Endogenous cannabinoid control of reward substrates

描述(由申请人提供)：与自然奖励和滥用药物一样，脑内自我刺激(ICS)的增强效应涉及从腹侧被盖区(VTA)到伏核(NAC)的多巴胺能投射(Wise，1996)。我们之前在参与ICS任务的动物身上同时检测了NAC核心神经元的活动和同一电极的亚秒多巴胺释放(Cheer等人，2005年)。唯一观察到的神经元对电刺激的反应是时间锁定的，但优先由GABA介导。然而，我们在NAC壳中的最新发现表明，在发出奖赏可获得性信号的线索中，放电和亚秒多巴胺释放发生了一致的变化，这在功能上是通过ICS期间D1受体的激活而联系在一起的(cheer等人，2007b，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赏处理，包括脑内皮层(ICS)(Gardner，2005)。鉴于这些发现，我们提出了三个实验来研究在ICS过程中NAC的外壳编码与奖励相关的信息的机制。第一个实验将考察在学习ICS期间，操纵内源性大麻素信号对模式化细胞激发和壳中亚秒多巴胺释放的影响。具体地说，将在第一次手术前系统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在ICS获得中的作用及其对模式活动和相性多巴胺释放的影响。第二个实验将评估在训练有素的动物的ICS维持期间，增强体特异的细胞激活和贝壳中亚秒多巴胺的释放。在这个实验中，大麻素受体拮抗剂和内源性大麻素摄取阻滞剂将在ICS会议期间提供，以评估ICS的行为执行和相关的神经生理和神经化学反应是否由内源性大麻素控制。第三个实验将借助脑内微量注射，评估VTA中特定的内源性大麻素信号是否改变了NAC中ICS的执行以及相关的神经和多巴胺释放模式。总之，这些实验应该会对奖赏的伏隔编码及其内源性大麻素的生理调节提供一个前所未有的洞察力。

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.