5-HT_1A receptor function in major depressive disorder

Abstract

Dysfunction of the serotonin 1A receptor (5-HT_1A) may play a role in the genesis of major depressive disorder (MDD). Here we review the pharmacological, post-mortem, positron emission tomography (PET), and genetic evidence in support of this statement. We also touch briefly on two MDD-associated phenotypes, cognitive impairment and somatic pain. The results of pharmacological challenge studies with 5-HT_1A receptor agonists are indicative of blunted endocrine responses in depressed patients. Lithium, valproate, selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), and other treatment, such as electroconvulsive shock therapy (ECT), all increase post-synaptic 5-HT_1A receptor signaling through either direct or indirect effects. Reduced somatodendritic and postsynaptic 5-HT_1A receptor numbers or affinity have been reported in some post-mortem studies of suicide victims, a result consistent with well-replicated PET analyses demonstrating reduced 5-HT_1A receptor binding potential in diverse regions such as the dorsal raphe, medial prefrontal cortex (mPFC), amygdala and hippocampus. 5-HT_1A receptor knockout (KO) mice display increased anxiety-related behavior, which, unlike in their wild-type counterparts, cannot be rescued with antidepressant drug (AD) treatment. In humans, the G allele of a single nucleotide polymorphism (SNP) in the 5-HT_1A receptor gene (HTR1A; rs6295), which abrogates a transcription factor binding site for deformed epidermal autoregulatory factor-1 (Deaf-1) and Hes5, has been reported to be over-represented in MDD cases. Conversely, the C allele has been associated with better response to AD drugs. We raise the possibility that 5-HT_1A receptor dysfunction represents one potential mechanism underpinning MDD and other stress-related disorders.

Introduction

The decreased levels of serotonin metabolites in cerebrospinal fluid (CSF), coupled with the mood-lowering effects of tryptophan depletion and the efficacy of serotonin-modulating antidepressants, have lent support to the notion that a dysfunctional serotonergic system is a vulnerability factor for major depressive disorder (MDD; or “unipolar depression”) and other forms of affective illness (Jans et al., 2006).

At least 14 different serotonin receptors have been identified (Hoyer et al., 2002). These receptors can be divided into distinct families – denoted 1, 2, 3, 4, 5, 6, and 7, with subtypes in each family denoted by letters such as a, b, and c. A number of these receptors may play a role in the genesis of psychiatric illness. For example, polymorphisms of the HTR2A gene [Entrez ID 3356], which codes for the 5-HT_2A receptor, have been associated with major depressive illness (MDD) (Christiansen et al., 2007) and the efficacy of antidepressant drug (AD) treatment (McMahon et al., 2006). In addition, variants of the HTR3A gene [Entrez ID 3359], which codes for the A subunit of the 5-HT₃ receptor, have been associated with bipolar disorder and schizophrenia (Niesler et al., 2008). This study will, however, focus on one of the best characterized of these receptors, the serotonin 1A receptor (5-HT_1A), which is a key mediator of serotonergic signaling in the central nervous system.

Central serotonergic neurons are located in the raphe nuclei in the brain stem (Jans et al., 2006). The 5-HT_1A receptor is a G-protein-coupled receptor widely distributed in regions that receive serotonergic input from the raphe nuclei: the frontal cortex, septum, amygdala, hippocampus, and hypothalamus (Lesch and Gutknecht, 2004, Sharp et al., 2007). In these cortico-limbic regions 5-HT_1A is distributed post-synaptically (Celada et al., 2004, Sharp et al., 2007). The 5-HT_1A receptor also serves as the predominant (somatodendritic) autoreceptor of the raphe nuclei, reducing the firing rate of these neurons, the amount of serotonin released per action potential, and the synthesis of the neurotransmitter; and thus by implication, the serotonergic activity of its projection areas (Wang and Aghajanian, 1977, Verge et al., 1985, Sprouse and Aghajanian, 1986, Blier and de Montigny, 1987, Hutson et al., 1989, Meller et al., 1990, Hjorth and Sharp, 1991, Kreiss and Lucki, 1994). Activation of the somatodendritic (i.e., presynaptic) 5-HT_1A receptors may also indirectly reduce serotonergic transmission through the inhibition of tyrosine hydroxylase synthesis (reviewed in Drevets et al. (2007)), as well as an excitatory, glutamatergic pathway that originates in the medial prefrontal cortex (mPFC) and projects to the raphe nuclei (Sharp et al., 2007).

The 5-HT_1A receptor not only contributes not only to the dynamic modulation of serotonergic activity impacting diverse functions such as cognition and emotion, but is thought to play a crucial role in the neuronal migration, neurite outgrowth and synapse formation inherent to the neurodevelopmental process (Whitaker-Azmitia et al., 1996). The 5-HT_1A receptor is therefore a natural candidate for impacting an array of phenotypes, among them affective disorders.

There are four strands of evidence implicating the 5-HT_1A receptor in affective illness, especially MDD: pharmacological challenge studies; post-mortem studies; neuroreceptor imaging, and genetic analyses. We will discuss each of these in turn.