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的行为或药物治疗依赖于增加我们对寻求药物的行为和神经相关的理解。据报道，积极和消极的情感状态在开始吸毒(Newcomb&Felix-Ortiz 1992)、酗酒行为(Barker等人，2010；Maier等人，2010)、戒毒(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，研究情感和情感在药物依赖中扮演的角色的神经生物学相关性的研究仍然有限。在过去的15年里，通过超声发声(USV)可以可靠地指示大鼠的情感状态的假设得到了广泛的支持；在各种实验范式中，50 kHz和22 kHz的USV在成年大鼠中分别与积极和消极的情感状态指数相关。因此，将USVs与自我管理行为结合起来，将允许建立更全面的成瘾动物模型。我们实验室的初步结果(Barker等人，2010年)表明，防止药物饱腹感的可卡因剂量会产生更高比例的负性情感USV，而那些允许动物达到首选血液浓度的可卡因会产生更高比例的积极情感USV。对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制22和50 kHz的USV。这些系统中的第一个系统--中脑边缘多巴胺系统--据称在50 khz紫外线的调制中起着作用。另一方面，22 khz的USV被认为是由起源于被盖外侧背侧核的第二个胆碱能回路调制的(Brudzynski，2008)。这些系统之间的一个关键重叠区域是伏隔核。适当地，电生理和神经化学证据也暗示NAcc参与处理欲望和厌恶的结果(例如Wheeler等人，2008)以及促进接近和回避行为(例如Rada&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，以及影响药物寻找行为恢复的作用，我们将记录超声波发声，以及在零剂量生理盐水条件下、两次自我给予可卡因剂量和恢复测试中NAcc核心和内侧壳神经元的放电。 公共卫生相关性：拟议的研究符合NIDA预防药物使用和防止当前药物使用者不断增加摄入量的战略。具体地说，该项目旨在帮助我们了解情感的神经生物学基础，并洞察情感在影响药物使用、暴饮暴食、戒断和复发所涉及的大脑回路中可能发挥的作用。

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. PUBLIC HEALTH RELEVANCE: The proposed research is in line with NIDA's strategies for the prevention of drug use and prevention of escalated intake in current substance users. Specifically, the project serves to inform our understanding of the neurobiological substrates of affect and provide insight into the role affect may play in influencing the brain circuitry involved in the initiation of drug use, bingeing, withdrawal, and relapse.