Ethanol consumption by Fawn-Hooded rats following abstinence: effect of naltrexone and changes in mu-opioid receptor density.
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.


METHODS
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 mg/kg/day 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 micro-opioid receptor density through the forebrain using the ligand [125I]FK-33824.


RESULTS
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 micro-opioid receptor density in all brain regions examined (p < 0.05). Finally, ethanol consumption alone also upregulated micro-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 micro-opioid receptor density in other regions including the substantia nigra pars reticulata, which was suggestive of an indirect effect on micro-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 micro-opioid receptor density.
Department of Pharmacology, Monash University, Clayton, VIC, Australia. cowenm@its-med.cc.monash.edu.au
M S
MS
Cowen
A H
AH
Rezvani
B
B
Jarrott
A J
AJ
Lawrence
D000428:Alcohol Drinking / Q000188:drug therapy*; D000818:Animals; D001665:Binding Sites; D002492:Central Nervous System Depressants / Q000008:administration & dosage*; D005405:D-Ala(2),MePhe(4),Met(0)-ol-enkephalin / Q000032:analysis / Q000494:pharmacology; D000431:Ethanol / Q000008:administration & dosage*; D008297:Male; D009271:Naltrexone / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D016548:Prosencephalon / Q000737:chemistry / Q000187:drug effects; D051381:Rats; D017450:Receptors, Opioid, mu / Q000032:analysis / Q000187:drug effects*; D013695:Temperance
D002492:Central Nervous System Depressants; D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; D000431:Ethanol; D009271:Naltrexone; D005405:D-Ala(2),MePhe(4),Met(0)-ol-enkephalin