NUCLEUS ACCUMBENS INVOLVEMENT IN COCAINE REINFORCEMENT

描述：（申请人摘要） 长期使用可卡因造成的巨大健康风险促使人们 认真的研究努力，以确定神经生物学基板， 是寻求毒品和复吸的动机的基础。 这一领域的研究主要集中在细胞核（NAc）上， 被认为是动机和 行动上 NAc接受来自几个神经递质系统的传入 (e.g.多巴胺，血清素，谷氨酸），每一个都与 在药物强化方面。 尽管取得了重大进展，但我们的理解是， 在药物的动机方面涉及的神经化学机制 寻找仍然不完整。 已知NAc含有胆碱能物质 中间神经元的活动可能具有重要的动机后果。 这项研究的第一个具体目标是确定可卡因的影响 自身给药对NAc内乙酰胆碱（ACh）释放的影响， 运动控制，背外侧纹状体 Sprague-Dawley大鼠 植入静脉导管，并接受训练， 注射可卡因 微透析将用于测量ACh在4 时间点：1）初始暴露于可卡因期间，2）2周后， 每日自我给药，3）停药10天后，最后4） 在恢复自我管理期间。 这些实验的第二个目的 是为了确定NAc内ACh中间神经元对 可卡因2周后的GABA能和多巴胺能药物 自我给药和停药10天后。 微透析探针 将用于在测量ACh释放的同时将药物施用到NAc中。 本研究的第三个目的是描述ACh在多大程度上 调节可卡因自我给药。 大鼠将接受训练， 对于静脉注射可卡因的渐进比例时间表， 加固. ACh激动剂和拮抗剂的微量输注将是 在药物可用之前，将其双边递送到NAc中。 响应 在药物活性和非活性杠杆上，将测量5小时， 输液 选择性增加对药物活性水平的反应 应表明获取可卡因的动机增加， 反应的降低将表示抑制。 希望这些 结果将进一步了解胆碱能参与 寻找药物的机制和潜在的临床发展 有效治疗毒瘾和复发。

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.