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, antialcoh ol effects of the 1,4-dihydropyridine (DHP) L-type calcium (Ca2+) chan nel agonist BAY k 8644 were investigated in alcohol-preferring AA rats . In this Wistar line, selectively bred for a high 10% v/v ethanol (Et OH) preference in a free choice situation, effects on EtOH preference and intake, as well as on food and total fluid intake were evaluated f or 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 (+)-enant iomer (10-50 mg/kg IP and PO). Irrespective of route of application, B AY l-e 8644 was found to be effective in reducing both EtOH intake and preference (minimal effective dose: 0.5O mg/kg; maximum effect: appro ximately 60% of baseline levels). The (+)-enantiomer, acting as a low- potency Ca2+ channel antagonist, also reduced EtOH intake and preferen ce but the effects were not very selective as food intake was also sub stantially reduced. Moreover, the effects were only obtained at relati vely high doses (50 mg/kg). The essential enantiomer involved in the a ntialcohol effects of BAY k 8644 seems to be the (-)-enantiomer, actin g as a strong Ca2+ channel agonist. This latter compound was potent (m inimal effective dose: 0.3 mg/kg), very effective in reducing EtOH int ake (maximum effect: 29% of baseline level) and preference (26% of bas eline) and apparently more selective. Although slightly decreasing ove r days, effects of (-)-BAY k 8644 on EtOH intake and preference were s hown to remain after repealed treatment (10 successive days, 0.3 mg/kg IP).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+ channe l 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 effect s of (+/-)- and (-)-BAY k 8644. Alternatively, it is possible that the previously described antialcohol effects of DHP Ca2+ channel antagoni sts 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 agon ists and antagonists.