Modulation of the ethanol-like discriminative stimulus effects of diazepam and phencyclidine by L-type voltage-gated calcium-channel ligands in rats

Rationale: Administration of voltage-gated Calcium-channel (VGCC) modulators with ethanol can result in enhancement or attenuation of some behavioral effects of ethanol, including its discriminative stimulus effects. Objectives: The present study used a drug-discrimination paradigm to characterize modulation of the ethanol-like discriminative stimulus effects of a γ-amino-butyric acid (GABA)(A) and N-methyl-D-aspartate (NMDA) ligand by administration of VGCC ligands. Methods: Two groups of adult male Long- Evans rats were trained to discriminate either 1.0 g/kg ethanol (n=8) or 2.0 g/kg ethanol (n=9) from water under a fixed-ratio (FR) 20 schedule of food presentation. Following training, ethanol substitution tests were conducted with cumulative doses of the GABA(A)-positive modulator diazepam (0.3-10 mg/kg, i.p.) (DZP) and the uncompetitive NMDA antagonist phencyclidine (0.3- 5.6 mg/kg, i.p) (PCP). Next, a single dose of the VGCC antagonist nimodipine, nifedipine, isradipine, or the VGCC agonist (-)-BAY k 8644 (0.3 mg/kg, i.p.) was administered prior to a cumulative DZP or PCP dose-response determination. Results: None of the VGCC modulators produced robust or consistent alterations in the ethanol-like discriminative stimulus effects of DZP in animals trained with either 1.0 g/kg or 2.0 g/kg ethanol. However, the ethanol-like discriminative stimulus effects of PCP were significantly enhanced in the presence of the VGCC antagonists and attenuated in the presence of the agonist in animals trained with 2.0 g/kg ethanol. Conclusions: Overall, these data show that VGCC modulation is not a robust component of ethanol-like discriminative stimulus effects of DZP in animals trained with 1.0 g/kg or 2.0 g/kg ethanol. However, the ethanol-like effects of PCP, particularly at higher training doses, appear to be modulated by dihydropyridine-sensitive VGCCs.