Abstract
High abstinence rates characterize alcohol-dependent liver graft recipients. The immunosuppressants cyclosporine A (CsA) and tacrolimus (TRL) also inhibit calcineurin (CLN) in the brain. Previously, we found that CsA reduces alcohol consumption in C57BL/6J mice. The goals of the present study were: 1) to compare the ethanol preference effects of CsA against TRL, as well as sirolimus (SRL), an immunosuppressant without CLN inhibition and 2) to establish that reduction of alcohol consumption is not caused by caloric reinforcement from these ligands. C57BL/6J mice trained to imbibe ethanol consumed ethanol or sucrose in a modified limited-access drinking-in-the-dark paradigm; test groups received vehicle or doses of CsA (5–50 mg/kg), TRL (0.5–2.5 mg/kg), or SRL (1.0–5.0 mg/kg) for 5 consecutive days, 30 min before each 2-h limited-access session. Brain CsA, TRL, and SRL concentrations were measured. CsA (p < 0.001) and TRL (p < 0.01) each decreased ethanol consumption, whereas SRL showed no significant effects at any dose. Effective doses included CsA at 10 mg/kg and above and TRL at 2.5 mg/kg. CsA (50 mg/kg) did not reduce sucrose consumption. Both CsA and TRL reached significant brain concentrations compared with very low values of SRL. These data suggest that CsA and TRL may reduce alcohol preference through central CLN inhibition rather than by immunosuppression.
Footnotes
This work was supported by the National Institutes of Health National Institute on Alcohol Abuse and Alcoholism [Grant AA016175].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
ABBREVIATIONS:
- AD
- alcohol-dependent
- CsA
- cyclosporine A
- TRL
- tacrolimus
- SRL
- sirolimus
- CLN
- calcineurin
- FKBP
- FK506 binding protein
- mTOR
- mammalian target of rapamycin
- LC
- liquid chromatography
- MS
- mass spectrometry
- ANOVA
- analysis of variance
- CyD
- cyclophyllin D.
- Received October 1, 2011.
- Accepted February 27, 2012.
- U.S. Government work not protected by U.S. copyright
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