Neural Substrates of Human Cocaine Self-Administration

人们普遍认为，可卡因加强自身作用的能力导致了可卡因的持续、重复和大量使用。治疗人类可卡因滥用的干预措施试图改变与强迫性使用相关的奖励或动机。作为药物诱导强化的模型，自我给药（SA）范式被认为最接近自然的可卡因滥用。这些和其他依赖模型表明，可卡因激活多巴胺能中皮质边缘（MCL）系统。与此同时，从临床前和现在的人体模型中出现的新证据表明，尽管与纹状体、边缘和副边缘结构的激活有关，但滥用药物的快感效应对滥用药物的强化效应可能不是必需的。事实上，许多神经成像研究已经证实，被动服用可卡因会激活人类的中脑边缘结构，而这种激活与行为效应有关。另一方面，被动注射可卡因的神经生物学后果与自我注射可卡因有很大不同。虽然存在几种强迫性药物寻求行为的动物模型，但对人类可卡因使用动机和强化的神经基质知之甚少。本研究旨在利用功能磁共振成像技术确定人类可卡因依赖个体中与可卡因SA强化和奖赏相关的神经解剖部位和神经认知机制。药理学和行为学模型将用于识别和表征与可卡因剂量反应、与SA相关的奖励预期相关的神经区域，并确定与被动研究者给药相比，与自我注射的强化和奖励相关的神经区域。对可卡因强化的人类神经基质的表征将有助于更好地理解支持使用可卡因的神经生物学途径，并可能有助于解释对药物滥用的脆弱性。预计这些信息将通过深入了解滥用这种成瘾药物的冲动，对制定更有效的临床治疗策略至关重要。

It is widely believed that cocaine's ability to reinforce its own administration leads to the sustained, repeated, and heavy use of cocaine. Interventions to treat human cocaine abuse attempt to alter the reward or motivation associated with compulsive use. As models of drug-induced reinforcement, self-administration (SA) paradigms are felt to best approximate naturalistic cocaine abuse. These and other models of dependence have demonstrated that cocaine activates the dopaminergic mesocorticolimbic (MCL) system. At the same time, there is emerging evidence from first preclinical and now human models to suggest that, the hedonic euphoriant effect response to drugs of abuse, although related to activation in striatal, limbic, and paralimbic structures may not be essential to the reinforcing effects of drugs of abuse. Indeed, a number of neuroimaging studies have confirmed that passive cocaine administration in humans activates mesolimbic structures and that this activation is related to behavioral effects. On the other hand, the neurobiological consequences of passive cocaine injections are substantially different from self-administered cocaine. While several animal models of compulsive drug seeking behavior exist, little is known about the neural substrates for the motivation and reinforcement of human cocaine use. This proposal seeks to determine the neuroanatomical sites and neurocognitive mechanisms associated with the reinforcement and reward of cocaine SA in human cocaine dependent individuals using fMRI. Pharmacological and behavioral models will be applied to identify and characterize those neural regions associated with cocaine dose-response, the anticipation of reward associated with SA, as well as determine those regions related to the reinforcement and reward of self-injection in contrast with passive investigator administered cocaine. The characterization of human neural substrates of cocaine reinforcement will lead to a better understanding of the neurobiological pathways underpinning the drive to use cocaine and may help to explain vulnerability to drug abuse. It is expected that such information will be essential to developing more effective clinical treatment strategies by providing insight into the compulsion to abuse this addicting drug.