GLUTAMATE SYNAPSES IN SENSITIZATION TO DRUGS OF ABUSE

描述(改编自申请人的摘要)： 滥用毒品，包括安非他明和可卡因，会产生持久的影响 对后续药物暴露的行为敏感化。这表现为 在动物和人类中，运动量的增加可能是进行性 与药物渴求有关的药物奖励特性的增强。 敏感化在中脑的腹侧被盖区(VTA)启动， 因为直接向VTA注射精神刺激剂会导致行为 像全身用药那样的致敏作用，而且因为 在特定情况下，防止对外周给药的刺激物过敏 拮抗剂被直接输送到VTA。有几条证据 支持谷氨酸能突触对多巴胺的修饰 VTA中的神经元需要启动敏感化。最令人信服的是 NMDA亚类拮抗剂阻断敏化作用的研究 谷氨酸受体，系统地或直接输送到VTA。 鉴于NMDA受体在其他地方的突触可塑性中的既定作用 在大脑中，这些数据表明，在行为过程中 敏化是一种NMDA受体依赖的突触可塑性形式，发生在 VTA多巴胺神经元导致谷氨酸能突触增强 变速箱。这个应用程序将检验突触 VTA的可塑性是由精神刺激剂改变的，这 修饰代表敏化的开始。我们将继续使用 电生理学方法检测苯丙胺对神经元的影响 在VTA切片准备过程中。

DESCRIPTION(Adapted from applicant's abstract): Drugs of abuse, including amphetamine and cocaine, produce long-lasting behavioral sensitization to subsequent exposures to drug. This is manifested as increased locomotion in animals, and in humans, may underlie a progressive augmentation in the rewarding properties of the drug related to drug craving. Sensitization is initiated in the ventral tegmental area (VTA) of the midbrain, because direct injection of psychostimulants into the VTA causes behavioral sensitization like that seen with systemically administered drug, and because sensitization to peripherally administered stimulant is prevented when specific antagonists are delivered directly into the VTA. Several lines of evidence support the idea that modification of glutamatergic synapses on dopamine neurons in the VTA is required to initiate sensitization. Most compelling is the finding that sensitization is blocked by antagonists of the NMDA subclass of glutamate receptor, delivered either systemically or directly into the VTA. Given the established role of NMDA receptors in synaptic plasticity elsewhere in the brain, these data suggest the hypothesis that during behavioral sensitization an NMDA receptor-dependent form of synaptic plasticity occurs in VTA dopamine neurons that results in strengthened glutamatergic synaptic transmission. This application will test the hypothesis that synaptic plasticity in the VTA is modified by psychostimulants, and that this modification represents the onset of sensitization. We will continue using electrophysiological methods to examine the effects of amphetamine on neurons in the VTA slice preparation.