LTPGABA in the VTA and its Modulation by Opioids

描述（申请人提供）：我的主要兴趣领域是腹侧被盖区（VTA）。该脑区由异质的神经元群组成，在内源性奖赏中起作用，并受到许多药物滥用的影响。我和我的同事在体外发现了一种新的长期增强（LTP） gaba能突触到VTA多巴胺能神经元上，这种突触可以被阿片类药物改变。我的项目侧重于这种抑制性LTP的表征及其潜在机制。此外，我对通过改变gaba能传递来定义阿片样物质改变VTA神经元兴奋性的分子机制感兴趣；和VTA的可塑性。所有实验均在大鼠中脑切片上进行，采用可视化膜片钳记录。目的1：表征LTPGABA诱导的细胞突触后机制。目的2：确定在LTP期间，突触后启动神经元向突触前末端传递的逆行信号，以释放更多的GABA。目的3：探讨阿片类药物对体内LTPGABA的影响。考虑到药物成瘾对社会的巨大负担，这项研究的重点是非常重要的。诸如此类的研究将更好地理解滥用药物如何以某种方式调节大脑回路，导致成瘾者表现出长期不想要的行为改变。该研究也为抗成瘾药物的开发提供了潜在的靶点。

DESCRIPTION (provided by applicant): My primary area of interest is in the ventral tegmental area (VTA). This brain area consists of a heterogeneous population of neurons, plays a role in endogenous reward and is affected by many drugs of abuse. My colleague and I have found a novel long-term potentiation (LTP) of GABAergic synapses onto VTA dopaminergic neurons which can be altered by opioids in vitro. My project focuses on the characterization of this inhibitory LTP, and its underlying mechanisms. Additionally, I am interested in defining the molecular mechanisms by which opioids modify the excitability of the VTA neurons through the alterations of GABAergic transmission; and plasticity in the VTA. All experiments will be conducted in midbrain slices of rats using visualized patch clamp recording.Aim 1:To characterize the cellular postsynaptic mechanisms underlying the induction of LTPGABA. Aim 2:To determine the retrograde signal that travels from the postsynaptic initiating neuron to direct the presynaptic terminal to release more GABA during LTP.Aim 3: To explore the effects of opioids on this LTPGABA in vivo. Considering the enormous burden of drug addiction on society, the focus of this research is highly important. Studies such as this will provide a better understanding of how drugs of abuse modulate brain circuitry in a way causing an addict to manifest long-term unwanted behavioral changes. This study could also provide the potential targets for anti-addiction drugs.