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      Raphe-Hippocampal Serotonin Neurotransmission In The Sex Related Differences of Adaptation to Stress: Focus on Serotonin-1A Receptor

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          Abstract

          Stress is the major predisposing and precipitating factor in the onset of depression which is the most significant mental health risk for women. Behavioral studies in animal models show that female sex though less affected by an acute stressor; exposure to repeated stressors induces coping deficits to impair adaptation in them. A decrease in the function of 5-hydroxytryptamine (5-HT; serotonin) in the hippocampus and an increased function of the 5-HT-1A receptor in the raphe nucleus coexist in depression. Pharmacological and neurochemical data are relevant that facilitation of serotonin neurotransmission via hippocampus due to desensitization of somatodendritic 5-HT1A receptors may lead to adaptation to stress. The present article reviews research on sex related differences of raphe-hippocampal serotonin neurotransmission to find a possible answer that may account for the sex differences of adaptation to stress reported in preclinical research and greater incidence of depression in women than men.

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          Epidemiology of women and depression.

          R Kessler (2003)
          Depression is the leading cause of disease-related disability among women in the world today. Depression is much more common among women than men, with female/male risk ratios roughly 2:1. Recent epidemiological research is reviewed. Implications are suggested for needed future research. The higher prevalence of depression among women than men is due to higher risk of first onset, not to differential persistence or recurrence. Although the gender difference first emerges in puberty, other experiences related to changes in sex hormones (pregnancy, menopause, use of oral contraceptives, and use of hormone replacement therapy) do not significantly influence major depression. These observations suggest that the key to understanding the higher rates of depression among women than men lies in an investigation of the joint effects of biological vulnerabilities and environmental provoking experiences. Advancing understanding of female depression will require future epidemiologic research to focus on first onsets and to follow incident cohorts of young people through the pubertal transition into young adulthood with fine-grained measures of both sex hormones and gender-related environmental experiences. Experimental interventions aimed at primary prevention by jointly manipulating putative biological and environmental risk factors will likely be needed to adjudicate between contending causal hypotheses regarding the separate and joint effects of interrelated risk factors.
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            Stress and hippocampal plasticity.

            B S McEwen (1999)
            The hippocampus is a target of stress hormones, and it is an especially plastic and vulnerable region of the brain. It also responds to gonadal, thyroid, and adrenal hormones, which modulate changes in synapse formation and dendritic structure and regulate dentate gyrus volume during development and in adult life. Two forms of structural plasticity are affected by stress: Repeated stress causes atrophy of dendrites in the CA3 region, and both acute and chronic stress suppresses neurogenesis of dentate gyrus granule neurons. Besides glucocorticoids, excitatory amino acids and N-methyl-D-aspartate (NMDA) receptors are involved in these two forms of plasticity as well as in neuronal death that is caused in pyramidal neurons by seizures and by ischemia. The two forms of hippocampal structural plasticity are relevant to the human hippocampus, which undergoes a selective atrophy in a number of disorders, accompanied by deficits in declarative episodic, spatial, and contextual memory performance. It is important, from a therapeutic standpoint, to distinguish between a permanent loss of cells and a reversible atrophy.
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              Molecular, pharmacological and functional diversity of 5-HT receptors.

              Daniel Hoyer, Jason Hannon, Graeme R Martin (2002)
              Serotonin (5-hydroxytryptamine, 5-HT) is probably unique among the monoamines in that its effects are subserved by as many as 13 distinct heptahelical, G-protein-coupled receptors (GPCRs) and one (presumably a family of) ligand-gated ion channel(s). These receptors are divided into seven distinct classes (5-HT(1) to 5-HT(7)) largely on the basis of their structural and operational characteristics. Whilst this degree of physical diversity clearly underscores the physiological importance of serotonin, evidence for an even greater degree of operational diversity continues to emerge. The challenge for modern 5-HT research has therefore been to define more precisely the properties of the systems that make this incredible diversity possible. Much progress in this regard has been made during the last decade with the realisation that serotonin is possibly the least conservative monoamine transmitter and the cloning of its many receptors. Coupled with the actions of an extremely avid and efficient reuptake system, this array of receptor subtypes provides almost limitless signalling capabilities to the extent that one might even question the need for other transmitter systems. However, the complexity of the system appears endless, since posttranslational modifications, such as alternate splicing and RNA editing, increase the number of proteins, oligomerisation and heteromerisation increase the number of complexes, and multiple G-protein suggest receptor trafficking, allowing phenotypic switching and crosstalk within and possibly between receptor families. Whether all these possibilities are used in vivo under physiological or pathological conditions remains to be firmly established, but in essence, such variety will keep the 5-HT community busy for quite some time. Those who may have predicted that molecular biology would largely simplify the life of pharmacologists have missed the point for 5-HT research in particular and, most probably, for many other transmitters. This chapter is an attempt to summarise very briefly 5-HT receptor diversity. The reward for unravelling this complex array of serotonin receptor--effector systems may be substantial, the ultimate prize being the development of important new drugs in a range of disease areas.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Curr Neuropharmacol
                Journal ID (publisher-id): CN
                Title: Current Neuropharmacology
                Publisher: Bentham Science Publishers
                ISSN (Print): 1570-159X
                ISSN (Electronic): 1875-6190
                Publication date (Print): September 2011
                Volume: 9
                Issue: 3
                Pages: 512-521
                Affiliations
                []Department of Biochemistry, Neurochemistry and Biochemical Neuropharmacology Research Unit, University of Karachi, Karachi 75270, Pakistan
                Author notes
                [* ]Address correspondence to this author at the Department of Biochemistry University of Karachi, Karachi 75270, Pakistan; Tel: 03003390776; E-mails: darakhshan_haleem@ 123456yahoo.com , djhaleem@ 123456uok.edu.pk
                Article
                Publisher ID: CN-9-512
                DOI: 10.2174/157015911796558019
                PMC ID: 3151603
                PubMed ID: 22379463
                SO-VID: fd93becd-e58d-44e2-ab58-c8b3776f793b
                Copyright © ©2011 Bentham Science Publishers
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.5/), which permits unrestrictive use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 19 January 2010
                Date revision received : 7 May 2010
                Date accepted : 29 October 2010
                Categories
                Subject: Article

                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: stress 5-ht-1a receptors,depression.,sex related differences,hippocampus,raphe,serotonin
                Data availability:
                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: stress 5-ht-1a receptors, depression., sex related differences, hippocampus, raphe, serotonin

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