Sensitization and Stimulant Self-Administration

描述（由申请人提供）：精神兴奋剂药物，如安非他明产生多种效果。其中值得注意的是，它们能够激活大脑多巴胺（DA）神经传递，增加运动活动，并支持人类和实验室动物的自我管理。当重复给药时，它们产生这些作用的能力变得增强，使得在数周至数月后再次暴露于药物，产生更大的DA激活、运动和旨在获得药物的工作输出。这些研究结果支持这样的建议，即安非他明和其他精神兴奋剂的食欲效应的敏感性促进了这些药物的追求和自我管理，并可能成为从偶然使用药物过渡到强迫性吸毒和滥用药物的基础。一些持久的神经适应已被确定在前脑区域，如神经核（NAcc），提供神经元相关的安非他明的行为敏化的表达。几行收敛的证据表明，DA和谷氨酸之间的协调相互作用的安非他明敏化的表达，其中AMPA受体的调节是必不可少的，这是依赖于突触前和突触后的PKC信号在NAcc。该提案建立在实验室的新数据基础上，这些数据表明DA可以调节AMPA受体的运输和功能，从而使行为敏化得以表达。它还结合了最近发表的研究结果，显示PKC可以直接和间接调节AMPA受体插入和功能的新机制。总之，这些研究结果支持的假设，NAcc AMPA受体激活中型多刺神经元和随后的动机行为的动物显示，而Gq偶联的DA受体能够通过启动PKC介导的信号传导，以调节AMPA受体的运输和功能的敏化的表达。为了开始验证这一假设，本提案中概述的实验将使用增强安非他明自我给药和恢复的模型来确定NAcc中不同PKC底物在这些致敏行为表达中所起的作用。拟议的实验利用多学科的方法，使用行为，生物化学，药理学和病毒介导的基因转移技术。在目的1和2中，将使用病毒介导的基因转移来确定NAcc神经元中特异性GluR1和神经颗粒蛋白的PKC磷酸化对致敏表达的贡献。在目标3中，PKC的药理学抑制将用于评估其通过调节突触前DA溢出来实现苯丙胺敏化表达的能力。通过破译敏化表达背后的神经适应，我们将增加对精神兴奋剂药物增强追求和自我管理的机制的理解，并为旨在扭转这些适应不良行为的治疗策略的发展提供信息。

DESCRIPTION (provided by applicant): Psychomotor stimulant drugs such as amphetamine produce multiple effects. Notable among them is their ability to activate brain dopamine (DA) neurotransmission, increase locomotor activity and support self-administration in humans and laboratory animals. When repeatedly administered, their ability to produce these effects becomes enhanced so that re-exposure to the drug, weeks to months later, produces greater DA activation, locomotion, and work-output aimed at obtaining the drug. These findings support the proposal that sensitization of the appetitive effects of amphetamine and other psychostimulants promotes the pursuit and self-administration of these drugs and may underlie the transition from casual drug use to compulsive drug taking and abuse. A number of long-lasting neuroadaptations have been identified in forebrain regions like the nucleus accumbens (NAcc) that provide neuronal correlates for the expression of behavioral sensitization by amphetamine. Several lines of converging evidence now indicate a coordinated interaction between DA and glutamate in the expression of amphetamine sensitization, one in which the regulation of AMPA receptors is essential, and that is dependent on pre- and postsynaptic PKC signaling in the NAcc. This proposal builds on new data from the laboratory showing that DA can regulate AMPA receptor trafficking and function to enable the expression of behavioral sensitization. It also incorporates recently published findings showing new mechanisms by which PKC can directly and indirectly regulate AMPA receptor insertion and function. Together, these findings support the hypothesis that NAcc AMPA receptors activate medium spiny neurons and the ensuing motivated behavior the animal displays while Gq-coupled DA receptors enable the expression of sensitization by initiating PKC-mediated signaling to regulate AMPA receptor trafficking and function. To begin testing this hypothesis, the experiments outlined in this proposal will use a model of enhanced amphetamine self-administration and reinstatement to determine the role played by different PKC substrates in the NAcc in the expression of these sensitized behaviors. The proposed experiments exploit a multidisciplinary approach, using behavioral, biochemical, pharmacological, and viral-mediated gene transfer techniques. In Aims 1 and 2, viral-mediated gene transfer will be used to determine the contribution of PKC phosphorylation of GluR1 and neurogranin specifically in NAcc neurons to the expression of sensitization. In Aim 3, pharmacological inhibition of PKC will be used to assess its ability to enable the expression of amphetamine sensitization by regulating presynaptic DA overflow. By deciphering the neuroadaptations that underlie the expression of sensitization, we will increase our understanding of the mechanisms underlying the enhanced pursuit and self- administration of psychostimulant drugs and inform the development of therapeutic strategies aimed at reversing these maladaptive behaviors.