Amphetamine administration during a rodent model of cocaine abuse

描述（由申请人提供）：可卡因（COC）滥用和依赖是一个主要的健康问题，目前没有FDA批准的药物治疗来帮助治疗。安非他明（AMPH）已被研究为COC滥用的潜在治疗方法，在啮齿动物，猴子和人类中具有良好的行为结果。有人提出，AMPH作为一种激动剂替代疗法，类似于美沙酮或尼古丁贴片。然而，我们的数据表明，AMPH可能通过稳定多巴胺（DA）系统来降低COC的强化功效。如果AMPH作为一种独立于其DA升高作用的药物治疗有效，它可能会导致开发更具针对性的治疗药物，而滥用潜力有限。在这里，我们的目的是确定长期访问COC自我管理（LGA）和/或禁欲期间的神经化学和行为的结果AMPH微型泵治疗。我们选择了LgA模型，因为它导致了几种行为和神经化学变化，这些变化与在人类COC滥用者中观察到的变化相似，包括COC摄入量的增加和对药物的DA升高和行为激活作用的耐受性。对COC的神经化学耐受性，沿着其他DA系统改变，如诱发DA释放增加，可能是COC摄入量增加以及给予COC的动机增加的基础，这是LGA后观察到的现象。在本申请中提出的具体目标表征COC自我给药的后果，并扩展我们的初步数据，证明AMPH可以逆转LGA诱导的神经化学变化和恢复多巴胺能功能。在具体目标1中，我们将确定AMPH治疗减弱COC摄入的能力，并评估LGA后DA系统的改变以及AMPH微型泵保护和/或逆转这些改变的能力。在具体目标2中，我们将研究给予COC和COC寻求LgA的动机变化以及AMPH预防/逆转任何LgA诱导的变化的能力。虽然以前的文献已经证明了有希望的行为结果表明AMPH作为一种潜在的有效治疗COC滥用，有，据我们所知，没有调查的神经化学机制，这些结果。我们提出的目标是探索在COC自我管理期间AMPH管理的神经化学和行为影响的综合评估，使这些研究对于了解AMPH及其作用机制对COC滥用的潜在治疗至关重要。

DESCRIPTION (provided by applicant): Cocaine (COC) abuse and dependence is a major health problem that currently has no FDA approved pharmacotherapies to aid in treatment. Amphetamine (AMPH) has been examined as a potential treatment for COC abuse, with promising behavioral results in rodents, monkeys and humans. It has been proposed that AMPH acts as an agonist replacement therapy, similar to methadone or nicotine patches. However, our data suggest that AMPH may be reducing the reinforcing efficacy of COC by stabilizing the dopamine (DA) system. If AMPH has efficacy as a pharmacotherapy independent of its DA elevating effects, it could lead to the development of more targeted therapeutics with limited abuse potential. Here we aim to determine the neurochemical and behavioral outcomes of AMPH mini-pump treatment during long-access COC self-administration (LgA) and/or during abstinence. We have selected the LgA model as it results in several behavioral and neurochemical changes that parallel those observed in human COC abusers, including escalation of COC intake and tolerance to the DA elevating and behavioral activating effects of the drug. Neurochemical tolerance to COC, along with other DA system alterations such as increased evoked DA release, may underlie escalation of COC intake as well as increased motivation to administer COC, a phenomenon observed following LgA. The specific aims proposed in this application characterize the consequences of COC self-administration and expand on our preliminary data demonstrating that AMPH may reverse LgA-induced neurochemical changes and restore dopaminergic function. In Specific Aim 1 we will determine the ability of AMPH treatment to attenuate COC intake as well as assess alterations to the DA system following LgA and the ability of AMPH mini-pumps to protect against and/or reverse these alterations. In Specific Aim 2 we will examine changes in motivation to administer COC and COC seeking following LgA and the ability of AMPH to prevent/reverse any LgA-induced changes. Although previous literature has demonstrated promising behavioral results suggesting AMPH as a potentially effective treatment for COC abuse, there has been, to our knowledge, no investigation of the neurochemical mechanisms for these results. Our proposed aims explore a comprehensive assessment of the neurochemical and behavioral effects of AMPH administration during COC self-administration, making these studies critical to understanding potential treatment of COC abuse with AMPH and its mechanisms of action.