Brain circuits regulated by the 5-HT2A receptor: Behavioural consequences on anxiety and fear memory

Abstract

Anxiety disorders including generalized anxiety disorder (GAD), panic disorder (PD), social anxiety disorder (SAD) or phobias are the most prevalent mental pathologies across the world with a median lifetime prevalence of approximately 15%. Anxiety imposes substantial economic costs which are among the highest of all mental disorders studied. Evidence is now accumulating that the serotonergic nervous system is involved in the pathology of anxiety and can provide benefits in the treatment of related disorders through its diverse functions, notably the modulation of stress, fear and memory. Among serotonin receptor subtypes, the 5-HT2A receptor arouses great interest. This receptor displays original pharmacological properties i.e., cooperation with β-arrestins and homo−/hetero-dimerization regulating its intracellular signaling and its ability to control the serotonergic system. The present chapter provides insight into the mechanisms by which the 5-HT2A receptor may alter the activity of 5-HT neurons but also of the brain regions receiving a dense serotonergic innervation (i.e, the amygdala, the hippocampus and the prefrontal cortex). An overview of the literature is proposed to recapitulate the pharmacological and genetic studies in patients or relevant animal models supporting a role of the 5-HT2A receptor on various forms of anxiety. Moreover, we envision the future directions that we might follow to develop new anxiolytic strategies based on the manipulation of 5-HT2A-mediated signaling. Doing so, we also point some inconsistencies illustrating the difficulty to target this receptor as a valid alternative to benzodiazepines.