INTEROCEPTIVE DRUG CUE CONDITIONING OF COCAINE EFFECTS

治疗可卡因滥用的一个主要障碍是在戒断期间出现对可卡因的渴望。引发渴望的一种方式是暴露于与毒品相关的刺激，如吸毒用具。虽然外感受性线索作为条件刺激激活药物反应的作用已被广泛承认，但对内感受性线索对条件刺激的作用的实验研究相对较少。特别是，由药物产生的刺激提供了广泛的可与条件刺激相互作用的内感受性线索。最近，我们已经证明丁螺环酮的刺激特性可以降低情境可卡因条件刺激和减弱可卡因条件效应。另一方面，如果丁螺环酮与可卡因有关联，那么丁螺环酮刺激可以获得可卡因条件刺激特性。因此，这些发现表明，内感受性药物线索可能会改善或加剧条件刺激引起的可卡因渴望，这取决于它们与条件作用过程的关系。本建议的总体目标是研究可卡因兴奋剂效应的内感受性药物线索条件反射。我们最初对丁螺环酮作为内感受性药物线索的依赖源于这样一个事实，即药物可以在低于诱导反应所需的剂量水平下诱导刺激效应。因此，药物刺激效应可以在没有药物反应效应的情况下发生。然而，对于丁螺环酮，我们已经确定了丁螺环酮功效的神经化学指标，即在低于行为反应阈值的剂量水平下，血清素和多巴胺神经传递的改变。这种在缺乏药物作用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受性条件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反射有关的问题，如消退和潜在抑制。由可卡因和丁螺环酮诱导的神经化学特征将用于鉴定可能替代丁螺环酮提示的新型药物组合，从而发挥可卡因条件刺激的作用。我们进一步计划评估可卡因滥用治疗中使用的其他药物，以确定它们的线索特性是否可以改变可卡因条件刺激。本研究对于确定内感受性药物线索激活或灭活可卡因条件刺激的方式具有重要意义。

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.