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 this, a considerable amount of antagonists for these ion channels has been found to suppress EtOH intake and preference in various animal models of alcoholism. The aim of the present study was to examine antialcohol 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 EtOH preference in a free-choice situation, have thus far not been subjected to systematic investigations with Ca2+ channel antagonists. Therefore, effects on EtOH preference and intake, as well as on food and total fluid intake, were evaluated for the 1,4-dihydropyridine (DHP) derivatives nimodipine, felodipine, isradipine, nicardipine, nifedipine, and nitrendipine, as well as for the phenylalkylamine verapamil and the 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. Irrespective of route of application (IP or PO), the effective dose ranges were found to be very similar across compounds (10-30 mg/kg). Nevertheless, because food intake was also reduced, the effects were not completely selective. For nimodipine, the (-)-enantiomer seemed to be more effective as its (+)-enantiomer, possibly reflecting stereoselectivity at central binding sites. Compared to the DHPs, verapamil produced a similar profile of activity, but diltiazem was found to be ineffective. These results confirm and extend previous findings with L-type Ca2+ channel antagonists obtained in other models of alcoholism and suggest that this class of compounds offers an interesting approach for the pharmacotherapy of alcoholism.