Buprenorphine: A Behavioral Analysis
Alcohol and Drug Abuse Research Center-McLean Hospital
Nancy K. Mello, Ph.D., Carrie A. Bowen, Ph.D., Jack H. Mendelson, M.D., S. Stevens Negus, Ph.D.,
John L. Neumeyer, Ph.D.
This multidisciplinary preclinical project focuses on the interactions between cocaine and a novel series of opioids that are selective for mu, kappa and delta receptors. The goal of the proposed studies is to identify and evaluate new pharmacological approaches for the treatment of cocaine abuse and dependence. Cocaine abuse is a significant public health problem and the development of effective anti-cocaine medications is one of NIDA's top priorities. Mu, kappa and delta receptor subtypes are found in the mesolimbic dopamine system, and activation of these receptors alters dopamine levels. Because cocaine's abuse-related effects are thought to be mediated by dopaminergic systems, opioids with mu, kappa and delta receptor selectivity may provide an alternative to dopaminergic compounds as a novel approach to cocaine abuse treatment.
Our medicinal chemistry collaborators have synthesized a new series of opioids that are selective for kappa/mu and delta opioid receptors, and are designed to have a long duration of action with minimal adverse side effects. Preclinical behavioral studies suggest that kappa agonists may function as indirect cocaine antagonists, whereas both delta and mu agonists may mimic or enhance cocaine's abuse-related effects. Moreover, efficacy at opioid receptors appears to influence opioid-cocaine interactions. These studies will test the hypothesis that mixed action kappa and mu agonists, low efficacy mu agonists, and high efficacy delta agonists will alter cocaine's abuse-related effects in preclinical behavioral models.
The acute and chronic effects of novel medications will be studied with both drug discrimination and drug self-administration procedures. Cocaine- and food-maintained responding will be studied to determine the relative selectivity of medication effects on cocaine self-administration. A new Rapid Assessment Procedure will be used to evaluate acute medication effects on complete cocaine-dose effect curves. Chronic medication effects on food-and cocaine-maintained responding will be studied to determine the stability of medication effects, and to evaluate adverse side effects, and medication withdrawal signs when treatment is discontinued. The effects of chronic treatment on complete cocaine dose-effect functions will be examined. The most safe and effective medications will be compared using a new Progressive Ratio Procedure to determine if cocaine's reinforcing efficacy is altered. This comprehensive evaluation of the effects of novel mu, kappa and delta selective opioids on cocaine's abuse-related effects should suggest new approaches to cocaine abuse treatment.
Key words: Cocaine, mu, kappa and delta opioids
Grant Support: NIDA DA-02519
Project Site. Alcohol and Drug Abuse Research Center, McLean Hospital, Belmont, MA
Project Director. N.K. Mello, Ph.D.
Contact Person. Rita Head, Administrative Assistant. Telephone (617) 855-2716. FAX: (617) 855-2519.
Training Opportunities. Postdoctoral training opportunities are available through a NIDA supported training grant (DA07252) to Jack H. Mendelson, M.D. and the Alcohol and Drug Abuse Research Center.
Representative Publications.
Gatch, M.B., Negus, S.S. and Mello, N.K.: Antinociceptive effects of cocaine in rhesus monkeys. Pharmacol. Biochem. Behav. 62:291-297, 1999.
Mello N.K. and Negus S.S.: Effects of flupenthixol and quadazocine on self-administration of speedball combinations of cocaine and heroin by rhesus monkeys, Neuropsychopharmacology 21:575-588, 1999.
Brandt, M.R., Negus, S.S., Mello, N.K., Furness, M.S., Zhang, X. and Rice, K.C.: Discriminative stimulus effects of the nonpeptidic d-opioid agonist SNC80 in rhesus monkeys. J. Pharmacol. Exp. Ther. 290:1157-1164, 1999.
Negus, S.S., Mello N.K. Effects of kappa opioid agonists on the discriminative stimulus effects of cocaine in rhesus monkeys. Exp. Clin. Psychopharm. 7:307-317, 1999.
Mello N.K. and Negus S.S.: Interactions between kappa opioid agonists and cocaine: Preclinical Studies. In: The Archer Conference on Drug Abuse: New Medications, S.D. Glick, I.M. Maisonneuve (eds.). N.Y. Academy of Sciences, pp. 104-132, 2000.
Mello, N.K. and Negus, S.S.: Effects of indatraline and buprenorphine on self-administration of speedball combinations of cocaine and heroin by rhesus monkeys. Neuropsychopharmacology 25:104-117, 2001.