. Infant satiety depends on transient expression of cholecystokinin-1 receptors on ependymal cells lining the third ventricle in mice. J Physiol 2012; 591:1295-312. [PMID: 23266937 DOI: 10.1113/jphysiol.2012.247676] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Cholecystokinin (CCK) is a hypothetical controller for suckling and infancy body weight, although the underlying mechanisms remain unclear. Therefore, the present study analysed the mechanisms using mice lacking the CCK-1 receptor (CCK1R-/-). Although CCK1R-/- mice displayed normal weights at birth and adulthood, CCK1R-/- pups had enlarged adipocytes and were overweight from the first to second week after birth, regardless of maternal genotype. The lacZ reporter gene assay and/or calcium imaging analysis demonstrated that CCK-1 receptors were abundant in satiety-controlling regions such as the hypothalamus, brainstem, nodose ganglion and pylorus in adults, whereas these signals were few to lacking at pre-weanling stages. At postnatal day (PD) 6, the increase in cFos expression in the medullary nucleus tractus solitarius was similarly triggered by gastrointestinal milk- or saline filling in both genotypes, further indicating immature CCK-1 receptor function in an ascending satiety-controlling system during infancy. Conversely, third ventricle ependymal tanycyte-like cells expressed CCK-1 receptors with expression peaking at PD6. At PD6, wild-type but not CCK1R-/- mice had increased cFos immunoreactivity in ependymal cells following gastrointestinal milk filling whereas the response became negligible at PD12. In addition, ependymal cFos was not increased by saline filling, indicating that these responses are dependent on CCK-1 receptors, developmental stage and nutrients. Furthermore, body weights of wild-type pups were transiently increased by blocking ependymal CCK receptor function with microinjection of a CCK-1 antagonist, but not a CCK-2 antagonist. Hence, we demonstrate de novo functions of ependymal CCK-1 receptors and reveal a new aspect of infant satiety-controlling mechanisms.
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Affiliation(s)
- Tomoya Ozaki
- 1Graduate School of Innovative Life Science, University of Toyama, 3190 Gofuku, Toyama 930-8555, Japan
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Bowers ME, Choi DC, Ressler KJ. Neuropeptide regulation of fear and anxiety: Implications of cholecystokinin, endogenous opioids, and neuropeptide Y. Physiol Behav 2012; 107:699-710. [PMID: 22429904 PMCID: PMC3532931 DOI: 10.1016/j.physbeh.2012.03.004] [Citation(s) in RCA: 115] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2012] [Revised: 02/24/2012] [Accepted: 03/05/2012] [Indexed: 11/23/2022]
Abstract
The neural circuitry of fear likely underlies anxiety and fear-related disorders such as specific and social phobia, panic disorder, and posttraumatic stress disorder. The primary pharmacological treatments currently utilized for these disorders include benzodiazepines, which act on the GABAergic receptor system, and antidepressants, which modulate the monamine systems. However, recent work on the regulation of fear neural circuitry suggests that specific neuropeptide modulation of this system is of critical importance. Recent reviews have examined the roles of the hypothalamic-pituitary-adrenal axis neuropeptides as well as the roles of neurotrophic factors in regulating fear. The present review, instead, will focus on three neuropeptide systems which have received less attention in recent years but which are clearly involved in regulating fear and its extinction. The endogenous opioid system, particularly activating the μ opioid receptors, has been demonstrated to regulate fear expression and extinction, possibly through functioning as an error signal within the ventrolateral periaqueductal gray to mark unreinforced conditioned stimuli. The cholecystokinin (CCK) system initially led to much excitement through its potential role in panic disorder. More recent work in the CCK neuropeptide pathway suggests that it may act in concordance with the endogenous cannabinoid system in the modulation of fear inhibition and extinction. Finally, older as well as very recent data suggests that neuropeptide Y (NPY) may play a very interesting role in counteracting stress effects, enhancing extinction, and enhancing resilience in fear and stress preclinical models. Future work in understanding the mechanisms of neuropeptide functioning, particularly within well-known behavioral circuits, are likely to provide fascinating new clues into the understanding of fear behavior as well as suggesting novel therapeutics for treating disorders of anxiety and fear dysregulation.
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Affiliation(s)
- Mallory E Bowers
- Center for Behavioral Neuroscience, Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, United States
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33
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Palouzier-Paulignan B, Lacroix MC, Aimé P, Baly C, Caillol M, Congar P, Julliard AK, Tucker K, Fadool DA. Olfaction under metabolic influences. Chem Senses 2012; 37:769-97. [PMID: 22832483 PMCID: PMC3529618 DOI: 10.1093/chemse/bjs059] [Citation(s) in RCA: 230] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Recently published work and emerging research efforts have suggested that the olfactory system is intimately linked with the endocrine systems that regulate or modify energy balance. Although much attention has been focused on the parallels between taste transduction and neuroendocrine controls of digestion due to the novel discovery of taste receptors and molecular components shared by the tongue and gut, the equivalent body of knowledge that has accumulated for the olfactory system, has largely been overlooked. During regular cycles of food intake or disorders of endocrine function, olfaction is modulated in response to changing levels of various molecules, such as ghrelin, orexins, neuropeptide Y, insulin, leptin, and cholecystokinin. In view of the worldwide health concern regarding the rising incidence of diabetes, obesity, and related metabolic disorders, we present a comprehensive review that addresses the current knowledge of hormonal modulation of olfactory perception and how disruption of hormonal signaling in the olfactory system can affect energy homeostasis.
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Affiliation(s)
- Brigitte Palouzier-Paulignan
- Centre de Recherche des Neurosciences de Lyon, Equipe Olfaction du Codage à la Mémoire, INSERM U 1028/CNRS 5292, Université de Lyon150 Ave. Tony Garnier, 69366, Lyon, Cedex 07,France
- Equal contribution
| | - Marie-Christine Lacroix
- INRA, UR1197 Neurobiologie de l’Olfaction et Modélisation en ImagerieF-78350, Jouy-en-JosasFrance
- IFR 144NeuroSud Paris, 91190 Gif-Sur-YvetteFrance
- Equal contribution
| | - Pascaline Aimé
- Centre de Recherche des Neurosciences de Lyon, Equipe Olfaction du Codage à la Mémoire, INSERM U 1028/CNRS 5292, Université de Lyon150 Ave. Tony Garnier, 69366, Lyon, Cedex 07,France
| | - Christine Baly
- INRA, UR1197 Neurobiologie de l’Olfaction et Modélisation en ImagerieF-78350, Jouy-en-JosasFrance
- IFR 144NeuroSud Paris, 91190 Gif-Sur-YvetteFrance
| | - Monique Caillol
- INRA, UR1197 Neurobiologie de l’Olfaction et Modélisation en ImagerieF-78350, Jouy-en-JosasFrance
- IFR 144NeuroSud Paris, 91190 Gif-Sur-YvetteFrance
| | - Patrice Congar
- INRA, UR1197 Neurobiologie de l’Olfaction et Modélisation en ImagerieF-78350, Jouy-en-JosasFrance
- IFR 144NeuroSud Paris, 91190 Gif-Sur-YvetteFrance
| | - A. Karyn Julliard
- Centre de Recherche des Neurosciences de Lyon, Equipe Olfaction du Codage à la Mémoire, INSERM U 1028/CNRS 5292, Université de Lyon150 Ave. Tony Garnier, 69366, Lyon, Cedex 07,France
| | - Kristal Tucker
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of MedicinePittsburgh, PA 15261USAand
| | - Debra Ann Fadool
- Department of Biological Science, Programs in Neuroscience and Molecular Biophysics, The Florida State UniversityTallahassee, FL 32306-4295USA
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Schiffmann SN, Mailleux P, Przedborski S, Halleux P, Lotstra F, Vanderhaeghen JJ. Cholecystokinin distribution in the human striatum and related subcortical structures. Neurochem Int 2012; 14:167-73. [PMID: 20504414 DOI: 10.1016/0197-0186(89)90118-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/27/1988] [Indexed: 11/19/2022]
Abstract
The distribution of cholecystokinin immunoreactive nerve cell bodies and processes is reported in the human striatum and adjacent structures such as the claustrum, the pallidum, the bed nucleus of the stria terminalis and the substantia innominata. Cholecystokinin-positive terminals are present in the striatum where they are arranged in a patchy pattern. Cholecystokinin-positive somata are observed in the claustrum and in the bed nucleus of the stria terminalis but not in the striatum, the pallidum or the substantia innominata. Dense networks of cholecystokinin-positive woolly fibres are present in the bed nucleus of the stria terminalis and the substantia innominata. These results suggested that cholecystokinin is involved in the compartmental organization of the human striatum. This compartmentalization has functional and pathological implications. Involvement of the cholecystokinin system in some basal ganglia diseases is therefore expected. Presence of neuronal cholecystokinin in the accumbens nucleus, bed nucleus of the stria terminalis and substantia innominata also suggests that this peptide may interact at different levels in the human limbic system.
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Affiliation(s)
- S N Schiffmann
- Laboratories of Neuropathology and Neuropeptide Research and Pathology and Electron Microscopy, Faculty of Medicine, Erasme and Brugmann Hospitals, Université Libre de Bruxelles, Brussels, Belgium
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De Witte P, Heidbreder C, Roques B, Vanderhaeghen JJ. Opposite effects of cholecystokinin octapeptide (CCK-8) and tetrapeptide (CCK-4) after injection into the caudal part of the nucleus accumbens or into its rostral part and the cerebral ventricles. Neurochem Int 2012; 10:473-9. [PMID: 20501120 DOI: 10.1016/0197-0186(87)90074-x] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/26/1986] [Indexed: 11/18/2022]
Abstract
Neurons with colocalized cholecystokinin and dopamine are present predominantly in the ventral tegmental area and project mainly to the caudal part of the medial nucleus accumbens. The activity of this dopamine system can be evaluated by means of the intracranial self-stimulation behavior on male Wistar rats having chronic electrodes implanted into the medial forebrain bundle in the postero-lateral area of the hypothalamus. The direct injection of 150 pmol CCK-8 into the medio-caudal accumbens induced an increase of intracranial self stimulation while a similar administration into its rostral portion produced a slight decrease of intracranial self-stimulation. The administration of 300 pmol CCK-4 into the same medio-caudal part of the accumbens produced an inhibitory action on intracranial self stimulation lasting for 25 min. The injection of 70 to 1300 pmol CCK-4 into the cerebral ventricles produced no change on intracranial self-stimulation. The intracerebroventricular injection of 70 pmol CCK-8 induced a large decrease of intracranial self-stimulation lasting for 20 min. Sodium chloride 0.15 M or unsulphated CCK-8 injection were without effect in either case. These results support the ideas that intracerebroventricular CCK-8 injection inhibits accumbens dopaminergic activity but that CCK-8 injection into the medio-caudal part of the accumbens, where nerve terminals with colocalized CCK and DA are present, facilitates this dopaminergic activity. In addition at the level of medio-caudal accumbens, CCK-8 and CCK-4 have opposite effects.
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Affiliation(s)
- P De Witte
- Laboratoire de Psychobiologie, Université Catholique de Louvain, 1 Place Croix du Sud, 1348, Louvain-La-Neuve, Belgique
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Nichols R. Isolation and expression of the Drosophila drosulfakinin neural peptide gene product, DSK-I. Mol Cell Neurosci 2012; 3:342-7. [PMID: 19912877 DOI: 10.1016/1044-7431(92)90031-v] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/1992] [Indexed: 11/15/2022] Open
Abstract
The Drosophila drosulfakinin (dsk) gene encodes the cholecystokinin homologues drosulfakinin-I (DSK-I) and drosulfakinin-II (DSK-II). The naturally occurring DSKI peptide was isolated from an extract of adult flies and its sequence determined by automated Edman degradation and sequence-specific radioimmunoassay. The dsk cDNA is expressed during the larval, pupal, and adult stages of development and is an abundant adult head transcript. Sequence-specific DSK antibodies localized DSK expression in the Drosophila larval central nervous system to medial neurosecretory cells and projections that extend from the neurons anteriorly into the brain and posteriorly down the ventral ganglion. The availability of the dsk transcript, sequence-specific DSK antibodies and the application of molecular genetics provide the opportunity to elucidate the role(s) of Drosophila CCK homologues in brain structure and function.
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Affiliation(s)
- R Nichols
- Departments of Biological Chemistry and Biology, University of Michigan, Ann Arbor, Michigan 48109-1048, USA
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Modulation of acetylcholine release by cholecystokinin in striatum: receptor specificity; role of dopaminergic neuronal activity. Brain Res Bull 2012; 89:177-84. [PMID: 22981453 DOI: 10.1016/j.brainresbull.2012.08.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2012] [Accepted: 08/29/2012] [Indexed: 11/20/2022]
Abstract
Cholecystokinin, a neuroactive peptide functioning as a neurotransmitter and neuromodulator in the central nervous system, mediates a number of processes and is implicated in neurological and psychiatric disorders such as Parkinson's disease, anxiety and schizophrenia. Striatum is one of the brain structures with the highest concentrations of CCK in the brain, rich in CCK receptors as well. The physiological effect of CCK on cholinergic interneurons, which are the major interneurons in striatum and the modulatory interactions which exist between dopamine, acetylcholine and cholecystokinin in this brain structure are still unclear. We studied the effect of cholecystokinin octapeptide (CCK-8) on the release of acetylcholine (ACh) from striatal slices of the rat brain. CCK-8 (0.01-0.1μM) showed no statistically significant effect on the basal but enhanced dose-dependently the electrically (2Hz)-evoked release of [(3)H]ACh. When slices were preperfused with 100μM sulpiride, a selective dopamine D(2) receptor antagonist, the CCK-8 (0.01μM) effect on electrically stimulated ACh release was increased nearly 2-fold. A similar increase was observed after depletion of endogenous dopamine (DA) from nigro-striatal dopaminergic neurons with 6-hydroxydopamine (6-OHDA) (2× 250μg/animal, i.c.v.). Furthermore in the presence of dopamine (100μM) or apomorphine (10μM), the prototypical DA receptor agonist, CCK-8 (0.01μM) failed to enhance the stimulation-evoked release of [(3)H]ACh. The D(2) receptor agonist quinpirol (1μM) abolished the CCK-8 effect on electrically stimulated ACh release as well. The increase in electrically induced [(3)H]ACh release produced by 0.01μM CCK-8 was antagonized by d,l loxiglumide (CR 1505), 10μM, a non-peptide CCK-A receptor antagonist and by Suc-Tyr-(OSO3)-Met-Gly-Trp-Met-Asp-β-phenethyl-amide (GE-410), 1μM, a peptide CCK-A receptor antagonist. The antagonistic effect of GE-410 on the CCK-8-potentiated, electrically induced release of [(3)H]ACh was studied in striatum for the first time. CAM 1028 (10μM), a CCK-B receptor antagonist, also prevented the potentiating effect of CCK-8 (0.01μM) on electrically stimulated release of [(3)H]ACh. The presented results indicate that (i) CCK-8 is capable of increasing ACh elicited by field electrical stimulation in striatum; (ii) CCK-8 is more effective in its ACh-stimulating effect when dopaminergic activity in striatum is blocked i.e. CCK-8-facilitated release of electrically induced ACh from cholinergic interneurons in the striatum is under the inhibitory control of the tonic activity of dopamine from the nigrostriatal pathway; (iii) the enhancing effect of CCK-8 on electrically evoked ACh release is mediated through both CCK-A and CCK-B cholecystokinin receptors located most likely on the cell bodies of cholinergic interneurons in striatum.
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Zwanzger P, Domschke K, Bradwejn J. Neuronal network of panic disorder: the role of the neuropeptide cholecystokinin. Depress Anxiety 2012; 29:762-74. [PMID: 22553078 DOI: 10.1002/da.21919] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2011] [Revised: 01/09/2012] [Accepted: 01/13/2012] [Indexed: 11/08/2022] Open
Abstract
Panic disorder (PD) is characterized by panic attacks, anticipatory anxiety and avoidance behavior. Its pathogenesis is complex and includes both neurobiological and psychological factors. With regard to neurobiological underpinnings, anxiety in humans seems to be mediated through a neuronal network, which involves several distinct brain regions, neuronal circuits and projections as well as neurotransmitters. A large body of evidence suggests that the neuropeptide cholecystokinin (CCK) might be an important modulator of this neuronal network. Key regions of the fear network, such as amygdala, hypothalamus, peraqueductal grey, or cortical regions seem to be connected by CCKergic pathways. CCK interacts with several anxiety-relevant neurotransmitters such as the serotonergic, GABA-ergic and noradrenergic system as well as with endocannabinoids, NPY and NPS. In humans, administration of CCK-4 reliably provokes panic attacks, which can be blocked by antipanic medication. Also, there is some support for a role of the CCK system in the genetic pathomechanism of PD with particularly strong evidence for the CCK gene itself and the CCK-2R (CCKBR) gene. Thus, it is hypothesized that genetic variants in the CCK system might contribute to the biological basis for the postulated CCK dysfunction in the fear network underlying PD. Taken together, a large body of evidence suggests a possible role for the neuropeptide CCK in PD with regard to neuroanatomical circuits, neurotransmitters and genetic factors. This review article proposes an extended hypothetical model for human PD, which integrates preclinical and clinical findings on CCK in addition to existing theories of the pathogenesis of PD.
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Affiliation(s)
- P Zwanzger
- Mood and Anxiety Disorders Research Unit, Department of Psychiatry and Psychotherapy, University of Muenster, Muenster, Germany.
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Laverman P, Sosabowski JK, Boerman OC, Oyen WJG. Radiolabelled peptides for oncological diagnosis. Eur J Nucl Med Mol Imaging 2012; 39 Suppl 1:S78-92. [PMID: 22388627 PMCID: PMC3304069 DOI: 10.1007/s00259-011-2014-7] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Radiolabelled receptor-binding peptides targeting receptors (over)expressed on tumour cells are widely under investigation for tumour diagnosis and therapy. The concept of using radiolabelled receptor-binding peptides to target receptor-expressing tissues in vivo has stimulated a large body of research in nuclear medicine. The 111In-labelled somatostatin analogue octreotide (OctreoScan™) is the most successful radiopeptide for tumour imaging, and was the first to be approved for diagnostic use. Based on the success of these studies, other receptor-targeting peptides such as cholecystokinin/gastrin analogues, glucagon-like peptide-1, bombesin (BN), chemokine receptor CXCR4 targeting peptides, and RGD peptides are currently under development or undergoing clinical trials. In this review, we discuss some of these peptides and their analogues, with regard to their potential for radionuclide imaging of tumours.
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Affiliation(s)
- Peter Laverman
- Department of Nuclear Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
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40
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Wyeth MS, Zhang N, Houser CR. Increased cholecystokinin labeling in the hippocampus of a mouse model of epilepsy maps to spines and glutamatergic terminals. Neuroscience 2011; 202:371-83. [PMID: 22155653 DOI: 10.1016/j.neuroscience.2011.11.056] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2011] [Accepted: 11/24/2011] [Indexed: 12/01/2022]
Abstract
The neuropeptide cholecystokinin (CCK) is abundant in the CNS and is expressed in a subset of inhibitory interneurons, particularly in their axon terminals. The expression profile of CCK undergoes numerous changes in several models of temporal lobe epilepsy. Previous studies in the pilocarpine model of epilepsy have shown that CCK immunohistochemical labeling is substantially reduced in several regions of the hippocampal formation, consistent with decreased CCK expression as well as selective neuronal degeneration. However, in a mouse pilocarpine model of recurrent seizures, increases in CCK-labeling also occur and are especially striking in the hippocampal dendritic layers of strata oriens and radiatum. Characterizing these changes and determining the cellular basis of the increased labeling were the major goals of the current study. One possibility was that the enhanced CCK labeling could be associated with an increase in GABAergic terminals within these regions. However, in contrast to the marked increase in CCK-labeled structures, labeling of GABAergic axon terminals was decreased in the dendritic layers. Likewise, cannabinoid receptor 1-labeled axon terminals, many of which are CCK-containing GABAergic terminals, were also decreased. These findings suggested that the enhanced CCK labeling was not due to an increase in GABAergic axon terminals. The subcellular localization of CCK immunoreactivity was then examined using electron microscopy, and the identities of the structures that formed synaptic contacts were determined. In pilocarpine-treated mice, CCK was observed in dendritic spines and these were proportionally increased relative to controls, whereas the proportion of CCK-labeled terminals forming symmetric synapses was decreased. In addition, CCK-positive axon terminals forming asymmetric synapses were readily observed in these mice. Double labeling with vesicular glutamate transporter 1 and CCK revealed colocalization in numerous terminals forming asymmetric synapses, confirming the glutamatergic identity of these terminals. These data raise the possibility that expression of CCK is increased in hippocampal pyramidal cells in mice with recurrent, spontaneous seizures.
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Affiliation(s)
- M S Wyeth
- Department of Neurobiology, CHS 73-235, David Geffen School of Medicine at the University of California Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095-1763, USA
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Abstract
Cholecystokinin (CCK), a peptide originally discovered in the gastrointestinal tract, is one of the most abundant and widely distributed neuropeptides in the brain. In spite of its abundance, recent data indicate that CCK modulates intrinsic neuronal excitability and synaptic transmission in a surprisingly cell-type specific manner, acting as a key molecular switch to regulate the functional output of neuronal circuits. The central importance of CCK in neuronal networks is also reflected in its involvement in a variety of neuropsychiatric and neurological disorders including panic attacks and epilepsy.
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Affiliation(s)
- Soo Yeun Lee
- Department of Anatomy and Neurobiology, University of California, Irvine, California, USA.
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Abstract
Panic disorder is one of the chronic and disabling anxiety disorders. There has been evidence for either genetic heterogeneity or complex inheritance, with environmental factor interactions and multiple single genes, in panic disorder's etiology. Linkage studies have implicated several chromosomal regions, but no research has replicated evidence for major genes involved in panic disorder. Researchers have suggested several neurotransmitter systems are related to panic disorder. However, to date no candidate gene association studies have established specific loci. Recently, researchers have emphasized genome-wide association studies. Results of two genome-wide association studies on panic disorder failed to show significant associations. Evidence exists for differences regarding gender and ethnicity in panic disorder. Increasing evidence suggests genes underlying panic disorder overlap, transcending current diagnostic boundaries. In addition, an anxious temperament and anxiety-related personality traits may represent intermediate phenotypes that predispose to panic disorder. Future research should focus on broad phenotypes, defined by comorbidity or intermediate phenotypes. Genome-wide association studies in large samples, studies of gene-gene and gene-environment interactions, and pharmacogenetic studies are needed.
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Affiliation(s)
- Hae-Ran Na
- Department of Psychiatry, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Eun-Ho Kang
- Department of Psychiatry, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jae-Hon Lee
- Department of Psychiatry, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Bum-Hee Yu
- Department of Psychiatry, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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43
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Woods SC, Taborsky GJ, Porte D. Central Nervous System Control of Nutrient Homeostasis. Compr Physiol 2011. [DOI: 10.1002/cphy.cp010407] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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45
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Correia JDG, Paulo A, Raposinho PD, Santos I. Radiometallated peptides for molecular imaging and targeted therapy. Dalton Trans 2011; 40:6144-67. [DOI: 10.1039/c0dt01599g] [Citation(s) in RCA: 99] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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46
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47
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Wierman ME, Kiseljak-Vassiliades K, Tobet S. Gonadotropin-releasing hormone (GnRH) neuron migration: initiation, maintenance and cessation as critical steps to ensure normal reproductive function. Front Neuroendocrinol 2011; 32:43-52. [PMID: 20650288 PMCID: PMC3008544 DOI: 10.1016/j.yfrne.2010.07.005] [Citation(s) in RCA: 101] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2010] [Revised: 07/08/2010] [Accepted: 07/14/2010] [Indexed: 12/23/2022]
Abstract
GnRH neurons follow a carefully orchestrated journey from their birth in the olfactory placode area. Initially, they migrate along with the vomeronasal nerve into the brain at the cribriform plate, then progress caudally to sites within the hypothalamus where they halt and send projections to the median eminence to activate pituitary gonadotropes. Many factors controlling this precise journey have been elucidated by the silencing or over-expression of candidate genes in mouse models. Importantly, a number of these factors may not only play a role in normal physiology of the hypothalamic-pituitary-gonadal axis but also be mis-expressed to cause human disorders of GnRH deficiency, presenting as a failure to undergo normal pubertal development. This review outlines the current cadre of candidates thought to modulate GnRH neuronal migration. The further elucidation and characterization of these factors that impact GnRH neuron development may shed new light on human reproductive disorders and provide potential targets to develop new pro-fertility or contraceptive agents.
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Affiliation(s)
- Margaret E Wierman
- Department of Medicine, University of Colorado-Denver, Aurora, CO 80045, USA
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Jacob C, Domschke K, Gajewska A, Warrings B, Deckert J. Genetics of panic disorder: focus on association studies and therapeutic perspectives. Expert Rev Neurother 2010; 10:1273-84. [PMID: 20662753 DOI: 10.1586/ern.10.76] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
There is evidence for either genetic heterogeneity or complex inheritance with an interaction of environmental factors and multiple single genes in the etiology of panic disorder. Although linkage analyses of panic disorder have implicated several chromosomal regions including 1q, 2q, 4q, 7p, 9q, 12q, 13q, 15q and 22q, they so far have not been able to identify a major gene responsible for panic disorder. Several genes of classical candidate neurotransmitter systems have been reported to be associated with panic disorder. Genetic variation in genes of monoamine oxidase A, catechol-O-methyltransferase, adenosine receptor (ADORA2A) and cholecystokinin B receptor have been inconsistently replicated. There are multiple lines of evidence for highly relevant effects of gender and ethnicity. Future research strategies might focus on broad phenotypes defined by comorbidity or intermediate phenotypes and include the use of animal models for identifying candidate genes, such as the regulator of G-protein signaling (RGS2) gene, genome-wide association studies in large samples, studies of gene-gene and gene-environment interactions and pharmacogenetic studies. The identification of novel pathophysiological pathways may provide the basis for the development of novel therapeutic interventions.
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Affiliation(s)
- C Jacob
- University of Wuerzburg, Wuerzburg, Germany
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Hermkens PHH, Ottenheijm HCJ, van der Werf-Pieters JML, Broekkamp CLE, de Boer T, van Nispen JW. CCK-A Agonists: Endeavours involving structure-activity relationship studies. ACTA ACUST UNITED AC 2010. [DOI: 10.1002/recl.19931120205] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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Roosenburg S, Laverman P, van Delft FL, Boerman OC. Radiolabeled CCK/gastrin peptides for imaging and therapy of CCK2 receptor-expressing tumors. Amino Acids 2010; 41:1049-58. [PMID: 20198494 PMCID: PMC3205271 DOI: 10.1007/s00726-010-0501-y] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2009] [Accepted: 01/25/2010] [Indexed: 11/30/2022]
Abstract
Cholecystokinin (CCK) receptors are overexpressed in numerous human cancers, like medullary thyroid carcinomas, small cell lung cancers and stromal ovarian cancers. The specific receptor-binding property of the endogenous ligands for these receptors can be exploited by labeling peptides with a radionuclide and using these as carriers to guide the radioactivity to the tissues that express the receptors. In this way, tumors can be visualized using positron emission tomography and single photon emission computed tomography imaging. A variety of radiolabeled CCK/gastrin-related peptides has been synthesized and characterized for imaging. All peptides have the C-terminal CCK receptor-binding tetrapeptide sequence Trp-Met-Asp-Phe-NH2 in common or derivatives thereof. This review focuses on the development and application of radiolabeled CCK/gastrin peptides for radionuclide imaging and radionuclide therapy of tumors expressing CCK receptors. We discuss both preclinical studies as well as clinical studies with CCK and gastrin peptides.
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Affiliation(s)
- Susan Roosenburg
- Department of Nuclear Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
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