5-HT1A and beyond: the role of serotonin and its receptors in depression and the antidepressant response

Abstract

Since its discovery 50 years ago, the role of the indoleamine 5-HT (5-hydroxytryptamine; serotonin) in the pathogenesis of depression and in the mechanism of action of antidepressant drugs has been the subject of considerable research. Advances in molecular biology and radioligand techniques have led to the functional characterisation of at least 14 serotonin receptor subtypes. This classification has led to the development of selective compounds that have aided in the efforts of dissecting the complex role of 5-HT in depression and in mediating the antidepressant response. This review focuses largely on novel strategies of targeting specific 5-HT receptors subtypes, especially the presynaptic 5-HT(1A) and 5-HT(1B/1D) receptors. These subtypes are of primary importance in that they control the firing of the 5-HT neuron and the release of 5-HT. In addition, a number of postsynaptic 5-HT receptors have been shown to be dysfunctional in depression and are also potential targets for a number of antidepressants. We conclude that selective targeting of 5-HT receptors may lead to a faster acting and more efficient antidepressant response. Copyright 2000 John Wiley & Sons, Ltd.

Participation of the 5-HT1A Receptor in the Antidepressant-Like Effect of Estrogens in the Forced Swimming Test

“…More evidence that sustains the participation of 5-HT 1A receptors in the effect of serotonergic antidepressants results from the use of antagonists to the 5-HT 1A receptor subtype, such as pindolol (Artigas et al, 1994(Artigas et al, , 1996 and WAY 100635 (Davidson and Stamford, 1995;Dawson and Nguyen, 1998;Gundlah et al, 1997;Hjorth et al, 1997;Millan et al, 1998), which, by blocking presynaptic serotonergic receptors, can facilitate the antidepressant action of serotonergic compounds in both clinical and preclinical studies (for a review, see Cryan and Leonard, 2000).…”

“…For example, it is accepted that the 5-HT 1A , 5-HT 2 , and 5-HT 3 receptors all participate in the antidepressant-like action induced by selective serotonin re-uptake inhibitors (SSRIs) such as fluoxetine (FLX), paroxetine or sertraline (Blier, 2001;Blier and Ward, 2003;Duman et al, 1997;Li et al, 1996Li et al, , 1997aRupprecht et al, 2001;Stahl, 1998a). In particular, the 5-HT 1A receptor has been proposed as a target of antidepressants that exhibit a clear therapeutic effect (for reviews see Blier and Ward, 2003;Cryan and Leonard, 2000). In this sense, in vitro and in vivo studies have shown that several SSRIs promote a desensitization of the presynaptic 5-HT 1A receptor subtype (Blier, 2001;Le Poul et al, 1995;Li et al, 1996Li et al, , 1997a, and that facilitates a general enhancement of serotonin levels.…”

Acute and chronic effects of citalopram on 5‐HT1A receptor—Labeling by [18F]MPPF and—Coupling to receptors‐G proteins

“…Dysregulation of brain 5-HT neurotransmission has been shown to be intricately associated with complex psychiatric disorders, such as depression and anxiety disorders (Cryan and Leonard, 2000;Jones and Blackburn, 2002;Kiss, 2008;Law et al, 2007). Among the diverse 5-HT receptor subtypes known to date, interactions with metabotropic 5-HT 1A receptors seem to be most relevant for understanding the mechanisms of action of antidepressants, anxiolytics such as azapir-ones, and some atypical antipsychotics (Blier and Ward, 2003;Bockaert et al, 2006;Diaz-Mataix et al, 2005;Meltzer et al, 2003;Pucadyil et al, 2005).…”

Metabotropic Glutamate Receptor Subtype 7 Ablation Causes Dysregulation of the HPA Axis and Increases Hippocampal BDNF Protein Levels: Implications for Stress-Related Psychiatric Disorders

“…In particular, the 5-HT 1A receptor (5-HT 1A R) is very susceptible to modulation by stress and HPA-axis activation and is well known to play an important role in the pathophysiology of mood disorders (Lopez et al, 1998;Cryan and Leonard, 2000;Leitch et al, 2003). Accumulating evidence points also to an important role for the neurotrophin brainderived neurotrophic factor (BDNF) in both the pathophysiology of mood disorders and in the therapeutic effects of antidepressants (Duman, 2002;Castren, 2004;Hashimoto et al, 2004).…”