Clinical Overview of Serotonin 1A Relationships of Agitation, Aggression, Anxiety and Mood

Educational Objectives

1. To educate in the area of clinical links of the serotonin 1A receptor subtype.
2. To discuss the clinical implications of the serotonin 1A receptor with regard to management options and problems.

Abstract

The serotonin receptors modulate a variety of basic psychological and behavioral functions. These functions may reflect serotonin 1A neuromodulation as well. The serotonin 1A receptor subtype is unique because it is found at the raphe nuclei level as the serotonin autoreceptor as well as post-synaptically in areas linked with limbic function. This may imply differential effects at different doses. Because of the low toxicity and receptor specificity of serotonin 1A related compounds their potential application in psychiatry and medicine is substantial.

Several drug groups modulate serotonin 1A receptor action. Non-specifically, beta-2-adrenergic receptor blockers (like propranolol) produce overall serotonin 1A receptor antagonist effects. The benzodioxines, an experimental group, which includes eltoprazine, act as partial agonists postsynaptically on both 5HT 1A and 1B receptors. Lithium cation is very non-specific but does impact the serotonin 1A receptor. Serotonin 1A receptor action can be measured relatively specifically by the azapirones which act as partial agonists postsynaptically and full agonists at the autoreceptor.

Beta-blockers have impacts on agitation, aggression, anxiety and depression. The effects appear bimodal, at lower dosage probably reflecting a peripheral beta-adrenergic blockade and at higher doses possibly reflecting post-synaptic serotonin 1A antagonism.

The benzodioxines are being researched specifically in aggression and may have a role in modulating serotonin 1A.

Agitation, aggression, anxiety and mood all are implicated in azapirone function. The azapirones can be used as a pharmacologic probe because these effects appear to be dose dependent, in part, and because of the specificity at serotonin 1A. At this point, most of the research has been performed on buspirone as the only marketed azapirone. It is FDA approved for use only in generalized anxiety and mixed anxiety depressive states, however, clinical experience in several other areas is interesting. Low doses of buspirone probably act presynaptically as may be applicable in irritability and lesser agitation; medium doses act post-synaptically possibly antagonizing excess serotonin 1A modulating anxiety; higher doses are weak agonists and may correspond with limited antidepressant effects and some modulation of obsessionality. Doses of the order of 60mg and beyond tentatively have possible effects on the irritability, confrontation and anger of the manic, although not effecting psychosis or sleep-this may imply a serotonin 1A agonist modulating role. The scanty literature is discussed.

From these approaches, a unified theory linking agitation, aggression, anxiety and mood with the serotonin receptor 1A subtype and its cross-talk with other receptors can be developed.