Neurophysiology of cocaine-seeking behavior

描述（由申请人提供）：目前尚无针对可卡因成瘾的有效药物或行为治疗方法。一种可能的解释是，人们对药物寻求的神经相关性知之甚少。了解可卡因寻求的神经生理学可能有助于开发旨在改变对产生这些行为很重要的神经元活动的治疗方法。对可卡因寻求行为至关重要的一个大脑区域是伏核（NAcc）。在过去的十年里，我们的实验室发现了在毒品和无毒品状态下单个 NAcc 神经元编码的可卡因寻求的几个相关因素。然而，可卡因成瘾是一种复杂的疾病，可能是由其他大脑区域编码的。由于大多数神经生理学研究都局限于 NAcc，因此缺乏支持这一主张的生理数据。腹侧苍白球（VP）可能是编码可卡因寻求的区域之一。 NAcc 主要向 VP 进行大量项目。与 NAcc 类似，VP 损伤可减少寻求可卡因的行为。然而，目前还没有对 VP 神经元编码可卡因寻求行为进行神经生理学研究。为了解决这种差异，我们将同时记录可卡因自我给药期间的 NAcc 和 VP 神经元，以及在戒断一段时间后寻找可卡因的过程中，其中与可卡因相关的线索是非偶然出现的。这些数据对于理解 VP 神经元在暴饮暴食和复发行为中的作用非常重要。由于绝大多数 NAcc 投射神经元是 GABA 能的（例如，抑制性的），因此 NAcc 神经元放电可能与 VP 神经元放电呈负相关。然而，最近关于 VP 神经元在寻找蔗糖行为期间的报告表明情况可能并非如此。大多数 NAcc 神经元在响应可卡因预测线索时表现出放电率增加；类似地，大多数 VP 神经元在响应食物预测线索时表现出放电率增加。 NAcc-VP 放电的 GABA 能逆关系预测 VP 神经元放电响应可卡因预测线索的显着减少。将评估可卡因寻求行为和线索反应期间 VP 次区域神经元的方向、大小和普遍性，并与之前以及同时记录的 NAcc 次区域神经元进行比较。尖峰触发同时记录的 NAcc 和 VP 神经元的平均值将提供对行为诱导的放电模式的深入了解。我们的初步结果表明，VP 神经元异质地编码可卡因自我给药行为。由于可卡因成瘾的典型特征是暴饮暴食和戒断循环，而线索会产生渴望，因此我们对药物和戒断条件下可卡因寻求和线索反应的神经生理学相关性的检查可能有助于深入了解这种疾病。

DESCRIPTION (provided by applicant): There are currently no effective pharmacological or behavioral treatments for cocaine addiction. One possible explanation is that the neural correlates of drug-seeking are poorly understood. Understanding the neurophysiology of cocaine-seeking may enable the development of treatments aimed at altering the activity of neurons important for generating these behaviors. One brain region critical for cocaine-seeking behavior is the nucleus accumbens (NAcc). Over the past ten years, our lab has found several correlates of cocaine- seeking encoded by single NAcc neurons during drug and drug-free states. However, cocaine addiction is a complicated disorder that is likely encoded by other brain regions. Since most neurophysiological studies were localized to the NAcc there is a paucity of physiological data supporting this assertion. One region likely to encode cocaine-seeking is the ventral pallidum (VP). The NAcc primarily and massively projects to the VP. Similar to the NAcc, VP lesions decrease cocaine-seeking behavior. However, there has been no neurophysiological investigation into the encoding of cocaine-seeking behavior by VP neurons. In order to address this discrepancy, we will simultaneously record NAcc and VP neurons during cocaine-self administration as well as cocaine-seeking following a period of abstinence in which cocaine-associated cues are noncontingently presented. Such data will be important for understanding the role of VP neurons during binge and relapse behavior. Since the vast majority of NAcc projection neurons are GABAergic (e.g., inhibitory), NAcc neuron firing may be inversely related to VP neuron firing. However, recent reports of VP neurons during sucrose-seeking behavior suggest this may not be the case. The majority of NAcc neurons show increases in firing rate in response to a cocaine predictive cue; a similar majority of VP neurons display increases in firing rate in response to a food predictive cue. A GABAergic inverse relationship of NAcc-VP firing predicts predominant decreases in VP neuron firing in response to cocaine predictive cues. The direction, magnitude, and prevalence of VP subregional neurons during cocaine-seeking behaviors and cue-reactivity will be assessed and compared with previously as well as simultaneously recorded NAcc subregional neurons. Spike triggered averaging of simultaneously recorded NAcc and VP neurons will provide insight into behavior-induced firing patterns. Our preliminary results suggest that VP neurons encode cocaine self-administration behavior heterogenously. Since cocaine addiction is typified by cycles of binging and abstinence, and cues produce cravings, our examination of the neurophysiological correlates of cocaine-seeking and cue-reactivity under drug and abstinent conditions may enable insight into the disorder.