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.
