Synaptic plasticity in the VTA studied in vivo

描述（由申请人提供）：本申请的目的是进一步了解多巴胺神经元上谷氨酸突触的突触可塑性在滥用药物引起的大脑长期改变中的作用。我们的假设是，多巴胺能奖赏通路中的兴奋性突触在高成瘾性物质（如安非他明和阿片类药物）存在时被病理激活，这种激活代表了成瘾发展的早期细胞贡献。在过去的三年里，我的实验室一直在使用脑切片准备来研究腹侧被盖区（VTA）突触抑制的细胞机制，这是成瘾行为发展所必需的区域。我们已经发现支持我们的假设，即滥用药物与突触可塑性相互作用，因为安非他明完全消除了谷氨酸突触的长期抑郁。这种形式的突触可塑性的阻断类似于去除多巴胺系统兴奋的正常制动；安非他命长时间持续存在引起的长期阻滞有望促进多巴胺神经元的异常增强放电，这是绝大多数成瘾物质的细胞反应特征，可能促进成瘾的发展。进一步研究长期突触抑制的机制以及安非他明干扰这种可塑性的机制是一个重要的研究领域。然而，在开始细胞层面的更详细的研究之前，我越来越觉得有必要在完整的大脑中验证我们的工作。到目前为止，还没有人在体内研究过VTA兴奋性突触的突触可塑性。因此，我们不知道长期抑郁是否发生在完整的大脑中，也不知道安非他明是否会阻止长期抑郁。这项小额拨款申请的目的是允许我的实验室使用一种全新的技术，VTA的体内记录，来验证我们在体外的基本发现。我们期望拟议的研究将证实我们的体外工作，并为该工作提供重要的新线索。

DESCRIPTION (provided by applicant): The goal of this application is to further our understanding of the role of synaptic plasticity of glutamate synapses on dopamine neurons in long-term modifications of the brain that occur with drugs of abuse. Our hypothesis is that excitatory synapses in the dopaminergic reward pathway are pathologically activated in the presence of highly addictive substances such as amphetamine and opiates, and that this activation represents an early cellular contribution to the development of addiction. Over the past three years, my laboratory has used the brain slice preparation to study cellular mechanisms of synaptic depression in the ventral tegmental area (VTA), a region necessary for the development of addictive behaviors. We have found support for our hypothesis that drugs of abuse interact with synaptic plasticity, as amphetamine entirely abolishes long-term depression at glutamatergic synapses. The block of this form of synaptic plasticity is analogous to the removal of a normal brake on excitation of the dopamine system; the long-term block induced by amphetamine continuously present for long periods of time is expected to promote abnormally enhanced firing of dopamine neurons, a cellular response characteristic of the great majority of addictive substances likely to promote the development of addiction. Further examination of the mechanisms normally underlying long-term synaptic depression and the mechanisms by which amphetamine interferes with this plasticity is an important area for further research. However, before embarking on more detailed work at the cellular level, I have increasingly felt it is necessary to verify our work in the intact brain. To date no one has examined synaptic plasticity at excitatory synapses in the VTA in vivo. Thus, it is not known whether long-term depression occurs here in the intact brain, nor whether amphetamine blocks tong-term depression. The purpose of this small grant application is to allow my lab to use an entirely new technique for us, in vivo recordings from the VTA, to verify our basic in vitro findings. We expect that the proposed studies will confirm our in vitro work, and provide important new leads to use in that work.