Amphetamine administration during a rodent model of cocaine abuse

在可卡因滥用的啮齿动物模型中使用安非他明

• 批准号: 8835240
• 负责人: Cody Siciliano
• 金额: $ 3.83万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2015-11-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8835240
• 关键词: Abstinence; Agonist; Amphetamines; Animals; Attenuated; Autoreceptors; Behavioral; Brain; Clinical Research; Cocaine; Cocaine Abuse; Cocaine Dependence; Data; Dependence; Development; Dopamine; Drug Addiction; Drug usage; FDA approved; Goals; Health; Hour; Human; In Vitro; Intake; Investigation; Lead; Literature; Measurement; Measures; Methadone; Modeling; Monkeys; Motivation; Neurobiology; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacotherapy; Procedures; Pump; Rattus; Replacement Therapy; Rodent; Rodent Model; Saline; Self Administration; Slice; Therapeutic; Therapeutic Agents; Time; Treatment Efficacy; base; behavioral economics; behavioral outcome; cocaine use; design; dopamine system; dopamine transporter; effective therapy; meetings; neurochemistry; nicotine patch; preclinical study; presynaptic; prevent; public health relevance; therapeutic target; uptake

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.

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批准的药物疗法来帮助治疗。安非他明（AMPH）作为COC滥用的一种潜在治疗方法已被研究，在啮齿动物、猴子和人类身上取得了有希望的行为结果。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的强化效果。如果AMPH作为一种药物治疗具有独立于其DA升高作用的疗效，它可能会导致更有针对性的治疗方法的发展，滥用潜力有限。在这里，我们的目的是确定AMPH迷你泵治疗在长期COC自我给药（LgA）和/或戒断期间的神经化学和行为结果。我们之所以选择LgA模型，是因为它会导致与人类COC滥用者相似的几种行为和神经化学变化，包括COC摄入量的增加和对药物的DA升高和行为激活效应的耐受性。对COC的神经化学耐受性，以及其他DA系统的改变，如增加诱发的DA释放，可能是COC摄入量增加以及服用COC动机增加的基础，这是LgA后观察到的一种现象。在本应用中提出的具体目标表征了COC自我给药的后果，并扩展了我们的初步数据，表明AMPH可能逆转lga诱导的神经化学变化并恢复多巴胺能功能。在具体目标1中，我们将确定AMPH治疗减少COC摄入的能力，并评估LgA后DA系统的变化，以及AMPH微型泵防止和/或逆转这些变化的能力。在具体目标2中，我们将研究LgA后COC治疗动机和COC寻求动机的变化，以及AMPH预防/逆转LgA引起的任何变化的能力。虽然以前的文献已经证明了有希望的行为结果，表明AMPH可能是COC滥用的有效治疗方法，但据我们所知，还没有对这些结果的神经化学机制进行调查。我们提出的目的是全面评估在COC自我给药过程中，AMPH给药对神经化学和行为的影响，使这些研究对了解AMPH对COC滥用的潜在治疗及其作用机制至关重要。