The acute anti-craving effect of acamprosate in alcohol-preferring rats is associated with modulation of the mesolimbic dopamine system.
Acamprosate (Campral) is a drug used clinically for the treatment of alcoholism. In order to examine further the time-course and mechanism of action of acamprosate, the effect of acute and repeated acamprosate administration was examined on (i) operant ethanol self-administration and (ii) voluntary home cage ethanol consumption by alcohol-preferring Fawn-Hooded, iP and Alko Alcohol (AA) rats. Acutely, acamprosate was shown to cause a significant decrease in operant ethanol self-administration by Fawn-Hooded and alcohol-preferring iP rats in part by decreasing the motivational relevance of a specific ethanol cue; however, repeated injection of acamprosate led to tolerance to this effect. Voluntary alcohol consumption in the home cage in Fawn-Hooded and AA rats was also reduced by an acute acamprosate injection; however, again tolerance developed to repeated injections. In a separate experiment, the effect of acamprosate on markers of the dopaminergic system was examined. Interestingly, acute acamprosate was also shown to cause increased dopamine transporter density and decreased dopamine D2-like receptor density within the nucleus accumbens but not in the caudate-putamen, suggesting a link between the decreased motivational salience of the ethanol cue and altered dopaminergic signalling within the nucleus accumbens. With repeated injections of acamprosate, markers of the dopaminergic system returned to steady state levels with a similar temporal profile to the development of tolerance in the behavioural studies. Along with previous studies, our findings indicate that acamprosate modulates the mesolimbic dopaminergic system and may thereby decrease ethanol reinforcement processes; however, these effects undergo tolerance in alcohol-preferring rats and may in part explain the fact why some subjects are non-responders to chronic acamprosate treatment.
Cowen
Michael S
MS
Howard Florey Institute, University of Melbourne, Australia.
Adams
Cameron
C
Kraehenbuehl
Tracey
T
Vengeliene
Valentina
V
Lawrence
Andrew J
AJ
D000077443:Acamprosate; D000208:Acute Disease; D000427:Alcohol Deterrents / Q000627:therapeutic use*; D000437:Alcoholism / Q000188:drug therapy*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002421:Caudate Nucleus / Q000187:drug effects; D002452:Cell Count; D002755:Choice Behavior; D004298:Dopamine / Q000378:metabolism*; D008032:Limbic System / Q000187:drug effects*; D008297:Male; D009042:Motivation; D009714:Nucleus Accumbens / Q000187:drug effects; D011699:Putamen / Q000187:drug effects; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D012646:Self Administration; D013654:Taurine / Q000031:analogs & derivatives* / Q000627:therapeutic use
D000427:Alcohol Deterrents; D017448:Receptors, Dopamine D2; D013654:Taurine; D000077443:Acamprosate; D004298:Dopamine