The 5-HT1A receptor in Major Depressive Disorder

Abstract

Major Depressive Disorder (MDD) is a highly prevalent psychiatric diagnosis that is associated with a high degree of morbidity and mortality. This debilitating disorder is currently one of the leading causes of disability nationwide and is predicted to be the leading cause of disease burden by the year 2030. A large body of previous research has theorized that serotonergic dysfunction, specifically of the serotonin (5-HT) 1A receptor, plays a key role in the development of MDD. The purpose of this review is to describe the evolution of our current understanding of the serotonin 1A (5-HT1A) receptor and its role in the pathophysiology MDD through the discussion of animal, post-mortem, positron emission tomography (PET), pharmacologic and genetic studies.

Keywords: 5-HT1A; Depression; Review.

Figure 1

Structure of the serotonin molecule.

Figure 2

Pathway of serotonin (5-HT) synthesis.

Figure 3

Functional activity of the 5-HT1A receptor. Binding of serotonin (5-HT) to the 5-HT1A receptor, both pre-synaptic and post-synaptic subtypes, signals the opening of a hyperpolarizing potassium (K+) channel and inhibition of adenylyl cyclase (AC). These actions, mediated by G proteins (G_i/G_o), serve to hyperpolarize the cell and reduce its firing rate. Gray circles associated with K⁺ channel represent K⁺ ions moving into extracellular space.

Figure 4

Effect of SSRI treatment on the 5-HT1A receptor. Efficacy of SSRI treatment putatively occurs through down-regulation of the raphe 5-HT_1A autoreceptors (red squares) that is seen after chronic treatment. These autoreceptors act to inhibit 5-HT postsynaptic neuronal release. Sustained administration of 5-HT_1A agonists or SSRIs induces the internalization of 5-HT_1A autoreceptors in the raphe nucleus of the midbrain (note reduction of 5-HT1A autoreceptors as treatment progresses from ‘acute’ to ‘chronic’. The reduction in autorecep-tor inhibition following chronic SSRI treatment allows increased neuronal firing and thus, more serotonin to be released. It is this subsequent increase in serotonin release in which SSRIs are able to exert their anxiolytic and antidepressant effects. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Figure 5

Mechanism of PET camera. Magnified area shows annihilation reaction that occurs when a positron, emitted from the radioactive PET tracer, collides with an electron, usually in nearby tissue. This reaction is able to convert mass, in the form of a positron and electron, into energy, in the form of two photons. Importantly, these photons are emitted at an angle of exactly 180° and are then detected via scintillation crystals within the PET camera that surrounds the subject’s head.

Figure 6

Effect of of the C(−1019)G 5-HT1A functional polymorphism. In subjects possessing the C allele, NUDR/DEAF-1 (blue block) acts to repress the expression of 5-HT1A autoreceptors (red squares) to a normal level. However, in subjects who possess the G allele, NUDR/DEAF-1 is unable to bind to the regulatory region, thus leading to an overexpression of 5-HT1A autoreceptors, reduced serotonergic firing, and increased predisposition to the depressive phenotype. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Figure 7

No significant C(−1019)G polymorphism genotype effect on 5-HT_1A expression in the raphe and hippocampus. There is no stepwise increase in the raphe or hippocampus with G allele frequency: CC<CG<GG. The height of the bar indicates the weighted mean BP_F, while the error bars represent the equivalent of standard error of each weighted mean. RN: Raphe, HIP: Hippocampus.

Figure 8

[¹¹C]WAY-100635 binding potential (BP_F) estimates for the 5-HT_1A receptor in male control and male MDD subjects in the raphe nuclei. Blue diamonds or red squares represent single measurements of raphe BP_F in control and MDD subjects, respectively. Thin capped vertical error bars represent standard errors computed using a bootstrap algorithm that takes into account errors in metabolite, plasma, and image data. Weighted group mean and standard error of the weighted mean of BP_F are represented by thick horizontal lines and thick vertical lines, respectively. BP_F, binding potential; [¹¹C]WAY- 100635, N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclo-hexanecarboxamide; 5-HT_1A, serotonin-1A receptor.