Accumbens firing and ultrasonic vocalizations during cocaine self-administration

描述（由申请人提供）：开发有效的可卡因依赖行为或药物治疗依赖于增加我们对药物寻求的行为和神经相关性的理解。据报道，积极和消极的情感状态都在开始使用药物（纽科姆和费利克斯-奥尔蒂斯1992）、暴食行为（巴克等人，2010; Maier等人，2010）、戒断（Covington & Miczek 2003; Barros & Miczek 1996; Mutschler & Miczek 1998 a; Mutschler & Miczek 1998 b）或复发（Hodgins et al.，1995年）。尽管如此，调查情感的神经生物学相关性以及情感在药物依赖中所起作用的研究仍然有限。在过去的15年里，大鼠的情感状态可以通过超声波发声（USVs）可靠地索引的假设已经得到了很多支持; 50 kHz的USVs和22 kHz的USVs一直被报道与指数的积极和消极的情感状态，分别在成年大鼠在各种实验范式。因此，使USV具有自我给药行为将允许更全面的成瘾动物模型。我们实验室的初步结果（Barker et al.，2010年）表明，防止药物“饱腹感”的可卡因剂量产生更高比例的负面情感USV，而允许动物达到其优选血液浓度的剂量产生更高比例的正面情感USV。研究USV产生的神经化学的研究表明，两个独立但重叠的系统分别调节22 kHz和50 kHz的USV。这些系统中的第一个-中脑边缘多巴胺系统-在50 kHz USV的调制中具有据称的作用。另一方面，22 kHz USV被认为是由起源于背外侧被盖核的第二胆碱能回路调制的（Brudzynski，2008）。这些系统之间重叠的一个关键区域是核神经元。适当地，电生理学和神经化学证据也暗示了NAcc在处理食欲和厌恶结果中的作用（例如，惠勒等人，2008）以及促进接近和回避行为（例如，Rada & Hoebel，2001年; Hoebel，Avena和Rada，2007）为了进一步研究自我管理期间情感处理的神经基质，以及情感在恢复药物寻求行为中的作用，我们将记录超声发声，以及在零剂量盐水条件、两次自我给予的可卡因剂量和恢复测试期间NAcc核心和内侧壳神经元的放电。

DESCRIPTION (provided by applicant): The development of effective behavioral or pharmacological treatments for cocaine dependence relies on increasing our understanding of the behavioral and neural correlates of drug-seeking. Positive and negative affective states both have a reported role in the initiation of drug use (Newcomb & Felix-Ortiz 1992), bingeing behavior (Barker et al., 2010; Maier et al., 2010), withdrawal (Covington & Miczek 2003; Barros & Miczek 1996; Mutschler & Miczek 1998a; Mutschler & Miczek 1998b), or relapse (Hodgins et al., 1995). Still, studies investigating the neurobiological correlates of affect and the role affect plays in drug dependence are limited. Over the last fifteen years, the hypothesis that the affective states of rats can be reliably indexed through ultrasonic vocalizations (USVs) has received much support; 50-kHz USVs and 22-kHz USVs are consistently reported to be correlated with indices of positive and negative affective states, respectively, in adult rats in a variety of experimental paradigms. Incorporating USVs with self-administration behavior would therefore allow for a more comprehensive animal model of addiction. Preliminary results from our lab (Barker et al., 2010) suggest that doses of cocaine that prevent drug 'satiety' produce a higher ratio of negative affective USVs while those that allow animals to reach their preferred blood concentration produce a higher ratio of positive affective USVs. Research examining the neurochemistry of USV production has suggested that two separate but overlapping systems modulate 22- and 50-kHz USVs, respectively. The first of these systems-the mesolimbic dopamine system-has a purported role in the modulation of 50-kHz USVs. On the other hand, 22-kHz USVs are thought to be modulated by a second, cholinergic circuit originating in the laterodorsal tegmental nucleus (Brudzynski, 2008). One key region of overlap between these systems is the nucleus accumbens. Appropriately, eletrophysiological and neurochemical evidence has also implicated the NAcc in processing appetitive and aversive outcomes (e.g. Wheeler et al., 2008) as well as facilitating approach and avoidance behaviors (e.g. Rada & Hoebel, 2001; Hoebel, Avena, & Rada, 2007) To further investigate the neural substrates of affective processing during self-administration, as well as the role that affect plays in the reinstatement of drug-seeking behavior, we will record ultrasonic vocalizations, and the firing of NAcc core and medial shell neurons during a zero dose saline condition, two self-administered cocaine doses, and tests of reinstatement.