Medial prefrontal cortex serotonin 1A and 2A receptor binding interacts to predict threat-related amygdala reactivity

5-HT1A binding in the mPFC significantly moderated an inverse correlation between mPFC 5-HT2A binding and threat-related amygdala reactivity. Specifically, mPFC 5-HT2A binding was significantly inversely correlated with amygdala reactivity only when mPFC 5-HT1A binding was relatively low.Our findings provide evidence that 5-HT1A and 5-HT2A receptors interact to shape serotonergic modulation of a functional circuit between the amygdala and mPFC. The effect of the interaction between mPFC 5-HT1A and 5-HT2A binding and amygdala reactivity is consistent with the colocalization of these receptors on glutamatergic neurons in the mPFC.Research in human and non-human animal models implicates a corticolimbic circuitry composed of structural and functional connections between the amygdala and regions of the medial prefrontal cortex (mPFC) including the anterior cingulate cortex (ACC) in generating and regulating behavioral and physiological responses to threat-related stimuli [1-4]. Regions of the mPFC are crucially involved in the integration and subsequent regulation of stimulus-driven amygdala response, partly via glutamatergic projections to populations of GABAergic neurons within the amygdala [5-7]. Variability in the structure and function of this corticolimbic circuitry has been associated with interindividual differences in personality measures, reflecting sensitivity to environmental threat and related risk for psychopathology [2,8-11].Serotonin (5-hydroxytryptamine, 5-HT) exerts potent modulatory effects on mood, affect, and responsiveness to stress and threat [12]. Neuroimaging studies in humans have mapped interindividual differences in amygdala reactivity to biologically salient environmental stimuli (for example, facial expressions of threat) onto variability in 5-HT signaling within this corticolimbic circuitry [2,13-21]. However, the role of specific 5-HT-receptor signaling pathways in mediating these effects are not fully understood [12]. Previous work in hum