Most information about the neurobiology of substance abuse derives from experiments on rats. These models address several phenomena characteristic of substance abusing humans (e.g., self administration of drugs abused by humans, uncontrolled use of drugs, relapse upon presentation of interoceptive or exteroceptive cues related to the drug, etc) and have established the mesoaccumbens dopaminergic system as one of the important mediators of the reinforcing effects of drugs. Many of the findings have been confirmed in monkeys and more recently in mice. The desirability of using the mouse species in substance abuse research is prompted by the development of mutant mice which lack genes for specific proteins (i.e. """"""""Gene Knockouts"""""""") important for neurotransmission in reward circuitry, as well as several well characterized inbred and transgenic strains. Technologies commonly used in substance abuse research on the rat such as jugular catheterization for i.v. self-administration and installation of indwelling cannulas for in vivo microdialysis have recently been down sized for use on mice. Using these techniques, the scant literature indicates that, like rats, mice self-administer most drugs which are abused by humans and the drugs appear to elicit similar increases in DA transmission in the anteroventral striatum as reported for rats. Notably absent from current literature using mice, however, are experiments to evaluate the effects of drug conditioned stimuli on behavior directed toward drug administration, models of relapse, and the effects of self administered drugs on DA systems. Thus, the proposed experiments will determine; 1) the extent to which cues present during lover responding for i.v. cocaine will maintain the behavior; 2) if the cocaine or cocaine conditioned cues will reinstate lever responding after extinction; and 3) if self-administered cocaine, and perhaps cocaine conditioned cues, will enhance extracellular DA consistent as seen in rats. The proposed experiments will initially be conducted on B6 mice, a strain which has been shown to self-administer i.v. cocaine. Additional experiments will be conducted on mutant mice with deletion of the DA D1 receptor gene to evaluate the role of the DA D1 receptor in the mediation of lever responding maintained by cocaine and cocaine conditioned stimuli, as well as reinstatement of 'cocaine-seeking behavior."""""""" These studies will significantly advance the use of the mouse species as a model for drug abuse and contribute toward establishing appropriate therapies for addiction.
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