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。 其中一种方式，其中渴望可以触发是通过暴露于药物相关的刺激，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被广泛承认，但内感受性线索对条件刺激的贡献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内感受性线索，这些线索可以与条件刺激相互作用。最近，我们已经表明，丁螺环酮的刺激特性可以降低情境可卡因条件刺激和钝可卡因条件效应。 另一方面，如果丁螺环酮与可卡因相关，则丁螺环酮刺激可以获得可卡因条件刺激特性。因此，这些研究结果表明，内感受性药物线索可能会改善或加剧条件刺激诱导的可卡因渴望取决于他们的关系，条件反射过程。 这项建议的总体目标是调查可卡因兴奋剂作用的内感受性药物线索调节。 我们最初依赖丁螺环酮作为内感受性药物提示的依赖性来源于这样一个事实，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，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血清素和多巴胺神经传递的改变。 这种在没有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药物作为内感受性条件刺激的研究提供了关键要素。 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，如消退和潜伏抑制。 由可卡因和丁螺环酮诱导的神经化学特征将用于鉴定可以替代丁螺环酮线索的新型药物组合，从而作为可卡因条件刺激发挥作用。 我们还计划评估可卡因滥用治疗中使用的其他药物，以确定它们的提示特性是否可以修改可卡因条件刺激。 本研究对于内感受性药物线索激活或抑制可卡因条件刺激的方式的确定具有重要意义。

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.