Division of Psychobiology, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
Exp Clin Psychopharmacol. 2011 Dec;19(6):401-8. doi: 10.1037/a0025008. Epub 2011 Aug 15.
Individual vulnerability to psychopathologies is linked to a number of genetic polymorphisms including the serotonin transporter (5HTT) promoter polymorphic region (5HTTLPR). A single copy of the short variant (s-variant) allele of 5HTTLPR confers increased susceptibility to anxiety disorders and depression and decreased efficacy of serotonin-releasing agents in pharmacotherapy compared to the homozygous long 5HTTLPR variant (l/L). The data suggesting that the 5HTTLPR polymorphism modulates the efficacy of serotonin-releasing agents in pharmacotherapy is inconsistent. Other factors such as age, gender, and hormonal status could interact with 5HTTLPR genotype to affect individual physiological and behavioral responses to serotonin reuptake inhibitors such as citalopram. Indeed, estradiol and progesterone, the primary female steroid hormones, exert an array of effects on the serotonergic system, including 5HTT expression. The present study used ovariectomized female rhesus monkeys to determine the interaction between the 5HTTLPR polymorphism and the effects of midfollicular levels of estradiol and luteal levels of progesterone on serotonergic responsivity to acute citalopram administration. The increase in serum prolactin, a surrogate measure of serotonin activity, following citalopram administration was significantly larger in l/L females than in s-variant females over the course of two hours during concurrent estradiol and progesterone hormone replacement only. These data suggest that ovarian function and the 5HTTLPR polymorphism interact to gate serotonergic reactivity in females, suggesting that clinicians should be aware of the ovarian status and 5HTTLPR genotype of women when considering serotonergic pharmacotherapy in women.
个体易感性与多种遗传多态性有关，包括 5-羟色胺转运体（5HTT）启动子多态区（5HTTLPR）。5HTTLPR 的短变异（s-变异）等位基因的单个拷贝与焦虑障碍和抑郁的易感性增加有关，并且与同型长 5HTTLPR 变异（l/L）相比，降低了 5-羟色胺释放剂在药物治疗中的疗效。提示 5HTTLPR 多态性调节药物治疗中 5-羟色胺释放剂疗效的数据不一致。其他因素，如年龄、性别和激素状态，可能与 5HTTLPR 基因型相互作用，影响个体对西酞普兰等 5-羟色胺再摄取抑制剂的生理和行为反应。事实上，雌激素和孕激素，主要的女性类固醇激素，对 5-羟色胺能系统产生多种影响，包括 5HTT 的表达。本研究使用去卵巢雌性恒河猴确定 5HTTLPR 多态性与中卵泡期雌激素和黄体期孕激素水平对西酞普兰急性给药时 5-羟色胺反应性的影响之间的相互作用。在雌二醇和孕激素激素替代治疗的两个小时期间，西酞普兰给药后血清催乳素（一种 5-羟色胺活性的替代指标）的增加在 l/L 雌性中明显大于 s-变异雌性，仅在同时存在雌二醇和孕激素的情况下。这些数据表明卵巢功能和 5HTTLPR 多态性相互作用，调节女性的 5-羟色胺反应性，这表明临床医生在考虑女性的 5-羟色胺药物治疗时，应该意识到女性的卵巢状态和 5HTTLPR 基因型。
