Central Cholinergic Involvement in Cocaine Addiction

描述：（申请人提供） 强迫性使用可卡因造成的巨大健康风险促使 一项认真的研究工作，以确定神经生物学基质， 是导致这种药物成瘾的原因尽管作出了重大的 进展，对介导神经化学系统的理解， 寻求毒品和渴望毒品的动机方面仍然不完整。扩大 根据这一理解，本建议将审查四个独立的参与， 胆碱能系统在强迫性可卡因摄入发展中的作用， 老鼠的可卡因寻找行为实验将集中在尼古丁 乙酰胆碱（ACh）受体激活在发育和表达中的作用 成瘾行为第一个具体目标是确定 递增剂量可卡因自身给药对杏仁核ACh释放的影响 腹侧被盖区（VTA）、背侧核（NAc）和背侧被盖区（VTA） 前额叶皮层（PFC）。老鼠将被训练按下杠杆， 通过颈静脉导管自我注射可卡因可用性 可卡因将从每天1小时增加到6小时（这已被证明 逐步增加每日可卡因摄入量）和微透析将测量ACh释放 可卡因摄入量增加前后的变化第二个实验将检查 脑内微量注射尼古丁或尼古丁拮抗剂的影响 美加明对可卡因摄入量的影响第二个目的是 建议是确定VTA，NAc，PFC或AmC中的尼古丁注射是否会 可卡因成瘾大鼠的主要非强化性按压行为。之前 测试中，大鼠将接受尼古丁或生理盐水的全身注射， 自我注射可卡因两周在测试日，将给予大鼠 脑内尼古丁和非增强反应将被测量为 可卡因渴望指数本研究的第三个目的是确定 AmC，VTA，NAc和PFC ACh系统在药物相关性能力中的作用 刺激来控制非强化反应。ACh将在 可卡因相关线索的呈现沿着由 在AmC内微量注射烟碱类药物后的可卡因条件刺激， VTA、NAc和PFC。在这四个区域注射烟碱拮抗剂是 预计将减少对呈现的响应的重复按压行为， 二阶刺激希望这些研究的结果将 进一步了解中枢胆碱能机制的参与 可卡因强化的行为和药物渴望以及大脑特定部位 尼古丁对可卡因成瘾和复吸影响

DESCRIPTION: (provided by applicant) The substantial health risk posed by the compulsive use of cocaine has prompted a serious research effort to identify the neurobiological substrates that underlie the development of addiction to this drug. Despite substantial progress, an understanding of the neurochemical systems that mediate the motivational aspects of drug seeking and craving remains incomplete. To expand this understanding, this proposal will examine the involvement of four discrete cholinergic systems in the development of compulsive cocaine intake and cocaine-seeking behaviors in rats. Experiments will focus on nicotinic acetylcholine (ACh) receptor activation in the development and expression of addictive behavior. The first specific aim is to identify the impact of escalating cocaine self-administration on the release of ACh in amygdaloid complex (AmC), ventral tegmental area (VTA), nucleus accumbens (NAc) and prefrontal cortex (PFC). Rats will be trained to press a lever to self-administer cocaine through indwelling jugular catheters. Availability of cocaine will be increased from 1 to 6 hr per day (which has been shown to escalate daily cocaine intake) and microdialysis will measure ACh release before and after escalated cocaine intake. A second experiment will examine the impact of intracerebral microinjections of nicotine or the nicotinic antagonist mecamylamine on the escalation of cocaine intake. The second aim of this proposal is to determine if nicotine injections in VTA, NAc, PFC or AmC will prime non-reinforced lever-press behavior in cocaine addicted rats. Prior to testing, rats will receive systemic injections of nicotine or saline before self-administering cocaine for 2 weeks. On test days, rats will be given intracerebral nicotine and non-reinforced responding will be measured as an index of cocaine craving. The third aim of this research is to determine the role of AmC, VTA, NAc and PFC ACh systems in the ability of drug-associated stimuli to control non-reinforced responding. ACh will be measured during the presentation of cocaine-associated cues along with responding elicited by a cocaine-conditioned stimulus after microinjection of nicotinic drugs into AmC, VTA, NAc and PFC. Injections of nicotinic antagonists in these four areas are expected to reduce lever-press behavior in response to presentation of second-order stimuli. It is hoped that the results of these studies will further our understanding of the involvement of central cholinergic mechanisms in cocaine-reinforced behavior and drug craving and the brain site-specific influence of nicotine on cocaine addiction and relapse.