Relapse to Cocaine-Seeking: Cellular Adaptations in the Ventral Tegmental Area

描述(由申请者提供)：估计表明，药物滥用和成瘾每年给美国经济造成近5000亿美元的损失。对可卡因上瘾的特点是强迫吸毒行为，尽管有不良后果。推动这种行为的机制还不是很清楚，但与压力有关，压力可能会引发渴望。在动物模型中，这归因于神经肽促肾上腺皮质激素释放因子(CRF)和腹侧被盖区(VTA)中的谷氨酸之间的相互作用。然而，对这种相互作用背后的细胞机制仍然缺乏了解。这妨碍了制定针对药物滥用和成瘾的有效药物治疗战略。这项建议的长期目标是识别VTA中的细胞异常，这些异常可能为恢复功能提供有效的治疗靶点，从而防止复发寻求药物。在多巴胺神经元中，放电模式部分由代谢性谷氨酸受体(MGluRs)的激活来调节，mGluRs通过激活钙激活的钾(SK)通道来调节放电“暂停”。这项提议的目的是证明可卡因引起的VTA多巴胺神经元神经可塑性的改变是由于突触后谷氨酸能神经传递的缺陷所致。为了探索CRF与多巴胺神经元谷氨酸抑制之间的相互作用，我们将记录mGluRs介导的电流，该电流耦合到抑制性SK通道。膜片钳记录将在育亨宾诱导的恢复之前或之后，在接受自我给药训练的大鼠和对照(带轭的生理盐水)大鼠的急性脑片中进行。CRF-R2/mGluR受体相互作用的功能影响和机制尚不清楚，将在AIM-1和AIM-2中进行研究。AIM-3将在体内操纵细胞靶点，并验证可卡因恢复和潜在的mGluR/SK通道抑制的变化。这一假设的核心假设是CRF-R2信号级联被慢性可卡因自身给药上调，并在恢复过程中抑制mGluR介导的抑制，这种可卡因诱导的病理的改善将抑制可卡因的寻求。拟议中的实验结果预计将对人类健康产生积极影响，因为它们将确定新的细胞靶点，用于开发治疗与压力相关的药物寻求行为的改进疗法。

DESCRIPTION (provided by applicant): Estimates indicate that drug abuse and addiction cost the U.S. economy nearly one half-trillion dollars per year. Addiction to cocaine is characterized by compulsive drug taking behavior, despite adverse consequences. The mechanisms driving this behavior are not well understood, but involve stress, which can trigger craving. In animal models this is attributed to an interaction between the neuropeptide corticotropin releasing factor (CRF) and glutamate in the Ventral Tegmental Area (VTA). However, there remains a lack of understanding of the cellular mechanism underlying this interaction. This hampers the development of effective pharmacological treatment strategies for drug abuse and addiction. The long-term objective of this proposal is to identify cellular abnormalities in the VTA that may provide effective therapeutic targets to restore function and thereby prevent relapse to drug seeking. In dopamine neurons, firing patterns are regulated in part by activation of metabotropic glutamate receptors (mGluRs), which mediate a firing 'pause' through activation of calcium activated potassium (sK) channels. The goal of this proposal is to demonstrate that cocaine-induced changes in neuroplasticity in VTA dopamine neurons result from a deficiency in post-synaptic glutamatergic neurotransmission. To explore the interaction between CRF and glutamate-inhibition in dopamine neurons, we will record currents mediated by mGluRs that are coupled to inhibitory sK channels. Patch-clamp recordings will be performed in acute brain slices from rats trained to self-administer cocaine and control (yoked saline) rats, before or afte yohimbine-induced reinstatement. The functional impact of and the mechanism underlying the CRF-R2/mGluR receptor interaction is unknown and will be investigated in Aim-1 and Aim-2. Aim-3 will manipulate cellular targets in vivo and validate the changes in cocaine-reinstatement and the underlying mGluR/sK channel inhibition. The hypothesis that is central to this proposal is that the CRF-R2 signaling cascade is upregulated by chronic cocaine self-administration and depresses mGluR mediated inhibition during reinstatement, and that amelioration of this cocaine-induced pathology will inhibit cocaine-seeking. The results of the proposed experiments are expected to positively influence human health because they should identify novel cellular targets for development of improved therapies to treat stress-related drug-seeking behaviors.