title: Acamprosate-responsive brain sites for suppression of ethanol intake and preference.
abstract: Acamprosate suppresses alcohol intake and craving in recovering alcoholics; however, the central sites of its action are unclear. To approach this question, brain regions responsive to acamprosate were mapped using acamprosate microimplants targeted to brain reward and circadian areas implicated in alcohol dependence. mPer2 mutant mice with nonfunctional mPer2, a circadian clock gene that gates endogenous timekeeping, were included, owing to their high levels of ethanol intake and preference. Male wild-type (WT) and mPer2 mutant mice received free-choice (15%) ethanol/water for 3 wk. The ethanol was withdrawn for 3 wk and then reintroduced to facilitate relapse. Four days before ethanol reintroduction, mice received bilateral blank or acamprosate-containing microimplants releasing ∼50 ng/day into reward [ventral tegmental (VTA), peduculopontine tegmentum (PPT), and nucleus accumbens (NA)] and circadian [intergeniculate leaflet (IGL) and suprachiasmatic nucleus (SCN)] areas. The hippocampus was also targeted. Circadian locomotor activity was measured throughout. Ethanol intake and preference were greater in mPer2 mutants than in wild-type (WT) mice (27 g·kg(-1)·day(-1) vs. 13 g·kg(-1)·day(-1) and 70% vs. 50%, respectively; both, P < 0.05). In WTs, acamprosate in all areas, except hippocampus, suppressed ethanol intake and preference (by 40-60%) during ethanol reintroduction. In mPer2 mutants, acamprosate in the VTA, PPT, and SCN suppressed ethanol intake and preference by 20-30%. These data are evidence that acamprosate's suppression of ethanol intake and preference are manifest through actions within major reward and circadian sites.
authors.affiliation: Department of Biological Sciences, Kent State University, Kent, Ohio 44242, USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Brager
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Prosser
authors.forename: J David
authors.initials: JD
authors.lastname: Glass
mesh_terms: D000077443:Acamprosate; D000427:Alcohol Deterrents / Q000494:pharmacology*; D000428:Alcohol Drinking / Q000503:physiopathology*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000502:physiology*; D002940:Circadian Rhythm / Q000502:physiology; D004326:Drinking / Q000187:drug effects / Q000502:physiology; D005518:Food Preferences / Q000187:drug effects* / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D023421:Models, Animal; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology; D045042:Pedunculopontine Tegmental Nucleus / Q000187:drug effects / Q000502:physiology; D056950:Period Circadian Proteins / Q000235:genetics / Q000502:physiology; D013493:Suprachiasmatic Nucleus / Q000187:drug effects / Q000502:physiology; D013654:Taurine / Q000031:analogs & derivatives* / Q000494:pharmacology; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000502:physiology
chemical_list: D000427:Alcohol Deterrents; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D013654:Taurine; D000077443:Acamprosate