Suppression of alcohol intake by chronic naloxone treatment in P rats: Tolerance development and elevation of opiate receptor binding

Background: This study was planned to determine the feasibility of using a slow release naloxone preparation to treat alcoholism, because compliance w ith medication is a significant problem in alcoholics. Methods: Experiments were performed in alcohol-preferring P rats maintained either on continuous access or on limited access (1 hr/day) to alcohol wit h water and food provided ad libitum. Naloxone (Nx) was administered either by twice daily subcutaneous injections or by slow release (1.1 mg/kg/hr) o smotic minipump. In limited access experiments, Nx was injected immediately before access to alcohol. Results: An initial experiment estimated the dose-effect curve for Nx subcu taneous suppression on alcohol intake. Nx (2.5-20 mg/kg) had a stronger eff ect during the first 2 hr after injection (ED50 = 2.1 mg/kg); however, the effect was more modest on 24-hr consumption. Similar results were found wit h chronic Nx treatment. Low doses of Nx (0.5 and 2.0 mg/kg) injected immedi ately before limited access to alcohol produced almost complete suppression of alcohol intake for at least 14 consecutive days. However, 14 days of tr eatment with 26 mg/kg/day by minipump or injection produced an initial 50% suppression of 24-hr alcohol intake with the gradual development of toleran ce. An acute challenge with Nx immediately after the pumps were scheduled t o be empty provided additional evidence of tolerance development in chronic ally Nx-treated rats. Brain mu-opiate receptors, estimated autoradiographic ally by using the ligand [H-3][D-Ala(2),N-Me-Phe(4), Gly-ol(5)][tyrosyl-3,5 -H-3]-enkephalin, showed that rats chronically exposed to Nx and showing to lerance to Nx suppression of drinking exhibited 17% to 250% increases in [H -3][D-Ala(2),N-Me-Phe(4), Gly-o(5)][tyrosyl-3,5-H-3]-enkephalin binding. Conclusions: High doses of Nx are required to suppress continuous access al cohol consumption in P rats, and tolerance develops to the ethanol consumpt ion-suppressing effect of Nx that may be related to increases in mu-opiate receptors.