CENTRAL CHOLINERGIC MECHANISMS IN COCAINE REINFORCEMENT

可卡因是一种强大的精神刺激剂，在人类身上具有很高的滥用倾向。 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 这是寻求毒品的动机方面的基础。这一领域的研究 在解剖学上集中在基底的腹内侧核 神经节称为伏隔核(NAC)，被认为是一种 在动机和行动之间的联系中不可或缺的组成部分。近期 神经化学研究表明，几种 神经递质系统(如多巴胺、5-羟色胺、谷氨酸)定位 在NAC内部调节药物强化。尽管如此， 进展，我们对神经化学机制的理解涉及到 关于寻求毒品的动机/行为方面的研究仍然不完整。 特别是，已知的NAC含有一群胆碱能 中间神经元，其活动可能具有重要的动机后果。 因此，拟议研究的一个主要目标是描述 ACh调节大鼠药物自我给药的程度。斯普拉格- Dawley大鼠将被植入静脉导管并接受训练 杠杆压力机，用于注射可卡因，按以下比例递增 增援。在稳定的基线响应水平之后 已建立的微量输注ACh激动剂、奥曲莫林和 甲氨基甲胆碱或胆碱能拮抗剂(阿托品和 甲氨基甲胺)将被送入侧脑室或双侧 在药物供应之前进入NAC。对两种药物都有反应-活性 不活动的杠杆将被测量五个小时，每一次 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 反应的减少将标志着可卡因的抑制 增强效果。希望这些研究的结果将 有助于理解神经化学底物 是毒品寻觅的基础，并可能有助于 对药物渴求和复发的临床有效治疗。

Cocaine is a potent psychostimulant with high abuse liability in humans. 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. Research in this area has concentrated anatomically on a ventromedial nucleus of the basal ganglia called the nucleus accumbens (NAc), which is considered to be an integral component in the link between motivation and action. Recent neurochemical investigations have suggested the importance of several neurotransmitter systems (e.g. dopamine, serotonin, glutamate) localized within the NAc in modulating drug reinforcement. Despite this substantial progress, our understanding of the neurochemical mechanisms involved in the motivational/behavioral aspects of drug seeking remains incomplete. In particular, the NAc is known to contain a population of cholinergic interneurons whose activity may have important motivational consequences. Therefore, a primary goal of the proposed studies is to characterize the extent to which ACh modulates drug self-administration in rats. Sprague- Dawley rats will be implanted with intravenous catheters and trained to lever-press for infusions of cocaine on a progressive ratio schedule of reinforcement. After a steady level of baseline responding is established, micro-infusions of ACh agonists, oxotremorine and methylcarbamylcholine or cholinergic antagonists (atropine and mecamylamine) will be delivered into the lateral ventricle or bilaterally into the NAc prior to drug availability. Responding on both a drug-active and an inactive lever will be measured for five hours following each infusion. 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 of cocaine's reinforcing effects. It is hoped that the results of these studies will contribute to an understanding of the neurochemical substrates which underlie drug-seeking and potentially contribute to the development of clinically efficacious treatments for drug craving and relapse.