Department of Psychiatry and Molecular & Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, Michigan 48109-5720, USA.
J Neurosci. 2012 Jul 4;32(27):9344-50. doi: 10.1523/JNEUROSCI.1260-12.2012.
Mesoaccumbal and nigrostriatal projections are sensitive to stress, and heightened stress sensitivity is thought to confer risk for neuropsychiatric disorders. Serotonin 2C (5-HT(2C)) receptors mediate the inhibitory effects of serotonin on dopaminergic circuitry in experimental animals, and preclinical findings have implicated 5-HT(2C) receptors in motivated behaviors and psychotropic drug mechanisms. In humans, a common missense single-nucleotide change (rs6318, Cys23Ser) in the 5-HT(2C) receptor gene (HTR2C) has been associated with altered activity in vitro and with clinical mood disorders. We hypothesized that dopaminergic circuitry would be more sensitive to stress in humans carrying the Ser23 variant. To test this hypothesis, we studied 54 healthy humans using positron emission tomography and the displaceable D(2)/D(3) receptor radiotracer [(11)C]raclopride. Binding potential (BP(ND)) was quantified before and after a standardized stress challenge consisting of 20 min of moderate deep muscular pain, and reduction in BP(ND) served as an index of dopamine release. The Cys23Ser variant was genotyped on a custom array, and ancestry informative markers were used to control for population stratification. We found greater dopamine release in the nucleus accumbens, caudate nucleus, and putamen among Ser23 carriers, after controlling for sex, age, and ancestry. Genotype accounted for 12% of the variance in dopamine release in the nucleus accumbens. There was no association of Cys23Ser with baseline BP(ND). These findings indicate that a putatively functional HTR2C variant (Ser23) is associated with greater striatal dopamine release during pain in healthy humans. Mesoaccumbal stress sensitivity may mediate the effects of HTR2C variation on risk of neuropsychiatric disorders.
中脑边缘和黑质纹状体投射对压力敏感，而压力敏感性增加被认为是神经精神障碍的风险因素。5-羟色胺 2C（5-HT（2C））受体介导 5-羟色胺对实验动物中多巴胺能回路的抑制作用，临床前研究表明 5-HT（2C）受体参与动机行为和精神药物机制。在人类中，5-羟色胺 2C 受体基因（HTR2C）中的一个常见错义单核苷酸变化（rs6318，Cys23Ser）与体外活性改变和临床情绪障碍有关。我们假设携带 Ser23 变体的人类多巴胺能回路对压力更敏感。为了验证这一假设，我们使用正电子发射断层扫描和可置换 D2/D3 受体放射性示踪剂[11C]raclopride 研究了 54 名健康人类。结合 20 分钟的中度深度肌肉疼痛的标准应激挑战前后，通过量化（11）C]raclopride 的结合潜力（BP（ND））作为多巴胺释放的指标。Cys23Ser 变体在定制阵列上进行了基因分型，并用祖先信息标记物来控制群体分层。我们发现，在控制性别、年龄和祖先后，Ser23 携带者的伏隔核、尾状核和壳核中的多巴胺释放更多。基因型解释了伏隔核中多巴胺释放的 12%的方差。Cys23Ser 与基线 BP（ND）之间没有关联。这些发现表明，一种假定的功能性 HTR2C 变体（Ser23）与健康人类疼痛期间纹状体多巴胺释放增加有关。中脑边缘压力敏感性可能介导 HTR2C 变异对神经精神障碍风险的影响。
