Discriminative and affective stimulus effects of dihydropyridine calcium channel modulators: relationship to antialcohol effects.

Voltage-operated calcium channels (VOCCs) have been implicated in alcoholism. Thus, dihydropyridine (DHP) VOCC antagonists, such as nimodipine, reduce ethanol (EtOH) intake and preference in a variety of animal models of alcoholism. Paradoxically, the DHP VOCC agonist BAY k 8644 also demonstrates antialcohol effects in such models. The antialcohol effects of BAY k 8644 are stereoselective [the "agonistic" (-)-enantiomer being more potent than the "antagonistic" (+)-enantiomer], and are not blocked by pretreatment with nimodipine. The present review summarizes studies on the effects of DHPs in drug discrimination (DD), conditioned taste aversion (CTA), and conditioned place preference (CPP) paradigms, and discusses the possibility that the apparent antialcohol effect of these compounds is related to their discriminative and/or affective stimulus effects. In rats trained to discriminate nimodipine from vehicle, (-)-BAY k 8644 completely generalizes to the nimodipine cue; whereas, in rats trained to discriminate (-)-BAY k 8644, nimodipine completely generalizes to, and is unable to block, the (-)-BAY k 8644 cue. The same stereoselectivity is obtained for BAY k 8644 in DD paradigms and models of alcoholism. The apparent similarity of these profiles of activity suggests that a common neurobiological mechanism underlies the discriminative stimulus and antialcohol effects of DHPs. It appears unlikely, however, that the antialcohol effects of DHPs are based on substitution for, or blockade of, the EtOH cue, as these compounds were not found to generalize to, or block, the EtOH cue. Comparison of the effects of DHPs in CTA and CPP paradigms suggests that the affective stimulus effects of these compounds are dissimilar, and that the mechanism underlying the latter effects is probably not related to the mechanism underlying the antialcohol effects of DHP VOCC modulators.