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

Authors

  • Michael S. Cowen,

    Corresponding author
    1. Department of Pharmacology (M.S.C., B.J., A.J.L.), Monash University, Clayton, VIC 3168, Australia; and the Skipper Bowles Center for Alcohol Studies (A.H.R.), University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7178.
    Search for more papers by this author
  • Amir H. Rezvani,

    1. Department of Pharmacology (M.S.C., B.J., A.J.L.), Monash University, Clayton, VIC 3168, Australia; and the Skipper Bowles Center for Alcohol Studies (A.H.R.), University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7178.
    Search for more papers by this author
  • Bevyn Jarrott,

    1. Department of Pharmacology (M.S.C., B.J., A.J.L.), Monash University, Clayton, VIC 3168, Australia; and the Skipper Bowles Center for Alcohol Studies (A.H.R.), University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7178.
    Search for more papers by this author
  • Andrew J. Lawrence

    1. Department of Pharmacology (M.S.C., B.J., A.J.L.), Monash University, Clayton, VIC 3168, Australia; and the Skipper Bowles Center for Alcohol Studies (A.H.R.), University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7178.
    Search for more papers by this author

  • This study was supported by the Australian Brewers’Foundation, and the National Health & Medical Research Council, Australia.

Reprint requests: Michael Cowen, B.Sc, Department of Pharmacology, Monash University, Clayton, VIC 3168, Australia; Fax: 613-9905-5851; E-mail: cowenm@its-med.cc.monash.edu.au

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.

Ancillary