Ethanol Consumption by Fawn‐Hooded Rats Following Abstinence Effect of Naltrexone and Changes in μ‐Opioid Receptor Density

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Abstract
Background: Relapse after abstinence can be modelled in rats using an alcohol deprivation effect (ADE) of enhanced ethanol consumption after a period of enforced abstinence from ethanol; however, not all rat strains display such an effect. We wanted to examine the effect of naltrexone on ethanol consumption by ethanol‐preferring Fawn‐Hooded (FH) rats using such a model. Method: FH rats were given continual free‐choice access to a 5% ethanol solution or water (4 weeks) followed by 2 weeks of water alone. At the end of this abstinence period, osmotic minipumps were implanted subcutaneously to deliver saline (n= 4) or naltrexone (n= 4; 8.4 mgkgiday for 4 weeks). After recovery from surgery, the rats were again given access to 5% ethanol under the same free‐choice conditions (4 weeks). A third group of age‐matched controls drank only water during the behavioral trial. At the end of the behavioral trial, the rats were decapitated and an autoradiographic examination was made of μ‐opioid receptor density through the forebrain using the ligand [125I]FK‐33824. Result: First, a period of enforced abstinence from ethanol consumption caused a significant (p < 0.05) and prolonged increase in ethanol preference (+18%) and decrease in water consumption (‐53%), although the volume of ethanol consumed (ml/day) did not vary, indicating an atypical ADE in this rat strain. Second, naltrexone significantly (p < 0.05) decreased ethanol consumption by the FH rats in terms of absolute amount of ethanol consumed and preference for ethanol solution, but this effect of naltrexone diminished over time, concurrent with a robust and significant elevation in μ‐opioid receptor density in all brain regions examined (p < 0.05). Finally, ethanol consumption alone also upregulated μ‐opioid receptor density relative to nondrinking controls in a number of brain regions, which included the nucleus accumbens (+29%) and caudate‐putamen (+ 15%,p < 0.05), but decreased μ‐opioid receptor density in other regions including the substantia nigra pars reticulata, which was suggestive of an indirect effect on μ‐opioid receptors. Conclusions: The data suggest that continual long‐term naltrexone treatment may not be effective in the treatment of alcoholism, possibly because of the induced increase in μ‐opioid receptor density.