The long-term objective is to characterize, on complex behavioral processes such as learning and memory, the effects of different therapeutically useful opioids which are subject to abuse. Drug effects on complex behavioral tasks in non-human primates is the major focus of investigation. A multiple schedule of repeated acquisition and performance of conditional discriminations will be used in order to make a direct comparison of drug effects on learning and performance. In addition, a fixed-ratio discrimination will be used to characterize the acute and chronic effects of these same drugs in different species. Opioids (sigma agonists) which produce psychotomimetic effects in man disrupt accuracy of responding under both of these procedures in patas and macaque monkeys. This action is not shared by other opioids (mu and kappa agonists), at doses which produce approximately equivalent rate-decreasing effects. Similar differential effects do not, however, obtain in the rat. Since species differences such as these may have important implications in terms of the mechanism(s) of action of these drugs the first series of studies will characterize the effects of various opioids (e.g., morphine, buprenorphine, cyclazocine, NANM) in squirrel monkeys responding under these same behavioral procedures. The isomers of NANM and cyclazocine will also be studied in order to determine the extent to which they may affect either accuracy or rate of responding in a steroselective manner. Relatively little is known concerning the behavioral consequences of polydrug abuse. The second series of proposed experiments will continue our studies of how the opioids in combination with other drugs of abuse effect the acquisition and performance of complex discriminations. Methadone and buprenorphine will each be studied in combination with four different drugs of abuse (cocaine, larazepam, phencyclidine, pentobarbital). Each interaction will be characterized on both an acute and chronic basis. The third series of experiments will investigate the development of tolerance to each of the isomers of cyclazocine. In addition, cross-tolerance will also be tested to other opioids and their isomers. The study of stereoselective tolerance and cross-tolerance can provide unique information concerning the mechanism(s) of action of the opioids. In addition, such studies may elucidate other behavioral determinants of the development of tolerance to abused drugs.
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