Insula serotonin 2A receptor binding and gene expression contribute to serotonin transporter polymorphism anxious phenotype in primates

Abstract

Genetic variation in the serotonin transporter gene (<i>SLC6A4</i>) is associated with vulnerability to affective disorders and pharmacotherapy efficacy. We recently identified sequence polymorphisms in the common marmoset <i>SLC6A4</i> repeat region (AC/C/G and CT/T/C) associated with individual differences in anxiety-like trait, gene expression, and response to antidepressants. The mechanisms underlying the effects of these polymorphisms are unknown, but a key mediator of serotonin action is the serotonin 2A receptor (5HT_2A). Thus, we correlated 5HT_2A binding potential (BP) and RNA gene expression in 16 <i>SLC6A4</i> genotyped marmosets with responsivity to 5HT_2A antagonism during the human intruder test of anxiety. Voxel-based analysis and RNA measurements showed a reduction in 5HT_2A BP and gene expression specifically in the right posterior insula of individuals homozygous for the anxiety-related variant AC/C/G. These same marmosets displayed an anxiogenic, dose-dependent response to the human intruder after 5HT_2A pharmacological antagonism, while CT/T/C individuals showed no effect. A voxel-based correlation analysis, independent of <i>SLC6A4</i> genotype, revealed that 5HT_2A BP in the adjacent right anterior insula and insula proisocortex was negatively correlated with trait anxiety scores. Moreover, 5HT_2A BP in both regions was a good predictor of the size and direction of the acute emotional response to the human intruder threat after 5HT_2A antagonism. Our findings suggest that genetic variation in the <i>SLC6A4</i> repeat region may contribute to the trait anxious phenotype via neurochemical changes in brain areas implicated in interoceptive and emotional processing, with a critical role for the right insula 5HT_2A in the regulation of affective responses to threat.