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 with 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 with 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) osmotic minipump. In limited access experiments, Nx was injected immediately before access to alcohol.

Results: An initial experiment estimated the dose-effect curve for Nx subcutaneous suppression on alcohol intake. Nx (2.5-20 mg/kg) had a stronger effect 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 with chronic Nx treatment. Low doses of Nx (0.5 and 2.0 mg/kg) injected immediately before limited access to alcohol produced almost complete suppression of alcohol intake for at least 14 consecutive days. However, 14 days of treatment with 26 mg/kg/day by minipump or injection produced an initial 50% suppression of 24-hr alcohol intake with the gradual development of tolerance. An acute challenge with Nx immediately after the pumps were scheduled to be empty provided additional evidence of tolerance development in chronically Nx-treated rats. Brain micro-opiate receptors, estimated autoradiographically by using the ligand [3H][D-Ala2,N-Me-Phe4, Gly-ol5][tyrosyl-3,5-3H]-enkephalin, showed that rats chronically exposed to Nx and showing tolerance to Nx suppression of drinking exhibited 17% to 250% increases in [3H][D-Ala2,N-Me-Phe4, Gly-ol5][tyrosyl-3,5-3H]-enkephalin binding.

Conclusions: High doses of Nx are required to suppress continuous access alcohol consumption in P rats, and tolerance develops to the ethanol consumption-suppressing effect of Nx that may be related to increases in micro-opiate receptors.