The dual role of serotonin in defense and the mode of action of antidepressants on generalized anxiety and panic disorders

Abstract

Antidepressants are widely used to treat several anxiety disorders, among which generalized anxiety disorder (GAD) and panic disorder (PD). Serotonin (5-HT) is believed to play a key role in the mode of action of these agents, a major question being which pathways and receptor subtypes are involved in each type of anxiety disorder. The dual role of 5-HT in defense hypothesis assumes that 5-HT facilitates defensive responses to potential threat, like inhibitory avoidance, related to anxiety, whereas it inhibits defensive responses to proximal danger, like one-way escape, related to panic. The former action would be exerted at the forebrain, chiefly the amygdala and medial prefrontal cortex (PFC), while the latter would be exerted at the dorsal periaqueductal gray (DPAG) matter of the midbrain. The present review is focused on studies designed to test this hypothesis, performed in animal models of anxiety and panic, as well as in human experimental anxiety tests. The reviewed results suggest that chronic, but not acute, administration of antidepressants suppress panic attacks by increasing the release of 5-HT and enhancing the responsivity of post-synaptic 5-HT1A and 5-HT2A receptors in the DPAG. The attenuation of generalized anxiety, also caused by the same drug treatment, would be due to the desensitization of 5-HT2C receptors and, less certainly, to increased stimulation of 5-HT1A receptors in forebrain structures. This action would result in less activation of the amygdala, medial PFC and insula by warning signals, as shown by the reviewed results obtained with functional neuroimaging in healthy volunteers and patients with anxiety disorders.