INTEROCEPTIVE DRUG CUE CONDITIONING OF COCAINE EFFECTS

治疗可卡因滥用的一个主要障碍是在戒毒期间发生对可卡因的渴求。引发渴望的一种方式是接触与毒品相关的刺激，如毒品用具。虽然外界感觉线索作为条件刺激激活药物反应的作用得到了广泛的认可，但关于内部感觉线索对条件刺激的贡献的实验研究相对较少。特别是，药物产生的刺激提供了一系列广泛的内感线索，这些线索可以与条件刺激相互作用。最近，我们发现丁螺环酮的刺激特性可以降低情景可卡因的条件性刺激和钝化可卡因的条件性效应。另一方面，如果丁螺环酮与可卡因相关，那么丁螺环酮刺激物可以获得可卡因条件刺激特性。因此，这些发现表明，根据它们与条件反射过程的关系，内感受性药物线索可能会缓解或加剧由条件刺激引起的可卡因渴望。这项建议的总体目标是研究可卡因刺激效应的感觉间药物线索条件作用。我们最初对丁螺环酮作为内感药物线索的依赖源于这样一个事实，即药物可以在比诱导反应效应所需的剂量水平更低的剂量水平诱导刺激效应。因此，在没有药物反应效应的情况下，可能会产生药物刺激效应。然而，对于丁螺环酮，我们已经确定了丁螺环酮疗效的神经化学指标，即在低于行为反应阈值的剂量水平下，5-羟色胺和多巴胺神经传递的变化。这种在缺乏药物效应的直接行为指标的情况下监测丁螺环酮疗效的能力，为研究药物作为内感条件性刺激提供了关键因素。在行为分析中，我们建议评估与药物线索条件作用有关的问题，如消退和潜在抑制。可卡因和丁螺环酮诱导的神经化学特征将被用来识别可能替代丁螺环酮线索的新药物组合，从而起到可卡因条件刺激的作用。我们进一步计划评估用于可卡因滥用治疗的其他药物，以确定它们的线索特性是否可以改变可卡因条件刺激。这项研究对于识别互感药物线索激活或失活可卡因条件刺激的方式是重要的。

A major obstacle to the treatment of cocaine abuse is the occurrence of cocaine craving during periods of abstinence. One way in which craving can be triggered is by exposure to drug associated stimuli such as drug paraphernalia. While the role of exteroceptive cues serving as conditioned stimuli to activate drug responses is widely acknowledged, there has been relatively little experimental investigation of the contribution of interoceptive cues to conditioned stimuli. In particular, stimuli generated by drugs provide an extensive array of interoceptive cues which could interact with conditioned stimuli. Recently, we have shown that the stimulus properties of buspirone can degrade situational cocaine conditioned stimuli and blunt cocaine conditioned effects. On the other hand, if the buspirone is experienced in association with cocaine, then the buspirone stimuli can acquire cocaine conditioned stimulus properties. Thus, these findings suggest that interoceptive drug cues potentially can ameliorate or exacerbate cocaine craving induced by conditioned stimuli depending upon their relationship to the conditioning process. The overall objective of this proposal is to investigate interoceptive drug cue conditioning of cocaine stimulant effects. Our initial reliance reliance upon the use of buspirone as an interoceptive drug cue derives from the fact that drugs can induce stimulus effects at lower dose levels than are needed to induce response effects. As a consequence, drug stimulus effects can occur in the absence of drug response effects. With buspirone, however, we have identified neurochemical indices of buspirone efficacy in terms of alterations in serotonin and dopamine neurotransmission at dose levels below the behavioral response threshold. This ability to monitor buspirone efficacy in the absence of direct behavioral indices of drug effects provides a key element for the study of drugs as interoceptive condtioned stimuli. In the behavioral analysis, we propose to assess issues pertainent to drug cue conditioning, such as extinction and latent inhibition. The neurochemical profiles induced by cocaine and buspirone will be used to identify novel drug combinations which may substitute for the buspirone cue and, thereby, function as cocaine conditioned stimuli. We further plan to evaluate additional drugs used in cocaine abuse treatment to ascertain if their cue properties can modify cocaine conditioned stimuli. This research is important for the identification of the ways interoceptive drug cues can activate or inactivate cocaine conditioned stimuli.