Cellular Plasticity Following Repeated Amphetamine

描述（由申请人提供）： 药物改变大脑的潜在细胞和神经化学机制是旨在为成瘾患者提供潜在治疗策略的研究的关键目标。我们的假设是，成瘾的一个重要组成部分是异常的多巴胺能神经元可塑性，涉及LTP和LTD的共同机制。本提案将通过确定重复安非他明对丘脑核（对滥用药物的敏感性表达至关重要的脑区）中谷氨酸受体运输的影响，并表征腹侧被盖区的多巴胺能/胆碱能相互作用，这是一个对提高敏感性至关重要的地区。我们建议在细胞水平上研究谷氨酸受体和胆碱转运体的运输，并利用在体微透析技术研究胆碱能对腹侧被盖兴奋性的调节。总之，这些方法将提供药物诱导的生化改变和多巴胺能神经可塑性之间的机制联系，并将提供生物化学和神经化学的洞察胆碱能系统在调节中脑兴奋性的关键作用，以及滥用药物引起的异常调节的后果。

DESCRIPTION (provided by applicant): The underlying cellular and neurochemical mechanisms by which drugs modify the brain are a critical target of research designed to provide potential treatment strategies for addicted patients. Our hypothesis is that an essential component of addiction is aberrant glutamatergic neuronal plasticity, involving mechanisms common to LTP and LTD. This proposal will test this hypothesis by determining the effect of repeated amphetamine on glutamate receptor trafficking in the nucleus accumbens, a brain region critical for the expression of sensitization to drugs of abuse, and characerizing glutamatergic/cholinergic interactions in the ventral tegmental area, a region critical in the development of sensitization. We propose to investigate glutamate receptor and choline transporter trafficking at the cellular level, and investigate the cholinergic regulation of ventral tegmental excitability using in vivo microdialysis. Together, these approaches will provide a mechanistic link between drug-induced biochemical alterations and glutamatergic neuroplasticity, and will provide biochemical and neurochemical insight into the critical role of the cholinergic system in the regulation of midbrain excitability, and the consequences of aberrant regulation elicited by drugs of abuse.