Neural Substrates of Human Cocaine Self-Administration

人们普遍认为，可卡因加强自身管理的能力导致了持续、反复和大量使用可卡因。治疗人类可卡因滥用的干预措施试图改变与强制使用相关的奖励或动机。作为药物诱导强化的模型，自我管理(SA)范式被认为是最接近自然主义可卡因滥用的范例。这些和其他依赖模型已经证明，可卡因激活了多巴胺能中皮质边缘(MCL)系统。同时，从最初的临床前和现在的人类模型中出现的证据表明，滥用药物的享乐性快感效应反应，尽管与纹状体、边缘和边缘旁结构的激活有关，但可能不是滥用药物强化效应的关键。事实上，许多神经成像研究已经证实，人类被动服用可卡因会激活中脑边缘结构，这种激活与行为影响有关。另一方面，被动注射可卡因的神经生物学后果与自我注射的可卡因有很大不同。虽然存在几种强迫寻求药物行为的动物模型，但对人类使用可卡因的动机和强化的神经底物知之甚少。这项建议试图利用功能磁共振成像来确定与可卡因SA在人类可卡因依赖个体中的强化和奖励相关的神经解剖位置和神经认知机制。药理学和行为学模型将被应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，以及与被动注射可卡因相比与自我注射的强化和奖励相关的区域。可卡因强化的人类神经底物的特征将有助于更好地理解支持使用可卡因的动力的神经生物学途径，并可能有助于解释药物滥用的脆弱性。预计这些信息将对开发更有效的临床治疗策略至关重要，因为它提供了对滥用这种令人上瘾的药物的冲动的洞察。

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.