The calcium channel agonist BAY k 8644 reduces ethanol intake and preference in alcohol-preferring AA rats.
Applying a 12-h limited access, two-bottle choice procedure, antialcohol effects of the 1,4-dihydropyridine (DHP) L-type calcium (Ca2+) channel agonist BAY k 8644 were investigated in alcohol-preferring AA rats. In this Wistar line, selectively bred for a high 10% v/v ethanol (EtOH) preference in a free choice situation, effects on EtOH preference and intake, as well as on food and total fluid intake were evaluated for racemic BAY k 8644 (0.1-1 mg/kg IP; 0.25-2 mg/kg PO), its agonistic (-)-enantiomer (0.1-1 mg/kg IP and PO) and its antagonistic (+)-enantiomer (10-50 mg/kg IP and PO). Irrespective of route of application, BAY k 8644 was found to be effective in reducing both EtOH intake and preference (minimal effective dose: 0.5 mg/kg; maximum effect: approximately 60% of baseline levels). The (+)-enantiomer, acting as a low-potency Ca2+ channel antagonist, also reduced EtOH intake and preference, but the effects were not very selective as food intake was also substantially reduced. Moreover, the effects were only obtained at relatively high doses (50 mg/kg). The essential enantiomer involved in the antialcohol effects of BAY k 8644 seems to be the (-)-enantiomer, acting as a strong Ca2+ channel agonist. This latter compound was potent (minimal effective dose: 0.3 mg/kg), very effective in reducing EtOH intake (maximum effect: 29% of baseline level) and preference (26% of baseline) and apparently more selective. Although slightly decreasing over days, effects of (-)-BAY k 8644 on EtOH intake and preference were shown to remain after repeated treatment (10 successive days, 0.3 mg/kg IP). Interestingly, the acute antialcohol effects of (-)-BAY k 8644 (0.3-1 mg/kg IP) could not be antagonized with the DHP L-type Ca2+ channel antagonists nimodipine (0.01-1 mg/kg IP) and (-)-nimodipine (1-30 mg/kg IP). The present results suggest that a mechanism of action other than L-type Ca2+ channel agonism is involved in the antialcohol effects of (+/-)- and (-)-BAY k 8644. Alternatively, it is possible that the previously described antialcohol effects of DHP Ca2+ channel antagonists are not related to antagonistic activity at Ca2+ channels. Finally, it cannot be excluded that a mechanism unrelated to Ca2+ channels is responsible for the antialcohol effects of both DHP Ca2+ channel agonists and antagonists.
de Beun
R
R
Institute of Neurobiology, Köln, Germany.
Schneider
R
R
Klein
A
A
Lohmann
A
A
Schreiber
R
R
De Vry
J
J
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology*; D000284:Administration, Oral; D000818:Animals; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage*; D005260:Female; D005518:Food Preferences / Q000187:drug effects*; D007274:Injections, Intraperitoneal; D008297:Male; D009553:Nimodipine / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013997:Time Factors
D002120:Calcium Channel Agonists; D000431:Ethanol; D009553:Nimodipine; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester