Neural mechanism of enduring cocaine effects on impulsive choice

描述(申请人提供)：吸毒成瘾是严重的公共卫生问题。大约2200万美国人(占12岁以上人口的9%)滥用或沉迷于酒精和非法药物。尽管吸毒成瘾的原因是多方面的，但越来越清楚的是，与吸毒有关的认知缺陷可能会导致成瘾过程。特别是，吸毒者表现出糟糕的决策能力，并异常地倾向于立即而不是延迟的满足(即“冲动的选择”)。这种增加的冲动选择可能会导致成瘾过程，使吸毒者更有可能选择进一步吸毒的短期回报，而不是与戒酒相关的延迟但最终更有益的回报(如健康、就业和家庭)。由于更多的冲动选择似乎在停止使用药物后很长一段时间内持续存在，这种认知变化可能在一定程度上解释了即使是目前最好的成瘾疗法也会导致高复发率。使用可以确定明确因果关系的动物模型，已经确定长期服用可卡因会导致更多的冲动选择，就像在人类吸毒者中观察到的那样，这种选择可以在可卡因停止后持续3个月。可卡因自身给药还导致大脑系统网络中的长期神经适应，包括伏隔核中多巴胺和谷氨酸能信号的变化，该结构与药物依赖者的冲动选择调节有关。然而，这些伏隔核的改变在可卡因诱导的冲动选择增加中的作用尚不清楚。这项提议中的实验将检验这样一个假设，即伏隔核多巴胺能和谷氨酸能神经传递的变化与可卡因自身给药导致的冲动选择的长期增加有关。具体地说，我们将在一个大鼠模型中确定：i)可卡因自我给药增加冲动选择的程序参数，ii)伏隔核多巴胺和谷氨酸能信号在药物导航受试者正常冲动选择中的作用，以及iii)可卡因诱导的冲动选择增加是否可以被已知的可卡因自我给药导致伏核多巴胺和谷氨酸能信号变化的药理学靶向逆转。从这些实验中获得的关于可卡因自我管理增加冲动选择的神经机制的知识，对于开发新的有效成瘾治疗方法至关重要。这样的治疗将有可能减少复发的发生率，并提高成瘾者的生产力和生活质量。可卡因的使用与冲动选择的长期增加有关(反映在对立即奖励的偏好而不是延迟奖励)，这可能会使吸毒者更有可能选择进一步吸毒的即时奖励(例如，短期快感、戒断症状的缓解)，而不是延迟但最终更有益的戒毒奖励(更好的健康、就业、家庭关系)。这个方案中的实验将使用一个大鼠模型来研究使用可卡因导致冲动选择持续增加的大脑机制。从这些实验中获得的知识对于开发新的治疗方法、减少复发的可能性和提高成瘾者的生活质量至关重要。

DESCRIPTION (provided by applicant): Drug addiction is a serious public health problem. Approximately 22 million Americans (9% of the population over 12 years of age) abuse or are addicted to alcohol and illicit drugs. Although the causes of drug addiction are multifaceted, it is becoming increasingly clear that cognitive deficits associated with drug use may contribute to the addiction process. In particular, drug addicts demonstrate poor decision-making and an abnormally increased preference for immediate over delayed gratification (i.e. - "impulsive choice"). This increased impulsive choice may contribute to the addiction process by rendering addicts more likely to choose the short-term rewards of further drug use over the delayed but ultimately more beneficial rewards (such as health, employment, and family) associated with abstinence. Because increased impulsive choice appears to persist long after cessation of drug use, this cognitive alteration may account in part for the high relapse rates that follow even the best currently available addiction therapies. Using animal models, in which clear cause-and-effect relationships can be determined, it has been established that chronic cocaine self-administration causes increased impulsive choice, just as is observed in human addicts, that can persist as long as 3 months after cocaine cessation. Cocaine self-administration also causes long-lasting neuroadaptations in a network of brain systems, including alterations in dopaminergic and glutamatergic signaling in the nucleus accumbens, a structure implicated in regulation of impulsive choice in drug-naove subjects. However, the role of these nucleus accumbens alterations in cocaine-induced increases in impulsive choice is unknown. The experiments in this proposal will test the hypothesis that alterations in dopaminergic and glutamatergic neurotransmission in the nucleus accumbens are involved in the long-lasting increases in impulsive choice caused by cocaine self-administration. Specifically, we will determine in a rat model: i) the procedural parameters under which cocaine self-administration increases impulsive choice, ii) the roles of nucleus accumbens dopaminergic and glutamatergic signaling in normal impulsive choice in drug-naove subjects, and iii) whether cocaine-induced increases in impulsive choice can be reversed by pharmacological targeting of alterations in nucleus accumbens dopaminergic and glutamatergic signaling known to result from cocaine self- administration. Knowledge gained from these experiments of the neural mechanisms by which cocaine self-administration increases impulsive choice is crucial for the development of novel effective treatments for addiction. Such treatments would have the potential to reduce the incidence of relapse and to enhance productivity and quality of life for addicted individuals. Cocaine use is associated with long-lasting increases in impulsive choice, (reflected in a preference for immediate over delayed rewards), which may contribute to addiction by rendering users more likely to choose the immediate rewards of further drug use (e.g., short-term euphoria, relief from withdrawal symptoms) over the delayed but ultimately more beneficial rewards of abstinence (better health, employment, family relationships). The experiments in this proposal will use a rat model to investigate brain mechanisms by which cocaine use causes persistent increases in impulsive choice. Knowledge gained from these experiments will be critical for development of novel treatments to reduce the likelihood of relapse and to enhance quality of life for addicted individuals.