Reduced 5-HT2Areceptor signaling following selective bilateral amygdala damage

Abstract

Neurobiological evidence implicates the amygdala as well as serotonergic (serotonin, 5-HT) signaling via postsynaptic 5-HT _2A receptors as essential substrates of anxiety behaviors. Assuming a functional interdependence of these substrates, we hypothesized that a low-fear behavioral phenotype due to bilateral lesion of the amygdala would be associated with significant 5-HT _2A receptor changes. Thus, we used [ ¹⁸ F]altanserin positron emission tomography (PET) referenced to radioligand plasma levels and corrected for partial volume effects to quantify the spatial distribution of 5-HT _2A receptor binding potential ( BP_P ) in a rare patient with Urbach–Wiethe disease and selective bilateral amygdala calcification damage relative to 10 healthy control subjects. Consistent with our a priori hypothesis, we observed a 70% global decrease in 5-HT _2A receptor BP_P in the Urbach–Wiethe patient relative to controls. Thus, brain abnormalities in this patient are not restricted to the amygdala, but extend to overall 5-HT neurotransmission via 5-HT _2A receptors. Our findings provide important insights into the molecular architecture of human anxiety behaviors and suggest the 5-HT _2A receptor as a promising pharmacological target to control pathological anxiety.