Long-Term Cocaine Effects on Impulsive Choice and Orbitofrontal Cortex Activity

长期可卡因对冲动选择和眶额皮层活动的影响

• 批准号: 7568925
• 负责人: Nicholas W Simon
• 金额: $ 2.95万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7568925
• 关键词: Abstinence; Acute; Address; Attenuated; Behavior; Behavioral; Brain; Brain imaging; Choice Behavior; Cocaine; Cognition; Cognitive; Data; Decision Making; Development; Dopamine; Dopamine Antagonists; Dopamine Receptor; Dose; Drug Addiction; Drug abuse; Drug usage; Employment; Etiology; Exposure to; FOS gene; Family; Flupenthixol; Foundations; Goals; Health; Human; Immediate-Early Genes; Impulsive Behavior; Impulsivity; Laboratories; Lead; Long-Term Effects; Modeling; Neurobiology; Neurophysiology - biologic function; Performance; Pharmaceutical Preparations; Population; Predisposing Factor; Problem behavior; Process; Proteins; Rattus; Regulation; Research; Rest; Rewards; Societies; Structure; Testing; Treatment Protocols; addiction; cocaine exposure; discount; discounting; drug abuser; drug addict; drug of abuse; frontal lobe; human subject; neurobiological mechanism; preference; programs; receptor binding; relating to nervous system; research study; response; restoration; transmission process; treatment strategy

DESCRIPTION (provided by applicant): It is well-established that drug abuse is associated with high levels of impulsivity and impaired decision making. This behavior may contribute to addiction by rendering drug abusers more likely to choose the short-term rewards of further drug use over the delayed rewards of abstinence (such as health, employment, and family). Impulsive behavior in drug abusers is associated with structural and functional changes in the orbitofrontal cortex, a frontal lobe brain structure that is critical for decision making and impulse control. However, the degree to which these alterations are caused by drug abuse as opposed to acting as predisposing factors for drug abuse remains unclear. This issue must be addressed to provide a better understanding of addictive processes and ultimately aid in development of treatment strategies for addiction. The overall goal of this research program is to determine the behavioral and neurobiological mechanisms by which exposure to drugs of abuse causes long-lasting deficits in impulsive choice. Behavior will be assessed via a delay discounting task in which rats must choose between a small, immediate reward and a large, delayed reward. Impulsivity in this model is defined as increased preference for the small reward over the large delayed reward. Preliminary data demonstrate that a relatively brief period of cocaine exposure causes increased impulsive choice that is evident as long as 3 months after cocaine cessation. Specific Aim 1 will determine the minimum dose of cocaine necessary to replicate this effect, as well as the duration of cocaine's effects on impulsive choice. Specific Aim 2 will use expression of the immediate early gene product c-Fos to determine how previous cocaine exposure alters neural activity in the orbitofrontal cortex, and whether such neurobiological alterations are related to impulsive choice behavior in the delay discounting task. Specific Aim 3 will involve the administration of the dopaminergic antagonist a-flupenthixol prior to the delay discounting task in cocaine-exposed rats. Excessive dopamine transmission in the orbitofrontal cortex (which seems to result from cocaine pre-exposure) appears to be related to high levels of impulsivity; therefore, this treatment is expected to reduce impulsive choice behavior in these subjects. This research will offer valuable information regarding the long term effects of cocaine exposure on behavioral and neurobiological aspects of impulsive choice behavior, as well as a treatment that may reverse these effects. Considering the prominence of drug-abuse in modern society, it is important to develop a thorough understanding of how drugs can impact the brain and cognition. Such information will be critical for controlling and/or treating drug addiction and the long-term debilitating effects of drug abuse.

描述（由申请人提供）：众所周知，药物滥用与高度冲动和决策受损有关。这种行为可能会导致药物成瘾，因为药物滥用者更有可能选择进一步吸毒的短期回报，而不是戒毒的延迟回报（例如健康、就业和家庭）。吸毒者的冲动行为与眶额皮质的结构和功能变化有关，眶额皮质是额叶大脑结构，对于决策和冲动控制至关重要。然而，这些改变在多大程度上是由药物滥用引起的，而不是作为药物滥用的诱发因素，目前尚不清楚。必须解决这个问题，以便更好地理解成瘾过程，并最终帮助制定成瘾治疗策略。该研究计划的总体目标是确定滥用药物导致冲动选择长期缺陷的行为和神经生物学机制。行为将通过延迟贴现任务进行评估，其中大鼠必须在小额即时奖励和大额延迟奖励之间进行选择。该模型中的冲动被定义为对小奖励的偏好超过对大延迟奖励的偏好。初步数据表明，相对较短的时间接触可卡因会导致冲动选择增加，这种现象在戒除可卡因后 3 个月内就很明显。具体目标 1 将确定复制这种效果所需的可卡因的最小剂量，以及可卡因对冲动选择的影响的持续时间。具体目标 2 将利用立即早期基因产物 c-Fos 的表达来确定先前的可卡因暴露如何改变眶额皮层的神经活动，以及这种神经生物学改变是否与延迟贴现任务中的冲动选择行为有关。具体目标 3 将涉及在对可卡因暴露的大鼠进行延迟贴现任务之前给予多巴胺能拮抗剂α-氟哌噻吨。眶额皮质中过多的多巴胺传输（这似乎是由于预先接触可卡因所致）似乎与高水平的冲动有关；因此，这种治疗有望减少这些受试者的冲动选择行为。这项研究将提供有关可卡因暴露对冲动选择行为的行为和神经生物学方面的长期影响的有价值的信息，以及可能扭转这些影响的治疗方法。考虑到药物滥用在现代社会中的突出地位，深入了解药物如何影响大脑和认知非常重要。这些信息对于控制和/或治疗药物成瘾以及药物滥用的长期衰弱影响至关重要。

项目成果

Effects of acute administration of nicotine, amphetamine, diazepam, morphine, and ethanol on risky decision-making in rats.

急性服用尼古丁、安非他明、地西泮、吗啡和乙醇对大鼠危险决策的影响。

• 发表时间: 2011-12
• 影响因子: 3.4
• 作者: Mitchell, Marci R;Vokes, Colin M;Blankenship, Amy L;Simon, Nicholas W;Setlow, Barry
• 通讯作者: Setlow, Barry

Risk, reward, and decision-making in a rodent model of cognitive aging.

认知衰老啮齿动物模型中的风险、奖励和决策。

• 发表时间: 2011
• 作者: Gilbert, Ryan J;Mitchell, Marci R;Simon, Nicholas W;Bañuelos, Cristina;Setlow, Barry;Bizon, Jennifer L
• 通讯作者: Bizon, Jennifer L

Prefrontal cortical-striatal dopamine receptor mRNA expression predicts distinct forms of impulsivity.

前额皮质纹状体多巴胺受体 mRNA 表达可预测不同形式的冲动。

• 发表时间: 2013-06
• 作者: Simon, Nicholas W;Beas, Blanca S;Montgomery, Karienn S;Haberman, Rebecca P;Bizon, Jennifer L;Setlow, Barry
• 通讯作者: Setlow, Barry