We have recently reported that """"""""legal"""""""" over-the-counter stimulants, when combined in appropriate dose ratios could engender drug-appropriate responding in amphetamine and cocaine drug discrimination tasks in rats. These results suggest that these legal stimulants may mimic the subjective effects of these psychomotor stimulants. Little is known about the abuse liability profile of these duplicitous drugs. The present proposal would extend the analysis of these legal stimulant combinations (e.g., caffeine (CAF), ephedrine (EPH), and phenylpropanolamine (PPA)). Project I utilizes a 4-hour limited access cocaine self-administration task to assess the """"""""reinforcing"""""""" properties of these duplicitous drug combinations using: (1) substitution tests, (2) preloading, and (3) progressive ratio schedules of reinforcement. Food and water will be available 20 h per day under concurrent FR10 schedules of reinforcement. The total amount and pattern of food and water consumption will be used as an index of behavioral toxicity of all drug challenges/conditions. Project II is designed to assess the discriminative stimulus properties of dual and triple combinations of legal stimulants (CAF + EPH, CAF + PPA, and CAF + EPH + PPA) and the cross-generalization profiles with the prototypic psychomotor stimulants cocaine [COC], d-amphetamine, and methamphetamine. The influence of drug and experimental history on the self-administration of cocaine will be assessed in Project II also. Two groups of rats will be utilized to assess the relative contribution of drug discrimination history (COC vs. saline, and the CAF + EPH + PPA combination vs. saline) on subsequent self-administration of COC. Three other groups will be yoked to the subjects in these discrimination tasks to match for drug history. Project III will assess the affective components of the stimulant withdrawal syndrome using two different 3-choice drug discrimination tasks (5 mg/kg chlordiazepoxide vs. saline vs. 15 mg/kg pentylenetetrazol and .03 mg/kg haloperidol vs. saline vs. 10 mg/kg COC). High dose pretreatments and 3-day chronic periods of both COC and the triple stimulant combination will be used to assess the """"""""rebound"""""""" phenomena. In sum, the biobehavioral assays in this proposal would provide information concerning the abuse liability profile of these """"""""legal"""""""" stimulants relative to that for cocaine. If these duplicitous drug compounds mimic the subjective effects of cocaine but lack cocaine's robust rewarding property and its withdrawal and behaviorally toxic effects, they might eventually provide a potential """"""""methadone-model"""""""" of cocaine supplementation therapy.
