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: 8271850
• 负责人: ARTHUR C RIEGEL
• 金额: $ 29.5万
• 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 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8271850
• 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; Photons; 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; prevent; receptor; receptor coupling; research study; response; 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. PUBLIC HEALTH RELEVANCE: Substance abuse costs the U.S. nearly one half-trillion dollars annually (NIDA), and pharmacological treatment can help reduce these costs. At present, there are no effective pharmacotherapeutic interventions for cocaine addiction. Identification of the CRF-mediated neuroadaptations in glutamate transmission in dopamine neurons after cocaine self-administration is expected to reveal novel cellular targets for therapeutic development and thereby lead to a better understanding of, and treatment for, relapse to drug seeking.

描述（由申请人提供）：估计表明，药物滥用和成瘾每年使美国经济造成近50万美元。尽管后果不利，对可卡因的成瘾以强迫性吸毒行为为特征。推动这种行为的机制尚不清楚，但涉及压力，这可能引发渴望。在动物模型中，这归因于神经肽皮质激素释放因子（CRF）与腹侧侧侧区域（VTA）之间的相互作用。但是，仍然缺乏对这种相互作用的细胞机制的了解。这阻碍了制定有效的药物治疗策略来滥用药物和成瘾。该提案的长期目标是确定VTA中的细胞异常，这些细胞异常可能提供有效的治疗靶标以恢复功能，从而防止寻求药物的复发。在多巴胺神经元中，放电模式部分通过代谢型谷氨酸受体（MGLURS）激活，该模式通过激活通过激活钙激活钾（SK）通道来介导“停顿”。该提案的目的是证明可卡因诱导的VTA多巴胺神经元中神经可塑性的变化是由于后突触后谷氨酸能神经传递的缺乏而导致的。为了探索多巴胺神经元中CRF和谷氨酸抑制作用之间的相互作用，我们将记录与抑制性SK通道耦合的mglurs介导的电流。斑块钳记录将在急性脑切片中进行，从受过训练的大鼠到自动可卡因和对照（Yoked Saline）大鼠，在Yohimbine诱导的恢复之前。 CRF-R2/MGLUR受体相互作用的功能影响和机制尚不清楚，并且将在AIM-1和AIM-2中进行研究。 AIM-3将在体内操纵细胞靶标，并验证可卡因复发的变化和基础MGLUR/SK通道的抑制。该提议至关重要的假设是，慢性可卡因自我给药会上调CRF-R2信号传导级联反应，并抑制MGLUR在恢复过程中介导的抑制作用，并且这种可卡因诱导的病理学的缓解将抑制可卡因的寻求可卡因。预计所提出的实验的结果将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，以开发改进的治疗压力相关的寻求药物行为的疗法。 公共卫生相关性：滥用药物损失每年将近五亿美元（NIDA），药理学治疗可以帮助降低这些成本。目前，还没有可卡因成瘾的有效药物治疗干预措施。预计可卡因自我给药后，多巴胺神经元中CRF介导的神经适应的鉴定有望揭示用于治疗性发育的新型细胞靶标，从而导致对药物寻求药物寻求药物的更好理解和治疗。