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

Voltage-operated calcium channels (VOCCs) have been implicated in alcoholis m. Thus, dihydropyridine (DHP) VOCC antagonists, such as nimodipine, reduce ethanol (EtOH) intake and preference in a variety of animal models of alco holism. Paradoxically, the DHP VOCC agonist BAY k 8644 also demonstrates an tialcohol 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 n imodipine. 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 a pparent antialcohol effect of these compounds is related to their discrimin ative and/or affective stimulus effects. In rats trained to discriminate ni modipine from vehicle, (-)-BAY k 8644 completely generalizes to the nimodip ine cue; whereas, in rats trained to discriminate (-)-BAY k 8644, nimodipin e 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 activit y suggests that a common neurobiological mechanism underlies the discrimina tive stimulus and antialcohol effects of DHPs. It appears unlikely, however , that the antialcohol effects of DHPs are based on substitution for, or bl ockade 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 a re dissimilar, and that the mechanism underlying the latter effects is prob ably not related to the mechanism underlying the antialcohol effects of DHP VOCC modulators. (C) 1999 Elsevier Science Inc.