Neurophysiology of cocaine-seeking behavior

描述(申请人提供)：目前尚无有效的药物或行为疗法治疗可卡因成瘾。一种可能的解释是，人们对寻求毒品的神经关联知之甚少。了解寻找可卡因的神经生理学可能有助于开发旨在改变神经元活动的治疗方法，这些神经元活动对产生这些行为至关重要。大脑中一个对寻找可卡因行为至关重要的区域是伏隔核(NAcc)。在过去的十年里，我们的实验室已经发现了在药物和非药物状态下，单个NAcc神经元编码的几个寻求可卡因的关联。然而，可卡因成瘾是一种复杂的疾病，可能由大脑其他区域编码。由于大多数神经生理学研究局限于NAcc，支持这一论断的生理学数据很少。可能编码寻找可卡因的一个区域是腹侧苍白球(VP)。NAcc主要和大规模地向副总裁投射。与NAcc类似，VP损毁可减少寻求可卡因的行为。然而，目前还没有关于VP神经元编码寻找可卡因行为的神经生理学研究。为了解决这一差异，我们将同时记录可卡因自我给药过程中的NAcc和VP神经元，以及在一段时间内非偶然呈现可卡因相关线索的可卡因寻找过程中。这些数据对于理解VP神经元在暴饮暴食和复吸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(如抑制性)，NAcc神经元的放电可能与VP神经元的放电成反比。然而，最近关于VP神经元在寻找蔗糖行为中的报道表明，情况可能并非如此。大多数NAcc神经元对可卡因预测线索的反应表现出放电频率的增加；类似的大多数VP神经元对食物预测线索的反应表现出放电频率的增加。NAcc-VP放电的GABA能逆关系预测，对可卡因预测线索的反应，VP神经元的放电明显减少。在可卡因寻找行为和线索反应过程中，VP亚区神经元的方向、大小和流行程度将被评估，并与先前和同时记录的NAcc亚区神经元进行比较。同时记录的NAcc和Vp神经元的尖峰触发平均将提供对行为诱导的放电模式的洞察。我们的初步结果表明，VP神经元编码可卡因的自我给药行为是异质性的。由于可卡因成瘾的典型特征是狂欢和禁欲的循环，而线索会产生渴望，我们对毒品和戒毒条件下寻求可卡因和线索反应的神经生理学相关性的研究可能有助于深入了解这种障碍。

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.