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谷氨酸能神经元可塑性，涉及LTP和LTD共同的机制。这项提议将通过确定反复安非他明对伏隔核谷氨酸受体运输的影响来验证这一假说，伏核是表达对滥用药物的敏化的关键大脑区域，并表征腹侧被盖区域的谷氨酸/胆碱能相互作用，腹侧被盖区域是敏化发展的关键区域。我们建议在细胞水平上研究谷氨酸受体和胆碱转运体的转运，并利用体内微透析来研究胆碱能对腹侧被盖兴奋性的调节。总之，这些方法将在药物诱导的生化改变和谷氨酸能神经可塑性之间提供机械联系，并将提供对胆碱能系统在调节中脑兴奋性中的关键作用的生化和神经化学洞察，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.