Serotonin 2c receptor gene expression in the rhesus amygdala predicts anxious temperament

• Main Authors: Patrick H. Roseboom, Steve A. Nanda, Jonathan A. Oler, Andrew S. Fox, Alexander J. Shackman, Steve E. Shelton, Ned H. Kalin
• Format: Article
• Language: English
• Published: Taylor & Francis Group 2012-09-01
• Series: European Journal of Psychotraumatology
• Subjects: serotonin; 2c receptor; gene expression; rhesus amygdale; anxiety; temperament

Rationale/statement of the problem : In the central nervous system, the serotonin (5HT) neurotransmitter system plays a key role in the regulation of mood and emotion. Alterations in the 5HT system are thought to contribute to psychopathologies. In addition, drugs targeting the 5HT system are effective in the treatment of depression and anxiety disorders. Children with anxious temperament (AT) are characterized by excessive shyness, worrying, and avoidant behavior. This temperament, when stable across development, increases the risk of later developing depression and anxiety disorders. Using a well-established, nonhuman primate model of AT, we tested whether variations in the 5HT system predict individual differences in AT. We focused on the central nucleus region of the amygdala (CeA) because we have established that metabolic activity in this region is predictive of AT. Methods : Using Affymetrix GeneChip® rhesus macaque genome arrays, we assessed gene expression from CeA tissue in 24 young male rhesus monkeys phenotyped for AT. Robust regression analysis was performed with correction for multiple comparisons across all annotated transcripts that are part of the neuroactive ligand pathway (KO04080) in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Results : As hypothesized, variation in gene expression predicted individual differences in AT. Specifically, of the thirteen 5HT receptors assessed, only the 5HT2C receptor (5HT2C; r= − 0.57, p<0.01) was identified in the microarray analysis as significantly negatively correlated with AT. Quantitative real-time polymerase chain reaction analysis using the same CeA RNA samples confirmed this association (r = −0.65, p<0.001). Underscoring the anatomical specificity of this effect, the significant relationship between 5HT2C receptor mRNA levels and AT was not observed in the motor cortex, a brain region not associated with AT (r=0.10, p=0.64). Conclusions : Previous work by others has shown robust levels of 5HT2C receptor mRNA and radioligand binding in the monkey CeA. In addition, rodent models have indicated a role for the 5HT2C receptor in anxiety-like responding. Our findings suggest that higher levels of 5HT2C receptor gene expression are associated with lower levels of AT. Increased expression of the gene encoding for this receptor may facilitate 5HT signaling in the amygdala thereby promoting adaptive responses and resilience to potentially anxiety provoking situations.