Stimulus properties of the L-type calcium channel agonist BAY k 8644 in rats

Calcium (Ca2+) channels appear to be involved in the regulation of ethanol (EtOH)) intake, as indicated by the effectiveness of both L-type Ca2+ channel antagonists and agonists in reducing EtOH intake in animals. The present study was aimed to investigate rewarding/aversive and discriminative stimulus effects of the Ca2+ channel agonist BAY k 8544, a compound showing pronounced anti-alcohol effects in rats. Therefore, a series of conditioned taste aversion (CTA), conditioned place preference (CPP) and two-lever drug discrimination (DD) experiments were conducted in Wistar rats, with (+/-)-BAY k 8644 and its enantiomers. After i.p. application, (+/-)-BAY k 8644 (0.0625-1 mg/kg), (-)-BAY k 8644 (0.12-1 mg/kg) and (+)-BAY k 8644 (2.5-20 mg/kg) all induced a dose-dependent CTA. The minimal effective doses (MED) for (+/-)-, (-)- and (+)-BAY k 8644 were 0.25, 0.25 and 10 mg/kg, respectively. In a CPP study, however (+/-)-BAY k 8644 (0.25-2 mg/kg, i.p.) showed neither aversive nor rewarding stimulus properties. Rats were trained to discriminate (-)-BAY k 8644 (0.3 mg/kg, i.p.), the enantiomer acting as a high potency Ca2+ channel agonist, from vehicle, in a two-lever DD procedure (ED(50) value: 0.05 mg/kg); full generalization: 0.1 mg/kg). The (-)-BAY k 8644 cue dose-dependently generalized to (+/-)-BAY k 8644 and (+)-BAY k 8644, the enantiomer acting as a low potency Ca2+ channel antagonist, with ED(50) values of 0.06 and 0.28 mg/kg, respectively. Both (+/-)- and (+)-BAY k 8644 produced full generalization at 1 mg/kg, the latter compound showing an inverted U-shaped curve (i.e., this was the only dose showing >80% drug lever selection). The stimulus patterns of BAY k 8644 and its enantiomers appear to resemble the anti-alcohol profiles of these compounds. Therefore, commonalities between the stimulus properties of the agonistic and antagonistic enantiomers might provide a clue for the mechanism underlying the anti-alcohol effects of L-type Ca2+ channel antagonists and agonists.