PharmacologyBiochemistry& Behavior, Vol, 41, pp. 219-226. ©Pergamon Press plc, 1991. Printed in the U.S.A. 0091-3057/92 $5.00 + .00 RAPID COMMUNICATION Concurrent Agonist-Antagonist Administration for the Analysis and Treatment of Drug Dependence JED E. ROSE 1 AND EDWARD D. LEVIN Nicotine Research Laboratory, VA Medical Center, Durham, NC and Department of Psychiatry, Duke University, Durham, NC Received 5 August 1991 ROSE, J. E. AND E. D. LEVIN. Concurrent agonist-antagonist administration for the analysis and treatment of drug depen- dence. PHARMACOL BIOCHEM BEHAV 41(1) 219-226, 1992.--Two key strategies for the treatment of drug dependence in- volve the use of agonists to substitute for the abused drug and the use of antagonists to block the reinforcing actions maintaining drug self-administration. A different strategy for the treatment of drug dependence is outlined, comprising the concurrent adminis- tration of an agonist and an antagonist. Concurrent administration of an agonist with an antagonist, in the proper ratio, should produce maximal occupancy of receptors and attenuation of the reinforcing actions of the abused drug. The addict would be relatively "insulated" from the reinforcing effects of the abused drug; at the same time the balance of agonist and antagonist effects is predicted to prevent withdrawal symptoms or intoxication resulting from an under- or over-stimulation of drug receptors. Advantages over the use of agonists alone and antagonists alone, and over mixed agonist-antagonist molecules, are discussed. Application of concurrent agonist-antagonist administration to the analysis of mechanisms underlying nondrug reinforcement and to the treatment of disorders involving receptor disregulation is also described. Drug dependence Self-administration Addiction Agonist Antagonist Nicotine Opioid Cocaine Reinforcement Behavior Regulation Sustained release TWO of the main strategies proposed in the treatment of drug dependence involve the use of agonists to substitute for the abused drug, and the use of antagonists to block the reinforcing actions maintaining drug self-administration (20). Thus, metha- done, an opioid agonist, is commonly used in the treatment of opiate dependence (e.g., heroin addiction). Likewise, nicotine, a potent agonist at nicotinic cholinergic receptors, is used in the treatment of tobacco dependence (16). Conversely, naltrexone, an opioid receptor antagonist, has also been utilized in the treat- ment of heroin addiction (17), and mecamylamine, a nicotinic antagonist, has been used to promote smoking cessation (49). While agonist substitution treatment and antagonist treatment each have potential advantages, they have usually been discussed as though they are mutually exclusive. A notable exception is the use of mixed agonist-antagonist drugs, such as buprenor- phine, which have received increasing attention in the treatment of opiate and cocaine dependence (19, 21, 24, 26, 31). However, the concurrent use of a combination of an agonist with an entirely different antagonist, in order to treat drug de- pendence, may have several advantages in clinical treatment (41,42). These include greater flexibility in titrating agonist and antagonist effects and greater generality of application to differ- ent drugs of abuse, as will be discussed below. Agonist-antago- nist combinations may also be useful in the analysis of tRequests for reprints should be addressd to Dr. Jed E. Rose, Nicotine NC 27705. neurotransmitters involved in mediating drug reinforcement. The general thesis is that concurrent administration of an agonist with an antagonist, in the proper ratio, has the advantages of both types of treatment, while minimizing the disadvantages of treat- ment with agonists or antagonists separately. Agonists and an- tagonists share one property in common, namely, they both occupy receptors or receptor-coupled effectors critical for the action of the abused drug. The combination treatment should produce maximal attenuation of the reinforcing actions of the abused drug. In addition, many side effects resulting from over- stimulation or understimulation of receptors can be diminished by the opposing balance of an agonist with an antagonist. The addict receiving a combination of an agonist and an antagonist would be predicted to be relatively "insulated" from the rein- forcing effects of the abused drug; at the same time that individ- ual is predicted to be relatively comfortable, i.e., neither in a state of withdrawal nor intoxication from an under- or over- stimulation of drug agonist receptors. WHAT ARE THE UNIQUE ASPECTSOF CONCURRENT AGONIST-ANTAGONIST ADMINISTRATION? A great number of studies in pharmacology have coadminis- tered an agonist and an antagonist; in fact, the simple demon- Research Laboratory (151-S), VA Medical Center, 508 Fulton St., Durham, 219