Serotonin 1A and Serotonin 4 Receptors Essential Mediators of the Neurogenic and Behavioral Actions of Antidepressants
TL;DR: It is proposed that novel antidepressant drugs that selectively target these serotonin receptors could be developed to yield improvements over current treatments for major depressive disorders.
Abstract: Selective serotonin reuptake inhibitors are the mostly widely used treatment for major depressive disorders and also are prescribed for several anxiety disorders. However, similar to most antidepressants, selective serotonin reuptake inhibitors suffer from two major problems: They only show beneficial effects after 2 to 4 weeks and only about 33% of patients show remission to first-line treatment. Thus, there is a considerable need for development of more effective antidepressants. There is a growing body of evidence supporting critical roles of 5-HT1A and 5-HT4 receptor subtypes in mediating successful depression treatments. In addition, appropriate activation of these receptors may be associated with a faster onset of the therapeutic response. This review will examine the known roles of 5-HT1A and 5-HT4 receptors in mediating both the pathophysiology of depression and anxiety and the treatment of these mood disorders. At the end of the review, the role of these receptors in the regulation of adult hippocampal neurogenesis will also be discussed. Ultimately, we propose that novel antidepressant drugs that selectively target these serotonin receptors could be developed to yield improvements over current treatments for major depressive disorders.
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TL;DR: It is argued that failure to recognize and consistently emphasize a distinction between circuits underlying two classes of responses elicited by threats has impeded progress in understanding fear and anxiety disorders and hindered attempts to develop more effective pharmaceutical and psychological treatments.
Abstract: Tremendous progress has been made in basic neuroscience in recent decades. One area that has been especially successful is research on how the brain detects and responds to threats. Such studies have demonstrated comparable patterns of brain-behavior relationships underlying threat processing across a range of mammalian species, including humans. This would seem to be an ideal body of information for advancing our understanding of disorders in which altered threat processing is a key factor, namely, fear and anxiety disorders. But research on threat processing has not led to significant improvements in clinical practice. The authors propose that in order to take advantage of this progress for clinical gain, a conceptual reframing is needed. Key to this conceptual change is recognition of a distinction between circuits underlying two classes of responses elicited by threats: 1) behavioral responses and accompanying physiological changes in the brain and body and 2) conscious feeling states reflected in sel...
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128 citations
TL;DR: This review, based on animal studies, discusses the possible involvement of serotonin receptor subtypes in depression and anxiety and uses genetically modified animals and selective or preferential agonists and antagonist to demonstrate the involvement.
109 citations
TL;DR: The aim of the present review is to document recent literature regarding the impact of inflammatory mechanisms on the pathophysiology of the depressive disorder.
Abstract: According to the World Health Organization, major depression will become the leading cause of disability worldwide by the year 2030. Despite extensive research into the mechanisms underlying this disease, the rate, prevalence and disease burden has been on the rise, particularly in the industrialized world. Epidemiological studies have shown biological and biochemical differences in disease characteristics and treatment responses in different age groups. Notable differences have been observed in the clinical presentation, co-prevalence with other diseases, interaction with the immune system and even in the outcome. Thus, there is an increased interest in characterizing these differences, particularly in terms of contribution of different factors, including age, cytokines and immunotherapy. Research into the possible mechanisms of these interactions may reveal novel opportunities for future pharmacotherapy. The aim of the present review is to document recent literature regarding the impact of inflammatory mechanisms on the pathophysiology of the depressive disorder.
100 citations
Cites background from "Serotonin 1A and Serotonin 4 Recept..."
...The antidepressants, selective serotonin re-uptake inhibitors (SSRIs) have been developed in order to ensure the abundance of serotonin in synapses, based on the particularly dynamic association between serotonin availability and serotonin transporters, and receptor function and depression (50)....
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University of Birmingham1, University of Melbourne2, Georgetown University Medical Center3, French Institute of Health and Medical Research4, University of Montpellier5, Mayo Clinic6, University of Texas Medical Branch7, University of Nottingham8, Columbia University9, University of Malta10, University of Toronto11, University of California, San Diego12, Albany Medical College13, École Polytechnique Fédérale de Lausanne14, University of Bari15, Oslo University Hospital16, University of Cambridge17, University of Paris18, Grünenthal GmbH19, University of Washington20, Dana Corporation21, University of Grenoble22, Centre national de la recherche scientifique23, Commissariat à l'énergie atomique et aux énergies alternatives24, University of North Carolina at Chapel Hill25, Queen Mary University of London26, University of Oxford27, CINVESTAV28, Michigan State University29, Florey Institute of Neuroscience and Mental Health30, Scripps Research Institute31
TL;DR: In this article, a comprehensive account of the classification and function of 5-hydroxytryptamine receptors, including how they are targeted for therapeutic benefit, is provided, where appropriate, the utility of therapeutics targeting these receptors.
Abstract: 5-HT receptors expressed throughout the human body are targets for established therapeutics and various drugs in development. Their diversity of structure and function reflects the important role 5-HT receptors play in physiologic and pathophysiological processes. The present review offers a framework for the official receptor nomenclature and a detailed understanding of each of the 14 5-HT receptor subtypes, their roles in the systems of the body, and, where appropriate, the (potential) utility of therapeutics targeting these receptors. SIGNIFICANCE STATEMENT: This review provides a comprehensive account of the classification and function of 5-hydroxytryptamine receptors, including how they are targeted for therapeutic benefit.
89 citations
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TL;DR: Although mental disorders are widespread, serious cases are concentrated among a relatively small proportion of cases with high comorbidity, as shown in the recently completed US National Comorbidities Survey Replication.
Abstract: Background Little is known about the general population prevalence or severity of DSM-IV mental disorders. Objective To estimate 12-month prevalence, severity, and comorbidity of DSM-IV anxiety, mood, impulse control, and substance disorders in the recently completed US National Comorbidity Survey Replication. Design and Setting Nationally representative face-to-face household survey conducted between February 2001 and April 2003 using a fully structured diagnostic interview, the World Health Organization World Mental Health Survey Initiative version of the Composite International Diagnostic Interview. Participants Nine thousand two hundred eighty-two English-speaking respondents 18 years and older. Main Outcome Measures Twelve-month DSM-IV disorders. Results Twelve-month prevalence estimates were anxiety, 18.1%; mood, 9.5%; impulse control, 8.9%; substance, 3.8%; and any disorder, 26.2%. Of 12-month cases, 22.3% were classified as serious; 37.3%, moderate; and 40.4%, mild. Fifty-five percent carried only a single diagnosis; 22%, 2 diagnoses; and 23%, 3 or more diagnoses. Latent class analysis detected 7 multivariate disorder classes, including 3 highly comorbid classes representing 7% of the population. Conclusion Although mental disorders are widespread, serious cases are concentrated among a relatively small proportion of cases with high comorbidity.
10,951 citations
TL;DR: It is shown that disrupting antidepressant-induced neurogenesis blocks behavioral responses to antidepressants, suggesting that the behavioral effects of chronic antidepressants may be mediated by the stimulation of neuroGenesis in the hippocampus.
Abstract: Various chronic antidepressant treatments increase adult hippocampal neurogenesis, but the functional importance of this phenomenon remains unclear. Here, using genetic and radiological methods, we show that disrupting antidepressant-induced neurogenesis blocks behavioral responses to antidepressants. Serotonin 1A receptor null mice were insensitive to the neurogenic and behavioral effects of fluoxetine, a serotonin selective reuptake inhibitor. X-irradiation of a restricted region of mouse brain containing the hippocampus prevented the neurogenic and behavioral effects of two classes of antidepressants. These findings suggest that the behavioral effects of chronic antidepressants may be mediated by the stimulation of neurogenesis in the hippocampus.
4,116 citations
TL;DR: A number of 5-HT receptor ligands are currently utilised, or are in clinical development, to reduce the symptoms of CNS dysfunction and the functional responses attributed to each receptor in the brain are reviewed.
3,074 citations
"Serotonin 1A and Serotonin 4 Recept..." refers background in this paper
...After chronic SSRI treatment, serotonin (5-HT) is released throughout the forebrain by axons emanating from cell bodies located in the midbrain raphe (Barnes and Sharp 1999) (Figure 1A)....
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...In addition, 5-HT levels are limited by two inhibitory autoreceptors (5-HT1A and 5-HT1B) expressed in the somatodendritic compartments (5-HT1A) and nerve terminals (5-HT1B) of the serotonergic raphe neurons (Barnes and Sharp 1999)....
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TL;DR: Investigation of the effect of antidepressants on hippocampal neurogenesis in the adult rat using the thymidine analog bromodeoxyuridine (BrdU) as a marker for dividing cells demonstrates that chronic antidepressant treatment significantly increases the number of BrdU-labeled cells in the dentate gyrus and hilus of the hippocampus.
Abstract: Recent studies suggest that stress-induced atrophy and loss of hippocampal neurons may contribute to the pathophysiology of depression. The aim of this study was to investigate the effect of antidepressants on hippocampal neurogenesis in the adult rat, using the thymidine analog bromodeoxyuridine (BrdU) as a marker for dividing cells. Our studies demonstrate that chronic antidepressant treatment significantly increases the number of BrdU-labeled cells in the dentate gyrus and hilus of the hippocampus. Administration of several different classes of antidepressant, but not non-antidepressant, agents was found to increase BrdU-labeled cell number, indicating that this is a common and selective action of antidepressants. In addition, upregulation of the number of BrdU-labeled cells is observed after chronic, but not acute, treatment, consistent with the time course for the therapeutic action of antidepressants. Additional studies demonstrated that antidepressant treatment increases the proliferation of hippocampal cells and that these new cells mature and become neurons, as determined by triple labeling for BrdU and neuronal- or glial-specific markers. These findings raise the possibility that increased cell proliferation and increased neuronal number may be a mechanism by which antidepressant treatment overcomes the stress-induced atrophy and loss of hippocampal neurons and may contribute to the therapeutic actions of antidepressant treatment.
3,053 citations
TL;DR: Analysis of preclinical cellular and behavioral models of depression and antidepressant actions, as well as clinical neuroimaging and postmortem studies, are consistent with the hypothesis that decreased expression of BDNF and possibly other growth factors contributes to depression and that upregulation ofBDNF plays a role in the actions of antidepressant treatment.
2,999 citations