Studies of the behavioral pharmacology of buprenorphine, a new mixed agonist-antagonist in a primate drug self-administration model are proposed. Buprenorphine significantly suppresses heroin self-administration by heroin addicts, and its safety and low toxicity suggest it may be an effective alternative alternative to methadone for the treatment of heroin addiction. Since buprenorphine is a positive reinforcer in primates, and """"""""liked"""""""" as well as morphine by opiate addicts, evaluation of its relative abuse liability remains an issue of concern which is difficult to assess directly in clinical studies. We propose to compare the relative reinforcing efficacy of buprenorphine with methadone and heroin, using established operant techniques; progressive ratio, discrete trial choice and concurrent schedule procedures. The sensitivity and concordance between these behavioral measures of abuse liability in a primate model will be determined. The contribution of the antagonist component of this mixed agonist-antagonist to its reinforcing effects will be examined by: (1) comparing the relative reinforcing efficacy of low and high buprenorphine doses to determine the behavioral """"""""ceiling effect""""""""; (2) determining the dose range over which simultaneous infusion or pre-treatment with diprenorphine (the antagonist component of buprenorphine) effects buprenorphine self-administration; and (3) determining if buprenorphine is a negative reinforcer under high dose maintenance conditions in an infusion termination paradigm. The role of biological factors in modulating the reinforcing properties of buprenorphine and heroin will be compared. The effects of pre-treatment with a gonadal steroid (which increases the duration of the heroin """"""""rush"""""""" in addicts) and a hypothalamic peptide (which decreases heroin """"""""rush"""""""" duration) on self-administration of buprenorphine and heroin will be studied. Data obtained should clarify the abuse liability of buprenorphine relative to other opiates. An increased understanding of the behavioral effects of this mixed agonist-antagonist should suggest future directions for basic and clinical research.
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