The role of serotonin receptor subtypes in treating depression: a review of animal studies

Abstract

Rationale Serotonin reuptake inhibitors (SSRIs) are effective in treating depression. Given the existence of different families and subtypes of 5-HT receptors, multiple 5-HT receptors may be involved in the antidepressant-like behavioral effects of SSRIs. Objective Behavioral pharmacology studies investigating the role of 5-HT receptor subtypes in producing or blocking the effects of SSRIs were reviewed. Results Few animal behavior tests were available to support the original development of SSRIs. Since their development, a number of behavioral tests and models of depression have been developed that are sensitive to the effects of SSRIs, as well as to other types of antidepressant treatments. The rationale for the development and use of these tests is reviewed. Behavioral effects similar to those of SSRIs (antidepressant-like) have been produced by agonists at 5-HT1A, 5-HT1B, 5-HT2C, 5-HT4, and 5-HT6 receptors. Also, antagonists at 5-HT2A, 5-HT2C, 5-HT3, 5- HT6, and 5-HT7 receptors have been reported to produce antidepressant-like responses. Although it seems paradoxical that both agonists and antagonists at particular 5-HT receptors can produce antidepressant-like effects, they probably involve diverse neurochemical mechanisms. The behavioral effects of SSRIs and other antidepressants may also be augmented when 5-HT receptor agonists or antagonists are given in combination. Conclusions The involvement of 5-HT receptors in the antidepressant-like effects of SSRIs is complex and involves the orchestration of stimulation and blockade at different 5-HT receptor subtypes. Individual 5-HT receptors provide opportunities for the development of a newer generation of antidepressants that may be more beneficial and effective than SSRIs.

Pharmacogenetics of antidepressant drugs: An update

“…The 5-HT1A receptors are present preand postsynaptically in different brain regions that receive serotonergic input from the raphe nuclei: the frontal cortex, septum, amygdala, hippocampus and hypothalamus [96]. Converging lines of evidence from the animal studies suggest that agonists of 5-HT1A receptors produce antidepressant-like effects [96]. Moreover, its desensitization is thought to be one possible antidepressant mechanism [97].…”

Interleukin-6 Attenuates Serotonin 2A Receptor Signaling by Activating the JAK-STAT Pathway

“…5-HT 2A receptors couple to multiple intracellular signaling cascades (Berg et al, 1998;Urban et al, 2007); however, G q/11 protein-mediated activation of phospholipase C is perhaps the best characterized pathway (Leysen, 2004;Nichols and Nichols, 2008). The 5-HT 2A receptor is thought to play an important role in regulating mood and cognition and has been implicated in the pathology of several psychiatric disorders (Gray and Roth, 2001;Carr and Lucki, 2011). In humans, depression and schizophrenia have been associated with increased expression of 5-HT 2A receptors in the brain (Gurevich and Joyce, 1997;Shelton et al, 2009), and effective treatment strategies have been shown to decrease 5-HT 2A receptor expression and/or function (Gray and Roth, 2001).…”

S32212, a Novel Serotonin Type 2C Receptor Inverse Agonist/α2-Adrenoceptor Antagonist and Potential Antidepressant: I. A Mechanistic Characterization

“…In the search for more effective drugs, recent years have witnessed a focus on drugs interacting selectively with one specific target. Despite encouraging observations with antagonists of N-methyl-D-aspartate and nicotinic ␣ 4 ␤ 2 receptors (Rosenzweig-Lipson et al, 2007;Rozas, 2009;Mineur and Picciotto, 2010;Carr and Lucki, 2011;Skolnick et al, 2011), no new agents have as yet been launched. Accordingly, in addition to the association of mechanistically distinct antidepressants, there is a rekindling of interest in agents that interact with several therapeutically relevant mechanisms (Morphy and Rankovic, 2005;Millan, 2006;Wong et al, 2008;Blier et al, 2009).…”

“…Blockade of tonically and/or constitutively active 5-HT 2C receptors on GABAergic interneurones inhibitory to monoaminergic pathways disinhibits the corticolimbic release of dopamine and nonadrenaline (NA), thereby alleviating depressed mood (Gobert et al, 2000;Millan et al, 2000b;Aloyo et al, 2009;Leggio et al, 2009;Di Giovanni et al, 2010). Although the influence of 5-HT 2C receptors is not necessarily unitary (Millan, 2005;Rosenzweig-Lipson et al, 2007;Siuciak et al, 2007;Dekeyne et al, 2008;Carr and Lucki, 2011), their antagonism also improves mood via other mechanisms, such as enhanced hippocampal neurogenesis (Dekeyne et al, 2008;Soumier et al, 2009). Moreover, blockade of 5-HT 2C receptors is associated with anxiolytic properties (Millan, 2005;Heisler et al, 2007;Dekeyne et al, 2008) and the promotion of sexual function (Hull et al, 2004;Millan, 2006;Kennedy and Rizvi, 2009).…”

“…5-HT 2C antagonists also favor restorative slow-wave sleep (Smith et al, 2002;Landholt and Wehrle, 2009;de Bodinat et al, 2010); although their precise role compared with their 5-HT 2A counterparts remains uncertain (Millan, 2006;Morairty et al, 2008). Although data are limited, blockade of 5-HT 2A receptors may, by analogy to antagonism of 5-HT 2C receptors, exert a positive influence on mood, as well as on certain domains of cognitive performance (Millan, 2006;Berg et al, 2008;Landholt and Wehrle, 2009;Pandey et el., 2010;Carr and Lucki, 2011).…”