Sensitization and Stimulant Self-Administration

说明(申请人提供)：安非他明等精神运动兴奋剂可产生多种效果。其中值得注意的是，它们能够激活脑多巴胺(DA)神经传递，增加运动活动，并支持人类和实验动物的自我管理。当重复给药时，它们产生这些效应的能力会增强，因此在几周到几个月后再次接触药物，会产生更大的DA激活、运动和旨在获得药物的功输出。这些发现支持这样的建议，即对苯丙胺和其他精神刺激剂的食欲作用的敏化促进了对这些药物的追求和自我管理，并可能为从临时吸毒向强制吸毒和滥用的转变奠定基础。在伏隔核(NAcc)等前脑区域已经发现了一些长期的神经适应，这些区域为苯丙胺行为敏化的表达提供了神经元关联。目前有几条证据表明，在苯丙胺敏化的表达中，DA和谷氨酸之间存在协调的相互作用，其中AMPA受体的调节是必不可少的，这依赖于NAcc中突触前和突触后的PKC信号。这一建议建立在来自实验室的新数据的基础上，该数据表明，DA可以调节AMPA受体的运输，并具有使行为敏化表达成为可能的功能。它还结合了最近发表的研究结果，表明PKC可以直接和间接调节AMPA受体插入和功能的新机制。综上所述，这些发现支持这样的假设，即NAcc AMPA受体激活中等刺神经元和随后动物表现出的动机行为，而GQ偶联DA受体通过启动PKC介导的信号来调节AMPA受体的运输和功能，从而使敏化表达。为了开始验证这一假说，本提案中概述的实验将使用增强的苯丙胺自我给药和恢复模型来确定NAcc中不同的PKC底物在这些敏化行为的表达中所起的作用。拟议的实验采用了一种多学科的方法，使用了行为、生化、药理学和病毒介导的基因转移技术。在目标1和目标2中，将使用病毒介导的基因转移来确定NAcc神经元中特异性的GluR1和神经颗粒素的PKC磷酸化对致敏表达的贡献。在目标3中，将使用对PKC的药理学抑制来评估其通过调节突触前DA溢出而使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，我们将增加我们对精神刺激药物增强追求和自我给药的潜在机制的理解，并为旨在逆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.