Monoamine oxidase A genotype predicts human serotonin 1A receptor availability in vivo.
Monoamine oxidase A genotype predicts human serotonin 1A receptor availability in vivo.
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DOI：
10.1523/jneurosci.2391-08.2008
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发表时间：
2008-10-29
期刊：
影响因子：
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通讯作者：
Zubieta JK
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文献类型：
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作者：
Mickey BJ;Ducci F;Hodgkinson CA;Langenecker SA;Goldman D;Zubieta JK
5-羟色胺能系统，包括5-羟色胺1A(5-HT1A)受体，与许多神经精神障碍的病理生理学有关。目前的数据显示，该受体位置的区域集中度在个体之间存在显著差异，其来源尚不清楚。单胺氧化酶A(MAO-A)是5-羟色胺代谢的关键调节因子，X连锁MAO-A基因的多态变异影响其表达。我们假设MAO-A基因的多态与5-HT1A受体表达的性别差异有关。我们使用正电子发射断层扫描和[11C]Way-100635对31名健康和未服用药物的抑郁症患者的5-HT1a受体进行了定量。对同一个体进行MAO-A基因启动子上游可变数目串联重复序列多态性的基因分型。5-HT1a受体可用性的方差分析显示MAO-A基因在中缝核团、内侧和下颞叶皮质、岛叶、内侧前额叶皮质和前扣带回有显著影响(p<；0.05)。当模型中包括年龄、种族、体重指数和诊断时，这种影响仍然存在。在女性中，具有较大MAO-A活性的基因型与较大的5-HT1A受体的可获得性相关，而在男性中则不相关。根据大脑区域的不同，基因型预测了女性受体可获得性变化的42%-74%(p<；0.05)。抑郁症的诊断与MAO-A基因或5-HT1A受体在这些地区的可获得性无关。这些结果证明了人类5-羟色胺能系统的两个关键分子之间存在性别特异性的相互作用，并提示了5-羟色胺调节的表型中性二型性的神经生物学基础。
The serotonergic system, including the serotonin 1A (5-HT1A) receptor, has been implicated in the pathophysiology of a number of neuropsychiatric disorders. Current data shows substantial inter-individual variation in the regional concentration of this receptor site, the source of which is unclear. Monoamine oxidase A (MAO-A) is a key regulator of serotonin metabolism, and polymorphic variation in the X-linked MAO-A gene influences its expression. We hypothesized that polymorphism in the MAO-A gene would be associated with sex-specific variation in 5-HT1A receptor expression. We used positron emission tomography and [11C]WAY-100635 to quantify 5-HT1A receptors in a group of 31 healthy and un-medicated depressed individuals. The same individuals were genotyped for an upstream variable number tandem repeat polymorphism in the promoter of the MAO-A gene. Analysis of variance of 5-HT1A receptor availability demonstrated a significant effect of MAO-A genotype in the raphe nuclei, medial and inferior temporal cortex, insula, medial prefrontal cortex, and anterior cingulate (p<0.05). The effect persisted when age, race, body mass index, and diagnosis were included in the model. Genotypes with greater putative MAO-A activity were associated with greater 5-HT1A receptor availability in women, but not in men. Genotype predicted a substantial 42-74% of the variance in receptor availability in women, depending on the brain region (p<0.05). Depression diagnosis was not associated with MAO-A genotype or 5-HT1A receptor availability in these regions. These results demonstrate a sex-specific interaction between two key molecules of the human serotonergic system, and suggest a neurobiological basis for sexual dimorphism in serotonin-modulated phenotypes.