Translational Genetics and Dopamine Signaling in Sensitivity to Amphetamines

描述（由申请人提供）：安非他明滥用是一个重大的公共卫生问题，需要识别可能导致成瘾预防和新治疗的遗传风险因素。由于安非他明也被临床用于注意缺陷多动障碍，帕金森病和嗜睡症等疾病，研究这些药物生物作用的遗传基础也可能导致改善药物治疗。本申请要求支持小鼠和人类遗传学培训，以检验候选基因酪蛋白激酶1-β（Csnk 1-e）的多态性有助于小鼠和人类对安非他明的行为和主观影响的敏感性这一假设。在目标1中，将在两个单独的同基因背景品系上用多态性Csnk 1-e等位基因饲养小鼠，假设Csnk 1-e多态性将调节对甲基苯丙胺（MA）的运动刺激反应。在目的2中，将沿着检查Csnkle基因表达的多态性诱导的变化以及小鼠中MA诱导的Darpp-32多巴胺信号传导途径的活化和MA诱导的运动活性的变化。假设Csnkle表达的增加将导致MA诱导的Darpp-32磷酸化的增加和对MA的运动刺激反应的增加。此外，我们预期Csnkle表达的这些变化导致对Csnkle的特异性药理学抑制的生化和行为效应的不同敏感性。在目标3中，与小鼠研究平行，将进行人类转化研究，由此将检查CSNK 1 E多态性与对d-苯丙胺（AMPH）的生理、行为和主观反应（包括AMPH欣快）的敏感性的关联.公共卫生相关性：对安非他明敏感性的遗传基础的新认识可能对成瘾预防以及开发与多巴胺系统失调相关的临床疾病的新治疗方法具有重要意义。

DESCRIPTION (provided by applicant): Abuse of amphetamines is a major public health problem that warrants the identification of genetic risk factors which could lead to addiction prevention and novel treatments. Because amphetamines are also used clinically for such conditions as Attention Deficit Hyperactive Disorder, Parkinson's disease, and narcolepsy, studying the genetic basis of the biological actions of these drugs could also lead to improved pharmaceutical treatments. This application requests support for training in mouse and human genetics to test the hypothesis that polymorphisms in the candidate gene casein kinase 1-epsilon (Csnk1-e) contribute to sensitivity to the behavioral and subjective effects of amphetamines in mice and humans. In Aim 1, mice will be bred with polymorphic Csnk1-e alleles on two separate isogenic background strains with the hypothesis that Csnk1-e polymorphisms will modulate the locomotor stimulant response to methamphetamine (MA). In Aim 2, polymorphism-induced changes in Csnkle gene expression will be examined along with changes in MA-induced activation of the Darpp-32 dopamine signaling pathway and MA-induced locomotor activity in mice. The hypothesis is that an increase in Csnkle expression will result in an increase in MA-induced Darpp-32 phosphorylation and an increase in the locomotor stimulant response to MA. Furthermore, we expect these changes in Csnkle expression to result in differential sensitivity to the biochemical and behavioral effects of specific pharmacological inhibition of Csnkle. In Aim 3, parallel to the mouse studies, a human translational study will be conducted whereby association of CSNK1E polymorphisms with sensitivity to the physiological, behavioral, and subjective responses to d- amphetamine (AMPH) will be examined, including AMPH euphoria. Public Health Relevance: New insight into the genetic basis for sensitivity to amphetamines may have important implications for addiction prevention as well as the development of novel treatments for clinical conditions related to dysregulation of the dopamine system.