Neural mechanism of enduring cocaine effects on impulsive choice

描述（由申请人提供）：吸毒成瘾是一个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。虽然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有助于成瘾过程。特别是，吸毒成瘾者表现出糟糕的决策能力，并且对即时满足的偏好异常地增加，而不是延迟的满足（即“冲动选择”）。这种增加的冲动选择可能有助于成瘾过程，使成瘾者更有可能选择进一步使用药物的短期奖励，而不是与戒断相关的延迟但最终更有益的奖励（如健康，就业和家庭）。因为增加的冲动选择似乎在停止使用药物后持续很长时间，这种认知改变可能部分解释了即使是目前最好的成瘾疗法之后的高复发率。使用动物模型，可以确定明确的因果关系，已经确定慢性可卡因自我管理导致冲动选择增加，就像在人类成瘾者中观察到的那样，在可卡因停止后可以持续长达3个月。可卡因自我给药还会在大脑系统网络中引起长期的神经适应，包括伏隔核中多巴胺能和谷氨酸能信号的改变，伏隔核是一种涉及调节吸毒受试者冲动选择的结构。然而，这些伏隔核改变在可卡因诱导的冲动选择增加中的作用尚不清楚。本研究的实验将检验伏隔核中多巴胺能和谷氨酸能神经传递的改变与可卡因自我服用引起的冲动选择的长期增加有关的假设。具体来说，我们将在大鼠模型中确定：1)可卡因自我给药增加冲动选择的程序参数，2)伏隔核多巴胺能和谷氨酸能信号在无药受试者正常冲动选择中的作用，以及3)可卡因诱导的冲动选择的增加是否可以通过药物靶向可卡因自我给药引起的伏隔核多巴胺能和谷氨酸能信号的改变来逆转。从这些实验中获得的关于可卡因自我服用增加冲动选择的神经机制的知识，对于开发新的有效的成瘾治疗方法至关重要。这种治疗方法有可能减少复发率，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（反映在对即时而不是延迟奖励的偏好上），这可能导致成瘾，因为它使使用者更有可能选择进一步使用毒品的即时奖励（例如，短期欣快感，缓解戒断症状），而不是延迟但最终更有益的禁欲奖励（更好的健康、就业、家庭关系）。本提案中的实验将使用大鼠模型来研究可卡因使用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以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.