Experiments with rats will determine whether drug doses (cocaine, PCP, caffeine, midazolam, hexobarbital, nicotine) that are delivered by either intragastric or IV cannula contingent upon drinking a specific fluid can institute an oral preference for the solution drunk, whether it is (a) a drug solution or (b) a neutral-flavored solution, in order to ascertain whether oral drug preferences and abuse can be initiated solely by pharmacological events, a relation not yet clearly established. The pharmacological events (e.g., serum drug and metabolite levels) consequent to gastric and IV drug delivery will be delineated, as well as the intragastric and IV drug reinforcement thresholds, to effect the pharmacokinetic-pharmacodynamic modeling of drug reinforcement, which clarification may prove useful in the design of drug agonist therapies. The pharmacological events initiating and sustaining oral drug self-administration will be compared to the environmental events (schedule-induced polydipsia) which also can give rise to chronic oral drug self-administration. The degree to which drug self-administration compromises ensuing timing behavior will measure the behaviorally toxic consequences of acute and chronic drug-taking. Temporal, stimulus control, and pharmacological factors affecting the relapse to oral cocaine solution preference will be evaluated.
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