DOPAMINE RESPONSE TO PREDICTED AND UNPREDICTED COCAINE

多巴胺神经传递通常与来自多种来源的阳性强化有关。然而，最近积累的相关研究表明，多巴胺可能作为一种普遍的激活信号，强调各种类型的神经信息，包括那些明显没有回报的信息。此外，多巴胺神经传递的增加被认为为各种生物相关的刺激提供了神经重点，从而增加了这些刺激对有机体的影响。尽管有大量相反的证据，但有一种观点认为，多巴胺参与阳性强化可能与刺激的积极方面不谋而合，更能反映其生物学重要性。例如，多巴胺神经元对可卡因或其他积极强化的提示做出反应，但也对不同重要性的刺激做出反应。这些发现为研究多巴胺和药物滥用提供了新的动力，并与药物滥用研究中的行为范式直接相关。例如，对可卡因的行为条件作用涉及反复给药。虽然人们经常认为不同的给药模式具有相同的整体效果，但对多巴胺作用的新情绪会让我们相信不同的观点。与这一观点一致的是，期待可卡因注射的动物(例如，在提示输液或自我注射期间)，以及接受意外可卡因注射的动物(随机或非提示药物注射)将有截然不同的神经体验。尽管这两种可卡因给药模式都会导致行为条件反射，但多巴胺激活的时间，甚至与每种体验相关的生物学意义都可能截然不同。为了支持这一观点，本提案中提出的初步数据显示，与可卡因相关的线索的存在增强了可卡因刺激的伏核多巴胺水平和运动活动。这些差异可能直接影响可卡因使用所激发的激励属性，从而影响支持寻求和吸毒行为的动机水平。使用线索和随机注射可卡因的模型，结合体内微透析和行为活动评估，拟议的研究将确定可预测和不可预测的可卡因输送如何影响多巴胺和运动水平。此外，来自对特定线索天真的动物的数据将决定新的刺激是否会影响多巴胺介导的反应。

Dopamine neurotransmission is commonly associated with positive reinforcement derived from many sources. Recently, however, an accumulation of relevant studies suggest that dopamine may serve as a general activation signal that accentuates various types of neural information, including those that are clearly not rewarding. In addition, increased dopamine neurotransmission is thought to provide neural emphases to various stimuli that are biologically relevant, thus increasing the influence that such stimuli have upon the organism. Although evidence to the contrary is substantial, there is momentum toward the view that the involvement of dopamine in positive reinforcement may be coincidental to the positive aspect of the stimuli and more reflective of its biological importance. For instance, dopamine neurons respond to cues predictive of cocaine or other positive reinforcement, but also to stimuli of dissimilar importance. These findings have provided a new impetus to examine dopamine and drug abuse, and has direct relevance to behavioral paradigms in drug abuse research. For example, behavioral conditioning to cocaine involves the repeated administration of the drug. While it is frequently assumed that different modes of drug administration have the same overall effects, emerging sentiments on the role of dopamine would lead us to believe otherwise. Consistent with this view, animals expecting cocaine administration (e.g., as during cued infusions or self- administration), and animals receiving unexpected cocaine injections (random or non-cued drug infusions) would have contrasting neural experiences. Although both modes of cocaine administration result in behavioral conditioning, the timing of dopamine activation, and even the biological relevance attached to each experience may be distinctively different. In support of this view, preliminary data presented in this proposal show the presence of cocaine-associated cues potentiate cocaine-stimulated levels of nucleus accumbens dopamine and locomotor activity. These differences may impact directly on incentive properties inspired by cocaine use, and hence, the level of motivation supporting drug-seeking and drug-taking behaviors. Using a model of cued and random cocaine infusion in conjunction with in vivo microdialysis and behavioral activity assessment, the proposed research will determine how predictable and unpredictable cocaine delivery affects levels of dopamine and locomotion. In addition, data from animals naive to a particular cue will determine whether novel stimuli affect dopamine-mediated responses.