Neurobiological Study of the Reinforcing Efficacy of Cocaine in Unique Models

描述（由申请人提供）：本申请建议使用新开发的自我给药范式和快速扫描循环伏安法来表征两种独特的模型。我们感兴趣的两个模型是长访问模型和断点升级模型。长通道升级模型反映了在可卡因成瘾者中观察到的反应和总体消费的升级性质。断点升级模型反映了瘾君子吸食可卡因动机的增加。我开发和完善的自我给药模式测量的是维持可卡因反应的最低剂量。在这个建议中，我新开发的自我给药范式将被用来测量动物在极低可卡因剂量下的暴食倾向的变化，这些变化是在长通道升级、断点升级或稳定的短通道控制训练模型下进行的。研究暴露于不同训练史的动物对最低剂量的反应，将为这些模型中可卡因自我给药的动机方面提供新的信息。在断点或长通道升级模型中，可卡因增强功效变化的神经生物学适应尚不清楚。快速扫描循环容量法允许高时间检测极低水平的多巴胺，多巴胺是一种神经化学物质，被广泛接受参与可卡因的急性强化效应。我们的实验室报道，高消耗自我给药训练可导致多巴胺转运体对可卡因反应的多巴胺再摄取率增加。目前的应用进一步提出了使用快速扫描循环伏安法来研究体内可卡因成瘾独特模型中多巴胺再摄取可能发生的变化。可卡因是美国最容易上瘾、滥用程度最高的毒品之一。动物模型的特征可以帮助我们对可卡因成瘾的神经生物学理解，并将有助于更好地研究可卡因成瘾者的潜在治疗方法。

DESCRIPTION (provided by applicant): This application proposes to use a newly developed self-administration paradigm and fast-scan cyclic voltammetry to characterize two unique models. The two models of interest are the long-access and the break-point escalation models. The long-access escalation model reflects the escalating nature of responding and overall consumption observed in cocaine addicts. The break-point escalation model reflects the incease in motivation to take cocaine reported by addicts. The self-administration paradigm that I have developed and refined measures the lowest possible dose that will maintain cocaine responding. In this proposal, my newly developed self-administration paradigm will be used to measure changes in an animal's propensity to binge at extremely low cocaine doses following training under either the long-access escalation, break-point escalation, or a stable short-access control training model. Investigating the lowest dose for which an animal will respond following exposure to different training histories will provide novel information pertaining to the motivational aspects of cocaine self-administration in these models. The neurobiological adaptations underlying changes in the reinforcing efficacy of cocaine in either the breakpoint or the long-access escalation model remains unknown. Fast-scan cyclic volumetric allows for the high-temporal detection of extremely low levels of dopamine, which is a neurochemical that is well-accepted to be involved in the acute reinforcing effects of cocaine. Our laboratory has reported that high consumption self-administration training can result in an increased rate of dopamine reuptake at the dopamine transporter in response to cocaine. The current application further proposes to use fast scan cyclic voltammetry in order to investigate changes that may occur in dopamine reuptake in the unique models of cocaine addiction in vivo. Cocaine is one of the most addictive and highly abused drugs in the United States. Characterizing animal models can help in our neurobiological understanding of cocaine addiction, and will enable a better investigation of potential treatments for cocaine addicts.