GLUTAMATE SYNAPSES IN SENSITIZATION TO DRUGS OF ABUSE

滥用药物（安非他明、可卡因、吗啡）会产生长期的- 对后续药物暴露的持续致敏性可能是 药物的奖励性质的逐渐增强 （渴望）在人类中。 在大鼠中，可观察到致敏作用， 对重复给药的反应是逐渐增强的运动。 直接向腹侧被盖区注射精神兴奋剂会导致 对外周给药药物致敏。 这些数据 证明精神兴奋剂的致敏作用是 在VTA内部进行调解。 最近的一些证据表明，修改 腹侧被盖区的突触需要启动 致敏 首先，谷氨酸的NMDA亚型的拮抗剂 受体阻断致敏，全身或局部给药 进入VTA。 第二，行为敏感性不会发展 大脑前额叶皮层的多巴胺能神经纤维被切断 第三，电刺激前额叶传入神经使动物敏感 随后的可卡因模仿行为致敏 最后， 在表现出行为敏感的动物中， 精神兴奋剂给药，腹侧被盖区单个多巴胺神经元 变得对谷氨酸有异常反应 综上所述，这些数据表明， 敏化是一种NMDA受体依赖性突触形式， 腹侧被盖区多巴胺神经元的可塑性 增强的突触传递。 绝大多数 的致敏工作已经在体内完成。 我建议使用 腹侧被盖区脑片多巴胺神经元的电生理记录 制备体外研究致敏的细胞基础， 这个大脑区域。 该提案的目标是：1）测试突触 通过腹侧被盖区的脑切片中谷氨酸突触的可塑性，2） 为了检测安非他明对兴奋性突触的直接影响， 传递到腹侧被盖区神经元，和3）检查多巴胺能 来自处理动物的VTA切片中的体外突触传递 长期服用安非他明 这些研究将提供证据 对于有助于行为敏感化的机制，以及 从而导致人类药物滥用中的药物渴求。

Drugs of abuse (amphetamine, cocaine, morphine) produce a long- lasting sensitization to subsequent drug exposures that may underlie a progressive enhancement in the rewarding properties of the drug (craving) in humans. In rats, sensitization can be observed as progressively enhanced locomotion in response to repeated drug. Injection of psychostimulants directly into the VTA causes behavioral sensitization to peripherally administered drugs. These data demonstrate that the sensitizing effects of psychostimulants are mediated within the VTA itself. Several lines of recent evidence indicate that modification of glutamatergic synapses within the VTA is required to initiate sensitization. First, antagonists of the NMDA subtype of glutamate receptor block sensitization, either delivered systemically or locally into the VTA. Secondly, behavioral sensitization does not develop when glutamatergic fibers from the prefrontal cortex are transsected. Third, electrical stimulation of prefrontal afferents sensitizes animals to subsequent cocaine, mimicking behavioral sensitization. Finally, in animals that exhibit behavioral sensitization following psychostimulant administration, single dopamine neurons in the VTA become abnormally responsive to glutamate. Taken together, these data suggest the hypothesis that during sensitization an NMDA-receptor dependent form of synaptic plasticity occurs in VTA dopamine neurons that results in strengthened glutamatergic synaptic transmission. The vast majority of work on sensitization has been done in vivo. I propose to use electrophysiogical recordings from dopamine neurons in a VTA slice preparation in vitro to investigate the cellular basis of sensitization in this brain area. The goals of this proposal are: 1) to test for synaptic plasticity at glutamate synapses in brain slices through the VTA, 2) to examine the direct effects of amphetamine on excitatory synaptic transmission onto VTA neurons, and 3) to examine glutamatergic synaptic transmission in vitro in VTA slices from animals treated chronically with amphetamine. This studies will provide evidence for the mechanisms that contribute to behavioral sensitization, and thus to drug craving in human drug abuse.