Reduced 5-HT(2A) receptor 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.

Fig. 1

Neurobiological evidence implicates the amygdala as well as serotonergic (serotonin, 5-HT) signaling via postsynaptic 5-HT_2AR as essential substrates of anxiety behaviors. However, the functional relationship between these substrates is unclear. We hypothesized that a low-fear behavioral phenotype due to bilateral lesion of the amygdala is associated with significant changes in 5-HT_2AR expression. Thus, we used [¹⁸F]altanserin PET referenced to radioligand plasma levels and corrected for partial volume effects to quantify the spatial distribution of 5-HT_2AR BP_P in a rare patient with Urbach–Wiethe disease and selective bilateral amygdala calcification damage relative to 10 healthy control subjects.

Fig. 2

MRI and [¹⁸F]altanserin PET data obtained from LP patient A.M. and 10 healthy control subjects. (A) T1-weighted high-resolution MRI demonstrates that brain calcification damage in A.M. is amygdala-selective, with particular emphasis on the BLA and no involvement of other nearby tissues. In brief, A.M. has bilateral and relatively circumscribed destruction of the BLA. (B) Parametric maps illustrate a 70% global reduction of 5-HT_2AR BP_P in A.M. relative to the average of controls. Presented are coronal sections and 3D-surface renderings in true proportions. (C) Scatter plot of global and regional 5-HT_2AR BP_P values (averaged across hemispheres) as measured in A.M. and controls.