EFFECTS OF NIMODIPINE AND OTHER CALCIUM-CHANNEL ANTAGONISTS IN ALCOHOL-PREFERRING AA RATS

Several lines of evidence suggest that L-type calcium (Ca2+) channels play a role in excessive ethanol (EtOH) intake. In accordance with thi s, a considerable amount of antagonists for these ion channels has bee n found to suppress EtOH intake and preference in various animal model s of alcoholism. The aim of the present study was to examine antialcoh ol effects of L-type Ca2+ channel antagonists in alcohol-preferring AA rats. These rats, a Wistar line selectively bred for a high 10% v/v E tOH preference in a free-choice situation, have thus far not been subj ected to systematic investigations with Ca2+ channel antagonists. Ther efore, effects on EtOH preference and intake, as well as on food and t otal fluid intake, were evaluated for the 1,4-dihydropyridine (DHP) de rivatives nimodipine, felodipine, isradipine, nicardipine, nifedipine, and nitrendipine, as well as for the phenylalkylamine verapamil and t he benzothiazepine diltiazem, utilizing a limited access, free-choice procedure. All DHPs were found to be highly effective in reducing both EtOH intake and preference, without affecting total fluid intake. Irr espective of route of application (IP or PO), the effective dose range s were found to be very similar across compounds (10-30 mg/kg). Nevert heless, because food intake was also reduced, the effects were not com pletely selective. For nimodipine, the (-)-enantiomer seemed to be mor e effective as its (+)-enantiomer, possibly reflecting stereoselectivi ty at central binding sites. Compared to the DHPs, verapamil produced a similar profile of activity, but diltiazem was found to be ineffecti ve. These results confirm and extend previous findings with L-type Ca2 + channel antagonists obtained in other models of alcoholism and sugge st that this class of compounds offers an interesting approach for the pharmacotherapy of alcoholism.