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Neuroendocrine consequences of social isolation
Abstracts / Frontiers in Neuroendocrinology 27 (2006) 134–138
The protective activity of brain dehydroepiandrosterone (DHEA) in behavioral disorders R. Maayan, D. Touati-Werner, D. Eizner, D. Biton, A. Weizman Felsenstein Medical Research Center, Campus Beilinson, Petach-Tikva and Sackler Faculty of Medicine, Tel-Aviv University, Israel DHEA, a neuoroactive neurosteroids, modulates ligand-gated ion-channel receptor activity via non-genomic mechanisms. Neurosteroids are known to be involved in behavioral processes such as response to stressful events, cognition, anxiety, aggression, and depression. The aim of the study was to verify whether DHEA has a protective role preventing the occurrence or enhancement in the severity of behavioral disorders such as depression and anxiety. Four groups of mice were tested: (1) controls , (2) mice having significantly high DHEA levels—achieved by DHEA ip injections, 1.6 mg/kg, (3) mice having significantly low DHEA levels—achieved by castration, and (4) mice which had significantly low DHEA levels treated with DHEA to reverse its level to normal—achieved by castration and DHEA ip injections, 0.4 mg/kg. Forced-Swim test (FST) was chosen as an animal model for depression and Elevated-Plus-Maze (EPM) as an animal model for anxiety. We have found that DHEA has an anti depressive-like effect, as shown by a decreased immobility time in mice having significantly high level of DHEA (less depressed), an increased immobility time in mice having significantly low level of DHEA (more depressed), and control’s level in mice which had significantly low DHEA levels treated to reverse it to normal. We have found as well that DHEA has an anti anxiety-like effect, as shown by the open-arm time in EPM. We can conclude that high levels of DHEA have an anti anxiety-like and an anti-depressive-like effects in mice and mice having low levels of brain DHEA are more vulnerable to depression and/or anxiety. doi:10.1016/j.yfrne.2006.03.280
Neuroendocrine consequences of social isolation Kinzo Matsumoto a,b, Graziano Pinna b, Alessandro Guidotti b, Erminio Costa b a Division of Medicinal Pharmacology, Institute of Natural Medicine, University of Toyama, Japan b Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, IL, USA Protracted social isolation (SI) of male mice induces a variety of behavioral abnormalities such as aggressive behavior (AGB), and has been proposed as a model of psychiatric disorders. We have previously demonstrated that SI not only causes AGB but also reduces responsiveness to drugs such as pentobarbital (PTB) that positively modulates the c-aminobutyric acid A receptor (GABAA-R).
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Several lines of evidence suggested that this decrease was partly due to impairment of GABAA receptor function which occurred via downregulation of neurosteroid biosynthesis in the brain. First, administration of neurosteroids with GABA mimetic properties normalized the responsiveness to PTB in SI mice (SIM) at doses that had no effect in group-housed control mice (GHM). Second, treatment of GHM with a type I 5a-reductase (5aR) inhibitor SKF105111 (SKF) depleted the brain content of allopregnanolone (Allo), a neurosteroid that positively modulates the GABAA-R, and concomitantly reduced sedative action of GABA mimetics. Third, in electrophysiological studies, depletion of brain Allo by SKF reduced the potency of GABAA-R agonists to evoke Cl currents and GABAmediated inhibitory postsynaptic currents. Finally, neurochemical analysis has indicated that SI reduces brain Allo content by downregulating type I 5aR. Thus, it could be hypothesized that endogenous level of brain Allo plays an upregulatory role in the GABAA-R function in GHM and that SI-induced reduction of the GABAA-R function is due to elimination of the upregulatory effect. This hypothesis was supported by pharmacological studies using fluoxetine (Flx), norfluoxetine (NFlx), and their stereoisomers. Administration of Flx, NFlx, and their S-isomers to SI mice normalized brain Allo content, reversed the decrease in responsiveness to PTB, and reduced AGB at the doses that are smaller than those needed to inhibit 5-HT uptake. The inhibition of 5-HT uptake by Flx and NFlx lacked stereospecificity. Our findings suggest that SI-induced Allo biosynthesis downregulation is relevant to behavioral abnormalities in SIM and that the drugs capable of stimulating Allo biosynthesis may be useful for treatment psychiatric disorders. doi:10.1016/j.yfrne.2006.03.281
Protective effects of neuropeptide S against MK-801-induced psychotic-like behavior and neuropathological changes Naoe Okamura a,b, Rainer K. Reinscheid a,b, Olivier Civelli a,c, Shintaro Ohgake d, Masaomi Iyo d,e, Kenji Hashimoto e a Department of Pharmacology, University of California, Irvine, CA 92697, USA b Program in Pharmaceutical Sciences, University of California, Irvine, CA 92697, USA c Department of Developmental and Cell Biology, University of California, Irvine, CA 92697, USA d Department of Psychiatry, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan e Division of Clinical Neuroscience, Chiba University, Center for Forensic Mental Health, Chiba 260-8670, Japan Neuropeptide S (NPS) is an endogenous ligand of a recently deorphanized G protein-coupled receptor. NPS was reported to have anxiolytic-like and arousal effects. NPS receptors (NPSR) are predominantly expressed in
The protective activity of brain dehydroepiandrosterone (DHEA) in behavioral disorders R. Maayan, D. Touati-Werner, D. Eizner, D. Biton, A. Weizman Felsenstein Medical Research Center, Campus Beilinson, Petach-Tikva and Sackler Faculty of Medicine, Tel-Aviv University, Israel DHEA, a neuoroactive neurosteroids, modulates ligand-gated ion-channel receptor activity via non-genomic mechanisms. Neurosteroids are known to be involved in behavioral processes such as response to stressful events, cognition, anxiety, aggression, and depression. The aim of the study was to verify whether DHEA has a protective role preventing the occurrence or enhancement in the severity of behavioral disorders such as depression and anxiety. Four groups of mice were tested: (1) controls , (2) mice having significantly high DHEA levels—achieved by DHEA ip injections, 1.6 mg/kg, (3) mice having significantly low DHEA levels—achieved by castration, and (4) mice which had significantly low DHEA levels treated with DHEA to reverse its level to normal—achieved by castration and DHEA ip injections, 0.4 mg/kg. Forced-Swim test (FST) was chosen as an animal model for depression and Elevated-Plus-Maze (EPM) as an animal model for anxiety. We have found that DHEA has an anti depressive-like effect, as shown by a decreased immobility time in mice having significantly high level of DHEA (less depressed), an increased immobility time in mice having significantly low level of DHEA (more depressed), and control’s level in mice which had significantly low DHEA levels treated to reverse it to normal. We have found as well that DHEA has an anti anxiety-like effect, as shown by the open-arm time in EPM. We can conclude that high levels of DHEA have an anti anxiety-like and an anti-depressive-like effects in mice and mice having low levels of brain DHEA are more vulnerable to depression and/or anxiety. doi:10.1016/j.yfrne.2006.03.280
Neuroendocrine consequences of social isolation Kinzo Matsumoto a,b, Graziano Pinna b, Alessandro Guidotti b, Erminio Costa b a Division of Medicinal Pharmacology, Institute of Natural Medicine, University of Toyama, Japan b Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, IL, USA Protracted social isolation (SI) of male mice induces a variety of behavioral abnormalities such as aggressive behavior (AGB), and has been proposed as a model of psychiatric disorders. We have previously demonstrated that SI not only causes AGB but also reduces responsiveness to drugs such as pentobarbital (PTB) that positively modulates the c-aminobutyric acid A receptor (GABAA-R).
137
Several lines of evidence suggested that this decrease was partly due to impairment of GABAA receptor function which occurred via downregulation of neurosteroid biosynthesis in the brain. First, administration of neurosteroids with GABA mimetic properties normalized the responsiveness to PTB in SI mice (SIM) at doses that had no effect in group-housed control mice (GHM). Second, treatment of GHM with a type I 5a-reductase (5aR) inhibitor SKF105111 (SKF) depleted the brain content of allopregnanolone (Allo), a neurosteroid that positively modulates the GABAA-R, and concomitantly reduced sedative action of GABA mimetics. Third, in electrophysiological studies, depletion of brain Allo by SKF reduced the potency of GABAA-R agonists to evoke Cl currents and GABAmediated inhibitory postsynaptic currents. Finally, neurochemical analysis has indicated that SI reduces brain Allo content by downregulating type I 5aR. Thus, it could be hypothesized that endogenous level of brain Allo plays an upregulatory role in the GABAA-R function in GHM and that SI-induced reduction of the GABAA-R function is due to elimination of the upregulatory effect. This hypothesis was supported by pharmacological studies using fluoxetine (Flx), norfluoxetine (NFlx), and their stereoisomers. Administration of Flx, NFlx, and their S-isomers to SI mice normalized brain Allo content, reversed the decrease in responsiveness to PTB, and reduced AGB at the doses that are smaller than those needed to inhibit 5-HT uptake. The inhibition of 5-HT uptake by Flx and NFlx lacked stereospecificity. Our findings suggest that SI-induced Allo biosynthesis downregulation is relevant to behavioral abnormalities in SIM and that the drugs capable of stimulating Allo biosynthesis may be useful for treatment psychiatric disorders. doi:10.1016/j.yfrne.2006.03.281
Protective effects of neuropeptide S against MK-801-induced psychotic-like behavior and neuropathological changes Naoe Okamura a,b, Rainer K. Reinscheid a,b, Olivier Civelli a,c, Shintaro Ohgake d, Masaomi Iyo d,e, Kenji Hashimoto e a Department of Pharmacology, University of California, Irvine, CA 92697, USA b Program in Pharmaceutical Sciences, University of California, Irvine, CA 92697, USA c Department of Developmental and Cell Biology, University of California, Irvine, CA 92697, USA d Department of Psychiatry, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan e Division of Clinical Neuroscience, Chiba University, Center for Forensic Mental Health, Chiba 260-8670, Japan Neuropeptide S (NPS) is an endogenous ligand of a recently deorphanized G protein-coupled receptor. NPS was reported to have anxiolytic-like and arousal effects. NPS receptors (NPSR) are predominantly expressed in