Jacobskind Jason S, Rosinger Zachary J, Zuloaga Damian G
University at Albany, Department of Psychology, Albany, NY 12222, United States.
University at Albany, Department of Psychology, Albany, NY 12222, United States.
Brain Res. 2017 Dec 15;1677:74-85. doi: 10.1016/j.brainres.2017.09.020. Epub 2017 Sep 21.
Sex differences in patterns of methamphetamine (MA) abuse have been reported with females (humans and rodents) showing an elevated addiction phenotype. Previous findings indicate MA-induced hypothalamic-pituitary-adrenal (HPA) axis activation is also sexually dimorphic with females exhibiting an elevated glucocorticoid release and differential neural activation patterns within HPA axis-associated brain regions. These effects may contribute to sex differences in abuse. To determine the role of gonadal hormones in mediating sex differences in MA-induced glucocorticoids, male and female C57BL/6J mice were gonadectomized or sham-operated, and following recovery, injected with MA (5mg/kg) and sacrificed 60min or 120min later. Blood was collected for corticosterone radioimmunoassay, and brains were used to assess c-Fos, and c-Fos co-localization with glucocorticoid receptor (GR). At 120min after MA injection, corticosterone levels were elevated in females compared to males and gonadectomy in males increased corticosterone to female levels. C-Fos was greater in females than males in the medial preoptic area, bed nucleus of the stria terminalis, basolateral amygdala, and central amygdala. Female gonadectomy had little effect on either corticosterone or c-Fos, while male gonadectomy elevated c-Fos in the central amygdala. Relative to sham males, gonadectomized males also showed decreased c-Fos/GR cell number in the CA3 hippocampal area compared to sham males, indicating a central site for attenuated negative feedback. Together, these findings indicate that androgens regulate MA-induced activation of the HPA axis, potentially by enhancing negative feedback. These sex and gonadal hormone effects on the HPA axis may contribute to sex differences in MA abuse patterns.
已有报道称甲基苯丙胺（MA）滥用模式存在性别差异，女性（人类和啮齿动物）表现出更高的成瘾表型。先前的研究结果表明，MA诱导的下丘脑 - 垂体 - 肾上腺（HPA）轴激活也具有性别差异，女性表现出更高的糖皮质激素释放以及HPA轴相关脑区不同的神经激活模式。这些影响可能导致滥用方面的性别差异。为了确定性腺激素在介导MA诱导的糖皮质激素性别差异中的作用，对雄性和雌性C57BL/6J小鼠进行去势或假手术，恢复后注射MA（5mg/kg），并在60分钟或120分钟后处死。采集血液进行皮质酮放射免疫测定，并用脑评估c-Fos以及c-Fos与糖皮质激素受体（GR）的共定位。MA注射后120分钟，雌性的皮质酮水平高于雄性，雄性去势后皮质酮水平升高至雌性水平。在内侧视前区、终纹床核、基底外侧杏仁核和中央杏仁核中，雌性的c-Fos高于雄性。雌性去势对皮质酮或c-Fos影响不大，而雄性去势则使中央杏仁核中的c-Fos升高。相对于假手术雄性，去势雄性在CA3海马区的c-Fos/GR细胞数量也减少，表明存在减弱负反馈的中枢位点。总之，这些发现表明雄激素可能通过增强负反馈来调节MA诱导的HPA轴激活。这些性别和性腺激素对HPA轴的影响可能导致MA滥用模式的性别差异。
