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

描述（由申请人提供）：众所周知，药物滥用与高度冲动和决策能力受损有关。这种行为可能导致成瘾，使吸毒者更有可能选择进一步使用药物的短期回报，而不是禁欲的延迟回报（如健康、就业和家庭）。药物滥用者的冲动行为与眶额皮质的结构和功能变化有关，眶额皮质是大脑额叶的一个结构，对决策和冲动控制至关重要。然而，这些变化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，以便更好地了解成瘾过程，并最终帮助制定成瘾治疗策略。本研究项目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。行为将通过延迟折扣任务来评估，在这个任务中，老鼠必须在一个小的、即时的奖励和一个大的、延迟的奖励之间做出选择。在这个模型中，冲动性被定义为对小奖励的偏好高于对大延迟奖励的偏好。初步数据表明，相对较短的可卡因暴露时间会导致冲动选择增加，这在可卡因停止后长达3个月的时间里仍然很明显。具体目标1将确定复制这种效果所需的最低可卡因剂量，以及可卡因对冲动选择的影响持续时间。特异性目标2将使用直接早期基因产物c-Fos的表达来确定先前的可卡因暴露如何改变眶额叶皮层的神经活动，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将涉及在可卡因暴露大鼠延迟贴现任务之前给予多巴胺能拮抗剂a-氟哌辛醇。过多的多巴胺在眼窝额叶皮层的传递（这似乎是可卡因暴露前的结果）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，以及可能逆转这些影响的治疗方法。考虑到药物滥用在现代社会的突出地位，对药物如何影响大脑和认知有一个全面的了解是很重要的。这类信息对于控制和（或）治疗药物成瘾和药物滥用的长期衰弱影响至关重要。

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.