5-HT(1A) [corrected] receptors in mood and anxiety: recent insights into autoreceptor versus heteroreceptor function

Abstract

Rationale: 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.

Objectives: 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.

Results: 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.

Conclusions: 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.

Figure 1

Model of 5-HT_1A autoreceptor effects on the serotonergic raphe nuclei. Schematic depicting representative raphe neurons in 1A-High and 1A-Low animals, emphasizing the differences between the two groups. (Top) In 1A-Low mice, low levels of somatodendritic 5-HT_1A autoreceptors result in weak negative feedback, resulting in higher firing rates of raphe neurons and concomitant increased release of serotonin. (Bottom) Conversely, 1A-High mice have lower basal firing rate and high levels of somatodendritic 5-HT_1A autoreceptor, which exert robust inhibitory effects on raphe firing. This results in a greater behavioral despair in response to stress, compared to 1A-Low mice. While 1A-High mice do not respond behaviorally to treatment with the antidepressant fluoxetine, 1A-Low mice display a robust behavioral response. 1A-High and 1A-Low mice provide a mechanistic model for humans carrying, respectively, the G/G and C/C alleles of the Htr1aI C(-1019)G polymorphism. Adapted from Richardson-Jones et al. 2010.

Figure 2

Figure summarizes data supporting a critical role for 5-HT_1A autoreceptors and heteroreceptors in establishing normal anxiety and depressive-like behavior circuits. (top) Transgenic forebrain expression of 5-HT_1A heteroreceptors in a knockout background beginning at day 15 is sufficient to rescue normal behavior, while graded re-expression of the heteroreceptor beginning a P21 results in an anxious phenotype (Gross et al. 2002). (Middle) Supression of 5-HT_1A autoreceptors throughout life resulted in an increase anxiety-like behavior in the adult. Conversely, loss of endogenous autoreceptors in adulthood is not sufficient to impact anxiety-like behavior (Richardson-Jones et al. 2011). (Bottom) Supression of 5-HT_1A heteroreceptors throughout life resulted in an increase immobilty in the forced swim test in the adult. Conversely, loss of endogenous heteroreceptors in adulthood is not sufficient to impact behavior (Richardson-Jones et al. 2011). These results suggest that a critical period exists beginning on the P15. The end of this critical period remains unclear.