Synaptic plasticity in the VTA studied in vivo

描述(申请人提供)：本申请的目的是加深我们对多巴胺神经元上谷氨酸突触的突触可塑性在药物滥用引起的大脑长期改变中的作用的理解。我们的假设是，在苯丙胺和阿片类等高度成瘾物质的存在下，多巴胺能奖赏通路中的兴奋性突触被病理激活，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，我的实验室使用脑片制备方法来研究腹侧被盖区(VTA)突触抑制的细胞机制，腹侧被盖区是成瘾行为发展所必需的区域。我们发现，滥用药物与突触可塑性相互作用的假设得到了支持，因为苯丙胺完全消除了谷氨酸能突触的长期抑制。这种形式的突触可塑性的阻断类似于对多巴胺系统兴奋的正常刹车的移除；安非他明持续存在很长一段时间引起的长期阻断预计会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一种细胞反应特征，可能促进成瘾的发展。进一步研究正常情况下长期突触抑制的机制以及苯丙胺干扰这种可塑性的机制是进一步研究的重要领域。然而，在开始细胞层面的更详细的工作之前，我越来越觉得有必要验证我们在完好无损的大脑中的工作。到目前为止，还没有人在体内检测VTA中兴奋性突触的突触可塑性。因此，目前还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让我的实验室使用一种全新的技术，来自VTA的活体记录，来验证我们的基本体外研究结果。我们期望拟议的研究将证实我们的体外工作，并为这项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.