5-HT1 receptor agonists
The 5-HT1A receptor is a serotonin receptor subtype found in presynaptic and postsynaptic regions of the brain that is implicated in the control of mood, cognition and memory.
The role of 5-HT in anxiety is well established. Of note, buspirone, originally thought to achieve its anxiolytic effects solely through antagonism of D2 receptors, was subsequently discovered to be an agonist of 5-HT1A receptors. It is now aknowledged that buspirone acts as a full agonist at presynaptic 5-HT1A receptors and as a partial agonist at postsynaptic receptors in the hippocampus and cortex. The role of 5-HT1A receptors in depression has also been demonstrated, indeed antidepressants such as MAOIs and TCAs, SSRIs, lithium and valproate are known to directly or indirectly increase postsynaptic 5-HT1A signalling, an action which may play a role in their antidepressant effect. In particular, research has shown that vilazodone may exert its antidepressant effect through the combined effect of serotonin reuptake inhibition and partial agonism of 5-HT1A receptors. Research also suggests that compounds possessing balanced 5-HT1A receptor agonism and D2 antagonism are effective antipsychotics, and might achieve the desired therapeutic benefit by targeting the receptors responsible for the beneficial drug effect but avoid modulation of receptors that are responsible for side-effects.
As can be seen, activation of 5-HT1A receptors contributes to the clinical effects of many anxiolytic, antidepressant and antipsychotic medications. In the future, ‘biased agonists’ (functionally selective agonists which optimise therapeutic benefit) may prove to be a novel solution for managing psychiatric disorders that are associated with 5-HT1A receptors.
Clinically relevant 5-HT1A partial agonists include the antianxiety agent, buspirone, the second-generation (atypical) antipsychotics, clozapine, ziprasidone, aripiprazole and brexpiprazole, and the antidepressant vilazodone.