title: Immunophyllin ligands show differential effects on alcohol self-administration in C57BL mice.
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.
authors.affiliation: Psychiatry and Research Services, Department of Veterans Affairs Medical Center, Denver, Colorado, USA. thomas.beresford@ucdenver.edu
authors.forename: Thomas
authors.initials: T
authors.lastname: Beresford
authors.forename: Tina
authors.initials: T
authors.lastname: Fay
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Serkova
authors.forename: Peter H
authors.initials: PH
authors.lastname: Wu
mesh_terms: D000428:Alcohol Drinking / Q000188:drug therapy*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D019703:Calcineurin / Q000187:drug effects*; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D000431:Ethanol; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012646:Self Administration; D020123:Sirolimus / Q000494:pharmacology*; D013395:Sucrose / Q000008:administration & dosage; D016559:Tacrolimus / Q000494:pharmacology*
chemical_list: D007166:Immunosuppressive Agents; D008024:Ligands; D000431:Ethanol; D013395:Sucrose; D016572:Cyclosporine; D019703:Calcineurin; D020123:Sirolimus; D016559:Tacrolimus