Subsecond dopamine release during compulsive drug taking

描述(申请人提供)：人类毒瘾的发展包括从实验和娱乐性药物使用到强制服药和习惯养成的转变。在这种转变之后，这种习惯很少被“戒除”，因为自愿戒毒的时期会被强烈的毒品渴望所阻挠，而这种渴望会导致复发。即使在长期禁欲和有意识地认识到长期的不良后果之后，复发的可能性也很高。这种不受控制的(强迫)行为是上瘾的标志。多巴胺释放到细胞外空间与动机行为高度相关，并被认为在药物滥用中起着核心作用。然而，直到最近，还不可能在清醒动物的行为相关时间刻度(秒)上测量它。随着快速扫描循环伏安法的发展，我们现在已经成功地以亚秒分辨率监测和表征了可卡因自我给药过程中大鼠的多巴胺释放，这些大鼠接受了适度的行为训练，类似于人类娱乐用药。我们现在建议扩展这项工作，以解决成瘾研究中最相关的问题之一：从娱乐性药物使用转变为强制药物使用的神经化学关联是什么？这项拟议的工作将研究伏隔核和背外侧纹状体中的亚秒多巴胺释放，在一种结合了习惯性和强迫性药物服用的成瘾动物模型中。深入了解促进这些行为的神经底物，对于充分了解成瘾的神经生物学，并分离出预防和治疗这些破坏性疾病的治疗靶点至关重要。

DESCRIPTION (provided by applicant): The development of drug addiction in humans involves a switch from experimentation and recreational drug use to compulsive drug taking and habit formation. Following this switch, the habit is rarely 'kicked', since periods of voluntary abstinence from drug taking are thwarted by intense drug craving that drives relapse. Even after extended periods of abstinence and conscious recognition of the long-term aversive consequences, the probability of relapse is high. This uncontrolled (compulsive) behavior is the hallmark of addiction. Release of dopamine into the extracellular space has been highly implicated in motivated behavior and is thought to have a central role in drug abuse. However, until recently it was not possible to measure it on a behaviorally-relevant timescale (seconds) in awake animals. With the development of fast-scan cyclic voltammetry, we have now successfully monitored and characterized dopamine release with subsecond resolution during cocaine self-administration in rats that had modest behavioral training, analogous to recreational drug use in humans. We now propose to extend this work to address one of the most pertinent questions in the study of addiction: what are the neurochemical correlates of the switch from recreational to compulsive drug use? The proposed work will study subsecond dopamine release in the nucleus accumbens and dorsolateral striatum in an animal model of addiction that incorporates habitual and compulsive drug taking. Insight into the neural substrates that promote these behaviors will be essential in fully understanding the neurobiology of addictions, and isolating therapeutic targets for the prevention and treatment of these devastating disorders.