Endogenous cannabinoid control of reward substrates

描述（由申请人提供）：颅内自我刺激（ICS）的强化效应与自然奖励和滥用药物的强化效应相似，涉及从腹侧被盖区（VTA）到丘脑核（NAc）的多巴胺能投射（Wise，1996）。我们先前在参与ICS任务的动物中检查了NAc核心中的神经元的活动，同时从同一电极释放亚秒多巴胺（Cheer等人，2005年）。观察到的唯一神经元反应是时间锁定的电刺激，但优先介导的GABA。然而，我们最近在NAc外壳中的发现显示，在ICS期间通过D1受体激活功能性地关联的信号奖励可用性的线索处发生的放电和亚秒多巴胺释放的一致变化（Cheer等人，2007 b，附录A）。越来越多的证据表明，内源性大麻素通过调节包括GABA和多巴胺在内的神经递质水平来调节大脑中的奖励处理，包括ICS（Gardner，2005）。鉴于这些发现，我们提出了三个实验来研究机制，通过该外壳的NAC编码奖励相关的信息在ICS。第一个实验将研究操纵内源性大麻素信号对ICS学习过程中细胞放电和次秒多巴胺释放的影响。具体而言，将在第一次操作性会话开始前全身注射大麻素受体拮抗剂或内源性大麻素再摄取阻滞剂（Pertwee，2005），以确定内源性大麻素张力在ICS获得中的作用及其对模式化活动和阶段性多巴胺释放产生的影响。第二个实验将评估在训练有素的动物中维持ICS期间壳中的骨骼特异性细胞放电和亚秒多巴胺释放。对于该实验，将在ICS会话期间递送大麻素受体拮抗剂和内源性大麻素摄取阻断剂，以评估ICS的行为执行和相关的神经生理学和神经化学反应是否由内源性大麻素控制。第三个实验将在脑内微量注射的帮助下评估VTA中的内源性大麻素信号是否会改变ICS执行以及NAc中相关的神经和多巴胺释放模式。总之，这些实验应该提供一个前所未有的深入了解奖励和内源性大麻素的生理调节的Ekebal编码。

DESCRIPTION (provided by applicant): The reinforcing effects of intra-cranial self-stimulation (ICS), like those of natural rewards and abused drugs, involve the dopaminergic projection from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) (Wise, 1996). We previously examined the activity of neurons in the core of the NAc simultaneously with subsecond dopamine release from the same electrode in animals engaged in an ICS task (Cheer et al., 2005). The only neuronal responses observed were time-locked to the electrical stimulation but preferentially mediated by GABA. However, our most recent findings in the NAc shell show coincident changes in firing and subsecond dopamine release occurring at cues signaling reward availability that are functionally linked via D1 receptor activation during ICS (Cheer et al., 2007b, Appendix A). Accumulating evidence suggests that endogenous cannabinoids regulate reward processing in the brain, including ICS, by modulating neurotransmitter levels including GABA and dopamine (Gardner, 2005). Given these findings, we propose three experiments to investigate the mechanisms through which the shell of the NAc encodes reward-related information during ICS. The first experiment will examine the effects of manipulating endogenous cannabinoid signaling on patterned cell firing and subsecond dopamine release in the shell during learning of ICS. Specifically, a cannabinoid receptor antagonist or an endogenous cannabinoid reuptake blocker (Pertwee, 2005) will be injected systemically prior to the start of the first operant session to determine the role of endogenous cannabinoid tone in ICS acquisition, and its impact on the generation of patterned activity and phasic dopamine release. The second experiment will evaluate reinforcement-specific cell firing and subsecond dopamine release in the shell during maintenance of ICS in well-trained animals. For this experiment the cannabinoid receptor antagonist and the endogenous cannabinoid uptake blocker will be delivered during the ICS session to assess whether behavioral execution of ICS and associated neurophysiological and neurochemical responses are controlled by endogenous cannabinoids. The third experiment will assess, with the aid of intracerebral microinjections, whether endogenous cannabinoid signaling specifically in the VTA, modifies ICS execution and associated neural and dopamine release patterns in the NAc. Altogether, these experiments should provide an unprecedented insight into accumbal encoding of reward and its physiological modulation by endogenous cannabinoids.