Medial Prefrontal Cortex 5-HT2A Density Is Correlated with Amygdala Reactivity, Response Habituation, and Functional Coupling

Feedback inhibition of the amygdala via medial prefrontal cortex (mPFC) is an important component in the regulation of complex emotional behaviors. The functional dynamics of this corticolimbic circuitry are, in part, modulated by serotonin (5-HT). Serotonin 2A (5-HT2A) receptors within the mPFC represent a potential molecular mechanism through which 5-HT can modulate this corticolimbic circuitry. We employed a multimodal neuroimaging strategy to explore the relationship between threat-related amygdala reactivity, assessed using blood oxygen level-dependent functional magnetic resonance imaging, and mPFC 5-HT2A density, assessed using [F-18]altanserin positron emission tomography in 35 healthy adult volunteers. We observed a significant inverse relationship wherein greater mPFC 5-HT2A density was associated with reduced threat-related right amygdala reactivity. Remarkably, 25-37% of the variability in amygdala reactivity was explained by mPFC 5-HT2A density. We also observed a positive correlation between mPFC 5-HT2A density and the magnitude of right amygdala habituation. Furthermore, functional coupling between the amygdala and mPFC was positively correlated with 5-HT2A density suggesting that effective integration of emotionally salient information within this corticolimbic circuitry may be modulated, at least in part, by mPFC 5-HT2A. Collectively, our results indicate that mPFC 5-HT2A is strongly associated with threat-related amygdala reactivity as well as its temporal habituation and functional coupling with prefrontal regulatory regions.