5-HT1 Receptor Augmentation Strategies as Enhanced Efficacy Therapeutics for Psychiatric Disorders

Abstract

Since the initial observations linking 5-HT to psychiatric illness, evidence for a role of 5-HT and, in particular, a decreased brain serotonergic function in the pathology of a plethora of related disorders, has grown. However, it is the role of 5-HT in the pathogenesis of anxiety disorders and depression and the mechanism of action of antidepressants which has received the most attention. Thus enhanced serotonergic neurotransmission has become one of the unifying mechanisms of action of modern day antidepressants/anxiolytics such as monoamine oxidase inhibitors, tricyclic antidepressants, and serotonin reuptake inhibitors. Interestingly all of these treatments are associated with a delay to therapeutic efficacy and in some cases treatment resistance, despite immediate enhancements in serotonergic neurotransmission. The postulated reason for this is the need for temporal neuroplastic changes in the control of serotonergic neurotransmission, and more specifically changes in 5-HT(1) autoreceptor function. Thus significant research has gone into pharmacologically targeting these 5-HT(1) autoreceptors as a means of augmenting the efficacy of current therapeutic mechanisms. Here we will review the rationale behind the various augmentation strategies adopted and the progress made in identifying novel therapeutics for conditions such as depression and anxiety disorders.

SLC6 Neurotransmitter Transporters: Structure, Function, and Regulation

“…It has been hypothesized that the late onset of action of SSRIs is due to negative feedback circuitry, mediated via 5-HT 1A autoreceptors (Hjorth et al, 2000); therefore, compounds that are inhibitors of SERT and agonists of 5-HT 1A receptors have been pursued as improved antidepressants (Adell et al, 2005;Dawson and Bromidge, 2008). Two compounds, vilazodone and Lu AA21004 (Fig.…”

Pharmacology for the Treatment of Premature Ejaculation

“…It can be inferred that 5-HT1A receptors intervene in the ejaculatory response when 5-HT levels become elevated and that concomitant inhibition of 5-HT1A receptors and increase in brain 5-HT levels prevent occurrence of ejaculation. Synthesis of pharmacological compounds exhibiting combined activities on 5-HT1A receptors (antagonism or partial agonism) and 5-HT transporters (inhibitor) has been described previously (Dawson and Bromidge, 2008). However, as far as we know, action of such a dual activity compound on ejaculatory response is not documented.…”

Dual- and Triple-Acting Agents for Treating Core and Co-morbid Symptoms of Major Depression: Novel Concepts, New Drugs

“…3 Possibly, other components of depressive states such as cognitive deficits and sexual dysfunction will be improved by this intriguing drug. 3,42,60,74,75 Although findings are less well established than for 5-HT 1A and 5-HT 1B autoreceptors, 5-HT 7 receptors may also be inhibitory to serotonergic transmission. Accordingly, 5-HT 7 antagonists enhance the actions of SSRIs and alone elicit modest antidepressant and anxiolytic effects in rodents.…”