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

可卡因复发：腹侧被盖区的细胞适应

• 批准号: 9043843
• 负责人: ARTHUR C RIEGEL
• 金额: $ 29.21万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-15 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9043843
• 关键词: Action Potentials; Acute; Addictive Behavior; Animal Model; Animals; Anxiety; Attenuated; Autoreceptors; Behavior; Behavioral Model; Brain; CRF receptor type 2; Calcium; Cells; Chemosensitization; Chronic; Cocaine; Cocaine Dependence; Corticotropin-Releasing Hormone; Cues; Cyclic AMP-Dependent Protein Kinases; Depressed mood; Development; Dopamine; Drug Addiction; Drug abuse; Functional disorder; Glutamates; Goals; Grant; Health; Human; Image; Intervention; Lead; Measures; Mediating; Metabotropic Glutamate Receptors; Microscope; Modeling; National Institute of Drug Abuse; Neurobiology; Neurologic; Neuronal Plasticity; Neuropeptides; Pathology; Pattern; Pharmaceutical Preparations; Pharmacological Treatment; Potassium; Primates; Rattus; Regulation; Relapse; Saline; Self Administration; Self-Administered; Signal Transduction; Slice; Stress; Substance abuse problem; Synapses; Testing; Training; Ventral Tegmental Area; Work; Yohimbine; addiction; adverse outcome; attenuation; cellular targeting; cocaine use; cost; craving; dopaminergic neuron; driving behavior; drug seeking behavior; flash photolysis; functional restoration; improved; in vivo; metabotropic glutamate receptor type 1; neuroadaptation; neuroimaging; neurotransmission; novel; patch clamp; predicting response; prevent; receptor; receptor coupling; research study; response; targeted treatment; therapeutic development; therapeutic target; transmission process; treatment strategy; two-photon

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.

描述（由申请人提供）：据估计，药物滥用和成瘾使美国经济每年损失近1.5万亿美元。可卡因成瘾的特点是强迫性吸毒行为，尽管有不良后果。驱动这种行为的机制尚不清楚，但与压力有关，压力会引发渴望。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）谷氨酸之间的相互作用。然而，对这种相互作用的细胞机制仍然缺乏了解。这阻碍了药物滥用和成瘾的有效药理学治疗策略的发展。这项建议的长期目标是确定VTA中的细胞异常，这可能提供有效的治疗靶点来恢复功能，从而防止复发的药物寻求。在多巴胺神经元中，放电模式部分受代谢性谷氨酸受体（mGluRs）的激活调节，该受体通过激活钙活化钾（sK）通道介导放电“暂停”。本研究的目的是证明可卡因诱导的VTA多巴胺神经元的神经可塑性变化是由于突触后谷氨酸能神经传递不足造成的。为了探索多巴胺神经元中CRF和谷氨酸抑制之间的相互作用，我们将记录由mGluRs介导的电流，这些电流与抑制性sK通道偶联。膜片钳记录将在育因宾诱导恢复之前或之后，对训练自我使用可卡因和对照（盐水）的大鼠的急性脑切片进行。CRF-R2/mGluR受体相互作用的功能影响及其机制尚不清楚，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。该建议的核心假设是，慢性可卡因自我给药上调了CRF-R2信号级联，并抑制了恢复期间mGluR介导的抑制，并且这种可卡因诱导的病理的改善将抑制可卡因寻求。拟议的实验结果有望对人类健康产生积极影响，因为它们应该确定新的细胞靶标，以开发改进的疗法来治疗与压力相关的药物寻求行为。