LTPGABA in the VTA and its Modulation by Opioids

描述(申请人提供)：我的主要兴趣区域是腹侧被盖区(VTA)。这一大脑区域由不同种类的神经元组成，在内源性奖赏中发挥作用，并受到许多药物滥用的影响。我和我的同事发现了一种新的GABA能突触与VTA多巴胺能神经元之间的长时程增强(LTP)，这种突触可以在体外被阿片类药物改变。我的项目重点是这种抑制性LTP的特征及其潜在的机制。此外，我感兴趣的是确定阿片类药物通过改变GABA能传递和VTA可塑性来改变VTA神经元的兴奋性的分子机制。所有实验将在大鼠中脑切片上进行，采用可视化膜片钳记录。目的1：研究LTPGABA诱导的细胞突触后机制。目的2：确定突触后起始神经元传递的逆行信号，以指导突触前终末在LTP过程中释放更多的GABA。目的3：探讨阿片类药物对体内LTPGABA的影响。考虑到吸毒给社会带来的巨大负担，本研究的重点具有十分重要的意义。这样的研究将更好地理解滥用药物如何调节大脑电路，从而导致成瘾者表现出长期不受欢迎的行为变化。本研究也可能为抗成瘾药物提供潜在的靶点。

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.