Neurophysiology of cocaine-seeking behavior

描述（由申请人提供）：目前没有有效的药物或行为治疗可卡因成瘾。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重要的神经元活动的治疗方法。可卡因寻求行为的一个关键大脑区域是丘脑核（NAcc）。在过去的十年里，我们的实验室已经发现了几个相关的可卡因寻求编码的单个NAcc神经元在药物和药物免费的状态。然而，可卡因成瘾是一种复杂的疾病，可能由其他大脑区域编码。由于大多数神经生理学研究局限于NAcc，因此缺乏支持这一论断的生理数据。一个可能编码可卡因寻求的区域是腹侧苍白球（VP）。NAcc主要和大量地投射到VP。与NAcc类似，VP病变减少可卡因寻求行为。然而，目前还没有神经生理学调查的编码可卡因寻求行为的VP神经元。为了解决这一差异，我们将同时记录NAcc和VP神经元可卡因自我管理以及可卡因寻求一段时间的禁欲，其中可卡因相关的线索是非偶然的。这些数据对于理解VP神经元在狂欢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），NAcc神经元放电可与VP神经元放电负相关。然而，最近关于VP神经元在寻求蔗糖行为中的报道表明，情况可能并非如此。大多数NAcc神经元显示响应于可卡因预测线索的发射率增加;类似的大多数VP神经元显示响应于食物预测线索的发射率增加。NAc-VP放电的GABA能反比关系预测VP神经元放电响应可卡因预测线索的显著减少。的方向，幅度，和流行的VP次区域神经元在可卡因寻求行为和线索反应将进行评估，并与以前以及同时记录的NAcc次区域神经元进行比较。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神经元编码可卡因自我管理行为的异质性。由于可卡因成瘾是典型的暴饮暴食和禁欲的周期，和线索产生的渴望，我们的检查可卡因寻求和药物和禁欲条件下的线索反应性的神经生理学相关性可能使洞察障碍。

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.