The widespread abuse of cocaine as well as i.v. cocaine plus heroin abuse increases the risk for AIDS through needle sharing and the direct immunosuppressive effects of these drugs. We found that buprenorphine, an opioid mixed agonist-antagonist, significantly suppresses cocaine self- administration in the rhesus monkey drug self-administration model. Since buprenorphine also suppresses heroin abuse in man, it may be a useful pharmacotherapy for dual abuse of cocaine plus heroin, as well as for the treatment of cocaine abuse. We propose to continue studies of the behavioral pharmacology of buprenorphine and of other opioid mixed agonist-antagonist drugs. One primary objective is to examine the range of conditions over which buprenorphine suppresses cocaine self-administration. We propose to study the duration of effect of single doses of buprenorphine and to determine if buprenorphine tolerance develops during chronic maintenance treatment. We also propose to evaluate the effects of buprenorphine as the available dose of cocaine (mg/kg/inj) is systematically increased. The effects of buprenorphine on cocaine's relative reinforcing efficacy will be studied with progressive ratio procedures. Since dual abuse of i.v. cocaine plus heroin is increasingly prevalent, we propose to examine the effects of buprenorphine treatment in two polydrug abuse models: (1) a simulation of the """"""""speedball,"""""""" i.e., the simultaneous i.v. injection of cocaine and heroin and (2) the sequential i.v. self-administration of cocaine and heroin. Operant behavioral techniques will be used to maintain cocaine and food self-administration in this established primate model of drug self- administration. The mechanisms by which this opioid mixed agonist-antagonist suppresses cocaine self-administration are unknown. A series of studies to examine possible mechanisms and the relative contribution of buprenorphines's agonist and antagonist components are planned. We proposed to compare the effects of buprenorphine and two opioid agonists used for the treatment of heroin abuse (methadone and LAAM) on cocaine self-administration. We also propose to compare the effects of buprenorphine and two opioid mixed agonist-antagonists with different putative opioid receptor binding affinities, (nalbuphine and butorphanol) on cocaine self-administration. One strategy suggested to reduce the potential abuse liability of buprenorphine is to combine it with an opioid antagonist, i.e., naloxone or naltrexone. We propose to determine if buprenorphine plus naltrexone combinations will increase of decrease buprenorphine's suppression of cocaine self-administration. The proposed studies are designed to evaluate the generality of opioid modulation of cocaine self-administration and to clarify the extent to which buprenorphine's opioid agonists or combined agonist-antagonist component is important for attenuation of cocaine self- administration.
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