Microsoft Word - Beresford JPET CLEAN Final w-o figures 0224 2012[1]

High abstinence rates characterize alcohol dependent (AD) liver graft recipients. The immunosuppressants cyclosporine (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 tacrolimus (TRL), as well as sirolimus (SRL), an immunosuppressant without CLN inhibition, and 2) to establish that reduction of alcohol consumption is not due to caloric reinforcement from these ligands. C57BL/6J mice trained to imbibe ethanol consume ethanol or sucrose in a modified limited access drinking-in-the-dark paradigm; test groups received vehicle or doses of CsA (5 to 50 mg/kg), TRL (0.5 to 2.5 mg/kg), or SRL (1.0 to 5.0 mg/kg) for 5 consecutive days, 30 min before each 2 hour limited access session. Brain CsA, TRL, and SRL concentrations were measured. CsA (p<0.001) and TRL (p <0.01) each decreased ethanol consumption while 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 to very low values of SRL. These data suggest that CsA and TRL may reduce alcohol preference through central CLN inhibition rather than by immunosuppression. This article has not been copyedited and formatted. The final version may differ from this version. JPET Fast Forward. Published on February 28, 2012 as DOI: 10.1124/jpet.111.188169 at A PE T Jornals on M ay 2, 2017 jpet.asjournals.org D ow nladed from