NUCLEUS ACCUMBENS INVOLVEMENT IN COCAINE REINFORCEMENT

描述：(申请人摘要) 长期使用可卡因带来的巨大健康风险促使人们 认真研究确定神经生物学底物 这是寻求毒品和毒品复发的动机方面的基础。 这方面的研究主要集中在伏隔核(NAC)。 被认为是动机和 行动。NAC接受来自几个神经递质系统的传入 (例如，多巴胺、5-羟色胺、谷氨酸)，每一种都有牵连 在药物强化方面。尽管取得了实质性进展，但我们的理解是 药物激励方面涉及的神经化学机制 寻找仍未完成。已知的NAC含有胆碱能 中间神经元，其活动可能具有重要的动机后果。 这项研究的第一个具体目的是确定可卡因的影响 NAC内乙酰胆碱(ACh)释放的自我给药，作为一种 运动控制，背外侧纹状体。斯普拉格-道利大鼠将成为 植入静脉导管，并接受杠杆按压治疗 注射可卡因。将使用微渗析在四点测量ACh 时间点：1)在首次接触可卡因期间，2)在2周后 每日自我给药，3)停药10天后，最后4) 在恢复自治期间。这些实验的第二个目的是 目的是确定NAC内ACh中间神经元对 可卡因2周后的GABA能和多巴胺能药 自我管理并在停药十天后。微渗析探头 将用于给药进入NAC，同时测量ACh的释放。 这项研究的第三个目标是表征ACH的程度 调节可卡因的自我给药。老鼠将被训练用杠杆按压 静脉注射可卡因的累进比率为 增援。微量注射ACh激动剂和拮抗剂将是 在药物可供使用之前以双边方式交付给NAC。正在响应 在接下来的五个小时内，将测量药物活性和非活性水平 输液。选择性增加对药物活性杠杆的反应 应该表明获得可卡因的动机增加了，而 回应减少将标志着一种压制。希望这些都是 这些结果将进一步加深我们对胆碱能参与的理解 药物寻找的机制及其对临床发展的潜在影响 对药物渴求和复发的有效治疗。

DESCRIPTION: (Applicant's Abstract) The substantial health risk posed by chronic cocaine use has prompted a serious research effort to identify the neurobiological substrates that underlie the motivational aspects of drug seeking and drug relapse. Research in this area has concentrated on the nucleus accumbens (NAc) which is considered to be an integral component in the link between motivation and action. The NAc receives afferents from several neurotransmitter systems (e.g. dopamine, serotonin, glutamate) and each of these has been implicated in drug reinforcement. Despite this substantial progress, our understanding of the neurochemical mechanisms involved in the motivational aspects of drug seeking remains incomplete. The NAc is known to contain cholinergic interneurons whose activity may have important motivational consequences. The first specific aim of this research is to identify the impact of cocaine self-administration on acetylcholine (ACh) release within the NAc and, as a motoric control, the dorso-lateral striatum. Sprague-Dawley rats will be implanted with intravenous catheters and trained to lever-press for infusions of cocaine. Microdialysis will be used to measure ACh at four time points: 1) during initial exposure to cocaine, 2) after 2 weeks of daily self-administration, 3) after 10 days of withdrawal and finally 4) during reinstated self-administration. The second aim of these experiments is to determine the responsiveness of ACh interneurons within the NAc to GABAergic and dopaminergic drugs following 2 weeks of cocaine self-administration and after ten days of withdrawal. Microdialysis probes will be used to administer drugs into the NAc while ACh release is measured. The third aim of this research is to characterize the extent to which ACh modulates cocaine self-administration. Rats will be trained to lever-press for intravenous infusions of cocaine on a progressive ratio schedule of reinforcement. Micro-infusions of ACh agonists and antagonists will be delivered bilaterally into the NAc prior to drug availability. Responding on drug-active and inactive levers will be measured for five hours following infusions. Selective increases in responding on the drug-active lever should indicate an increase in the motivation to obtain cocaine while decreases in responding would signal a suppression. It is hoped that these results will further our understanding of the involvement of cholinergic mechanisms in drug-seeking and potentially to the development of clinically efficacious treatments for drug craving and relapse.