Friday, October 12, 2007

The Role of the Serotonin 5-HT1A Receptor in the Pathophysiology and Treatment of Depression

By Gary Evoniuk, Ph.D.
Glaxo Smith Kline R&D


Major depressive disorder (MDD), the most common of the psychiatric disorders, is a serious illness that is associated with high rates of chronicity, relapse, recurrence, and mortality. MDD currently ranks as the fourth leading cause of disability among all medical illnesses, and is expected to rank second by the year 2030 (Murray and Lopez, 1996). It also has potentially life-threatening consequences – suicide is an all-too-frequent outcome – heightening the importance of understanding the pathophysiology of MDD and developing successful treatments.

There is a substantial body of evidence linking the neurotransmitter serotonin (5-HT) to the pathophysiology and treatment of MDD. 5-HT is produced by serotonergic neurons - it has been estimated that several hundred thousand serotonergic neurons are present in the human brain, primarily within discrete nuclei in the brainstem. The highest concentrations of serotonergic neurons reside in the dorsal raphe nucleus in the midbrain. This nucleus innervates the cerebral cortex, thalamus, basal ganglia, and the limbic system (hippocampus, amygdala). There 5-HT is thought to modulate or “balance” the circuitry between the frontal cortex and limbic system for normal affective function (Stahl, 1996).

Evidence gathered over several decades suggests that alterations in 5-HT function play a role in the etiology of MDD. Asberg et al (1976) examined the concentration of 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of 5-HT, in the brain of depressed patients. The results showed that up to 40% of these patients had significantly lower levels of 5-HIAA compared to normal controls. Importantly, patients showing decreased levels of 5-HIAA were significantly more likely to have attempted suicide. Other studies have demonstrated a significant reduction in 5-HT concentrations of whole brain, hypothalamus, and amygdala in postmortem tissues from depressed patients or suicide victims (Owens and Nemeroff, 1994). These findings suggest that alterations in brain 5-HT availability may significantly alter mood and may play an important role in the etiology of MDD.

Serotonergic neurotransmission appears to be terminated primarily by reuptake of 5-HT via the serotonin reuptake transporter (SERT). This effectively lowers concentrations of 5-HT to levels incapable of maintaining postsynaptic activation. Utilizing [3H]-imipramine and [3H]-paroxetine binding, decreased 5-HT transporter density and uptake capacity has been measured in platelets from depressed patients as well as in postmortem brain tissue from suicide victims (Owens and Nemeroff, 1994). The observation of decreased platelet and brain SERT binding in depression has been a consistent finding, and suggests that altered neuronal 5-HT disposition may play an important role in the pathophysiology of MDD.

Serotonin binds to specific receptors that are widely distributed throughout the brain. The serotonergic receptor family is extraordinarily large. To date, a total of 14 distinct serotonin receptors have been cloned. Each receptor is characterized by a unique structure, pharmacology, expression pattern, and second-messenger effector. Thirteen of these receptors belong to the superfamily of G protein–coupled receptors (linked either with excitatory or inhibitory G proteins). The large number of 5-HT receptor subtypes has posed a challenge to the design of subtype-specific agonists and antagonists (Glennon et al, 2000; Aghajanian and Sanders-Bush, 2002; Frazer and Hensler, 1999; Nestler et al, 2001).


The 5-HT1A receptor subtype has been demonstrated to play an important role in both the etiology and treatment of MDD (Stahl, 1996; Blier and Ward, 2003) and will be the focus of the remainder of this article. Both pre- and postsynaptic 5-HT1A receptors have been identified. Presynaptic receptors are located primarily on cell bodies (soma) and input-receiving dendrites (i.e. somatodendritic) of the dorsal raphe and act as inhibitory autoreceptors that exert a negative feedback influence on 5-HT neuronal firing. When these receptors are activated by excess amounts of 5-HT or by an exogenous agonist, they hyperpolarize the neuron, causing it to slow down its firing activity (Nestler et al, 2001; Blier and Ward 2003; Stahl, 1996). Because 5-HT release is proportional to the firing rate of 5-HT neurons, excessive activation of 5-HT1A1A receptors leads to desensitization, diminishing the negative feedback influence, and ultimately resulting in a gradual normalization of postsynaptic 5-HT release (Blier and Ward, 2003).

Animal studies have established that presynaptic 5-HT1A somatodendritic receptors of the dorsal raphe influence the postsynaptic release of 5-HT into the prefrontal cortex (Stahl, 1996). Changes in the activity or density of these autoreceptors may therefore alter serotonergic release in the prefrontal cortex and thereby play a significant clinical role in MDD. Stockmeier et al (1998) examined the density of 5-HT1A autoreceptors in the dorsal raphe of suicide victims with MDD. [3H]-8-OH-DPAT (a selective 5-HT1A ligand) binding was shown to be significantly increased in the dorsal raphe of depressed suicide victims compared to psychiatrically normal control subjects. This increase in 5-HT1A autoreceptors might act to abnormally dampen 5-HT neuronal cell firing and subsequent postsynaptic release of 5-HT. An increase in 5-HT1A

Positron emission tomography (PET) can now be employed to study 5-HT1A receptor distribution in the human brain. In addition to their localization in the raphe nucleus, 5-HT1A1A binding in several cortical regions (mediotemporal, orbitofrontal, anterior cingulate, insula, and dorsolateral prefrontal cortex) (Shively et al, 2006).
autoreceptors results in the short term in a decrease of postsynaptic 5-HT release to the areas where these neurons project (e.g., cortex, limbic system) (Stahl, 1996; Nestler et al, 2001). However, longer term activation of presynaptic 5-HT mediated negative feedback in MDD is also consistent with the hypothesis that the therapeutic effect of antidepressants may involve long term physiological desensitization (or disinhibition) of this negative feedback influence on postsynaptic 5-HT output. receptors have a distribution in cortical and limbic regions that roughly approximates that of the SERT (Figure 1). PET studies in humans with MDD have also shown decreases in postsynaptic 5-HT

Several investigators have also reported an increased density of postsynaptic 5-HT2 receptor binding sites in the frontal cortices of depressed suicide victims and unmedicated depressed patients. Up-regulation of cortical 5-HT2 receptors in MDD has been suggested to signal an adaptive response to reduced postsynaptic 5-HT output to these regions. (Owens and Nemeroff, 1994).


Currently, selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed medications for the treatment of MDD. Significant progress has been made in understanding the mechanisms by which these agents exert their antidepressant effects. Evidence gathered to date supports the following sequence of events in response to administration of an SSRI (Stahl, 1996):

As previously described, depressed individuals may start with a general deficit in the firing and postsynaptic release of 5-HT from neurons in the dorsal raphe. When SSRIs bind to the SERT in the somatodendritic region of 5-HT neurons, reuptake of 5-HT is blocked causing an immediate rise in presynaptic levels of 5-HT. Acutely, the rise in presynaptic 5-HT levels leads to increased binding to 5-HT1A somatodendritic autoreceptors, causing decreased firing of 5-HT dorsal raphe neurons and a consequent decrease in postsynaptic 5-HT output to cortical and other brain regions. Chronic (2–3 weeks) SSRI administration leads to desensitization and down-regulation of 5-HT1A receptors occurs, resulting in increased cell firing and consequent postsynaptic release of 5-HT, leading to improvement in depressive symptoms.

A further increase in postsynaptic 5-HT availability occurs because of ongoing reuptake inhibition there. This may result in additional therapeutic efficacy, but possibly at the expense of serotonergic side effects, due to flooding of postsynaptic 5-HT receptors (“overshoot”).

Approximately 40 to 50% of MDD patients report sexual dysfunction (Kennedy, 1999). Antidepressant treatments, particularly SSRIs, further compound this problem. Sexual dysfunction, such as loss of libido, impotence, ejaculatory problems, and anorgasmia, has been reported for most classes of antidepressants, with 30-70% of patients reporting treatment-related sexual dysfunction (Kennedy, 2000). In some cases, permanent deleterious effects on sexual functioning have been reported (Meston, 2004). The sexual side effects of SSRIs appear to be mediated by overactivation of 5-HT2A and 5-HT2C receptors.

Changes in appetite have also been shown to occur with the use of SSRIs, which may be manifest as significant changes in body weight. Preclinical studies have linked the effect of SSRIs on appetite to 5-HT2C receptors. Nausea has also been shown to be a major consequence of SSRI use and is mediated by the binding of 5-HT to 5-HT3 receptors (Stahl, 1996). As with all antidepressants, the adverse effects associated with SSRI use may have a significant negative impact on patient compliance, thus reducing their effectiveness in the treatment of MDD.


Selective 5-HT1A agonists, such as the azapyrones, appear to represent another serotonergic treatment strategy for MDD. Neurochemical studies of this drug class confirm their binding as agonists to both presynaptic and postsynaptic 5-HT1A receptor binding sites in animals and humans. Preclinical and clinical data also indicate antidepressant efficacy. Evidence gathered to date supports the following sequence of events in response to administration of 5-HT1A agonists (Blier and Ward, 2003):

Depressed individuals may start with a general deficit in the firing and postsynaptic release of 5-HT from neurons in the dorsal raphe. Acutely, the binding of 5-HT1A agonists (e.g. azapyrones) to 5-HT1A presynaptic autoreceptors triggers the negative feedback loop and causes decreased firing of 5-HT neurons in the dorsal raphe. Chronic (2–3 weeks) administration of 5-HT1A agonists leads to desensitization and down-regulation of 5-HT1A receptors, resulting in increased 5-HT cell firing and consequent postsynaptic release of 5-HT, leading to improvement in depressive symptoms. The increase in postsynaptic 5-HT release is also accompanied by 5-HT1A agonist binding to postsynaptic 5-HT1A receptors –the ultimate result is a net increase in 5-HT1A postsynaptic activity leading to improvement in depressive symptoms, but with less activation of other types of 5-HT receptors (i.e., “normalization”).

Preclinical data suggest that activation of postsynaptic 5-HT1A receptors is central to the antidepressant effect of antidepressants. Animal behavioral models of stress and depression have consistently shown that selective activation of postsynaptic 5-HT1A receptors produces effects similar to those elicited by SSRIs and other antidepressants. The phenomenon of hippocampal neurogenesis (sprouting of new neurons), which has been shown to occur in response to various types of antidepressant treatments, appears to be mediated by activation of postsynaptic 5-HT1A receptors (Blier and Ward, 2003; Haddjeri et al, 1998). Another potentially important additional consequence of the activation of 5-HT1A postsynaptic receptors is a reduction in the density of cortical 5-HT2 receptor binding sites. This effect has been linked with an improvement in sleep architecture and with anxiolysis (Blier and Ward 2003).

Although 5-HT1A agonists and SSRIs have different primary mechanisms of action, they appear to induce similar adaptive changes in the brain, probably as a consequence of their common downstream effects on postsynaptic 5-HT release. Both presynaptic 5-HT1A autoreceptors in the dorsal raphe, as well as postsynaptic 5-HT1A receptors in cortical and limbic areas, appear to play a key role in the therapeutic effects of these drugs. The similarity of adaptive changes seen with both mechanisms, coupled with the greater selectivity of 5-HT1A agonists suggest that the latter could represent a more targeted approach to the treatment of patients with MDD.


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