Enhanced hypothalamic–pituitary–adrenal (HPA) axis and cortisol responses to stress have been linked to high levels of hostility, pathogenesis of the metabolic syndrome and cardiovascular disease incidence.
Serotonin acts at multiple sites to contribute to stress-induced HPA axis activation, and signaling through 5HTR2C receptors plays a key role in this process. A single nucleotide polymorphism (SNP) – rs6318; 68G>C – that leads to a substitution of serine for cysteine at codon 23 (Cys23Ser) has been identified, and recent evidence indicates that the Ser23 C allele is constitutively more active than the Cys23 allele.
In this study, Beverly Brummett and colleagues from the Department of Psychiatry, Duke University Medical Center, Durham, NC demonstrate that the cortisol response to a stress task was signiﬁcantly larger in men hemizygous for the Ser23 C allele compared to those carrying the Cys23 G allele. Men hemizygous for the Ser23 C allele of the 5HT2C rs6318 SNP had both larger cortisol responses and larger increases in anger and depressive mood during the stress protocol. This suggests that the 5HT2C receptor is at least partially responsible for the increase in both HPA axis function and negative moods under stress. Previous research indicates that the Ser23 C variant is also associated with affective disorders, such as major depressive and bipolar disorder. This all together suggests that the rs6318 effects on 5HT2C receptor-mediated effects on both emotions and the HPA axis may be accounting, at least in part, for the linkages between depression and dysregulated HPA axis function. Moreover, the authors discuss that elevated cortisol levels have been recently associated with a broad range of endophenotypes such as central obesity, elevated glucose, insulin and insulin resistance, higher blood pressure and lipids, as well as diseases – hypertension, coronary heart disease and type-2 diabetes. Thus, according to the authors the present ﬁndings may also indicate that men carrying the 5HTR2C Ser23 C allele may be more likely than Cys23 G allele carriers to express these endophenotypes.
SOURCE: Biol Psychol 2012, 89:94. Epub 2011 Oct 1.