P5-HT1A receptors in mood and anxiety: recent insights into autoreceptor versus heteroreceptor function

Abstract

Serotonin (5-HT) neurotransmission is intimately linked to anxiety and depression and a diverse body of evidence supports the involvement of the main inhibitory serotonergic receptor, the serotonin-1A (5-HT(1A)) subtype, in both disorders. In this review, we examine the function of 5-HT(1A) receptor subpopulations and re-interpret our understanding of their role in mental illness in light of new data, separating both spatial (autoreceptor versus heteroreceptor) and the temporal (developmental versus adult) roles of the endogenous 5-HT(1A) receptors, emphasizing their distinct actions in mediating anxiety and depression-like behaviors. It is difficult to unambiguously distinguish the effects of different populations of the 5-HT(1A) receptors with traditional genetic animal models and pharmacological approaches. However, with the advent of novel genetic systems and subpopulation-selective pharmacological agents, direct evidence for the distinct roles of these populations in governing emotion-related behavior is emerging. There is strong and growing evidence for a functional dissociation between auto- and heteroreceptor populations in mediating anxiety and depressive-like behaviors, respectively. Furthermore, while it is well established that 5-HT(1A) receptors act developmentally to establish normal anxiety-like behaviors, the developmental role of 5-HT(1A) heteroreceptors is less clear, and the specific mechanisms underlying the developmental role of each subpopulation are likely to be key elements determining mood control in adult subjects.