Rethinking 5-HT1A receptors: emerging modes of inhibitory feedback of relevance to emotion-related behavior

Abstract

The complexities of the involvement of the serotonin transmitter system in numerous biological processes and psychiatric disorders is, to a substantial degree, attributable to the large number of serotonin receptor families and subtypes that have been identified and characterized for over four decades. Of these, the 5-HT(1A) receptor subtype, which was the first to be cloned and characterized, has received considerable attention based on its purported role in the etiology and treatment of mood and anxiety disorders. 5-HT(1A) receptors function both at presynaptic (autoreceptor) and postsynaptic (heteroreceptor) sites. Recent research has implicated distinct roles for these two populations of receptors in mediating emotion-related behavior. New concepts as to how 5-HT(1A) receptors function to control serotonergic tone throughout life were highlights of the proceedings of the 2012 Serotonin Club Meeting in Montpellier, France. Here, we review recent findings and current perspectives on functional aspects of 5-HT(1A) auto- and heteroreceptors with particular regard to their involvement in altered anxiety and mood states.

Figure 1

Inhibitory mechanisms of 5-HT_1A autoreceptors. (A) Serotonergic cell bodies expressing 5-HT_1A autoreceptors are located deep within the brainstem (blue box). Serotonin neurons projecting to the forebrain are organized into two main clusters designated as dorsal and median raphe nuclei with distinct subpopulations within these primary nuclei. 5-HT_1A heteroreceptors are localized postsynaptically in various brain regions including the hippocampus (HIP), prefrontal cortex (PFC), thalamus (TH), lateral septum (SEP), amygdala (AMYG), and hypothalamic nuclei (HYP). Many of these regions have been associated with the pathophysiology of mood and anxiety disorders. (B) The top panel depicts a “conventional” serotonin synapse. In the bottom panel, activation of 5-HT_1A autoreceptors controls serotonergic tone via one-to-one autoinhibitory feedback to reduce firing rates of serotonin neurons. 5-HT_1A heteroreceptors also regulate serotonergic activity through descending glutamatergic projections originating in the medial prefrontal cortex (mPFC). This pathway makes connections with serotonin neurons via brainstem GABAergic inhibitory interneurons. (C) Current hypotheses regarding inhibitory mechanisms of 5-HT_1A autoreceptor activation paint a more complex picture. For instance, emerging evidence suggests that serotonin neurons within a subpopulation or even across subpopulations affect each other via “lateral inhibition”. Taken together, new perspectives on the functional aspects of 5-HT_1A receptors associated with regulation of serotonergic activity are important avenues for future investigation, particularly regarding increased understanding of the roles of 5-HT_1A receptors in the etiology and treatment of psychiatric disorders.