Accumbens firing and ultrasonic vocalizations during cocaine self-administration

描述（由申请人提供）：可卡因依赖的有效行为或药物治疗的发展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，积极和消极情感状态在药物使用的开始（Newcomb & Felix-Ortiz 1992）、暴食行为（Barker等人，2010；Maier等人，2010）、戒断（Covington & Miczek 2003; Barros & Miczek 1996; Mutschler & Miczek 1998a; Mutschler & Miczek 1998b）或复发（Hodgins等人，1995）中都有作用。尽管如此，研究情感的神经生物学相关性和情感在药物依赖中的作用是有限的。在过去的十五年中，通过超声发声（usv）可以可靠地索引大鼠的情感状态的假设得到了广泛的支持；在不同的实验范式中，50-kHz usv和22-kHz usv分别与成年大鼠的积极和消极情感状态指数相关。因此，将usv与自我给药行为结合起来，可以建立更全面的成瘾动物模型。我们实验室的初步结果（Barker et al., 2010）表明，防止药物“饱腹感”的可卡因剂量产生更高比例的负性情感usv，而那些允许动物达到其首选血液浓度的可卡因剂量产生更高比例的正性情感usv。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——据称在调节50 khz usv中起作用。另一方面，22 khz的usv被认为是由起源于外侧背被盖核的第二种胆碱能回路调节的（Brudzynski, 2008）。这些系统之间重叠的一个关键区域是伏隔核。相应地，电生理和神经化学证据也暗示了NAcc在处理食欲和厌恶结果（例如Wheeler等人，2008）以及促进接近和回避行为(例如Rada和Hoebel, 2001；Hoebel, Avena, & Rada, 2007)为了进一步研究自我给药过程中情感加工的神经基础，以及情感在药物寻求行为恢复中所起的作用，我们将记录在零剂量生理盐水条件下、两种自我给药可卡因剂量下的超声波发声、NAcc核心和内侧壳神经元的放电以及恢复测试。

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.