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

Rationale: Administration of voltage-gated calcium-channel (VGCC) modulator s with ethanol can result in enhancement or attenuation of some behavioral effects of ethanol, including its discriminative stimulus effects. Objectiv es: The present study used a drug-discrimination paradigm to characterize m odulation of the ethanol-like discriminative stimulus effects of a gamma-am ino-butyric acid (GABA), and N-methyl-D-aspartatr (NMDA) ligand by administ ration of VGCC ligands. Methods: Two groups of adult male Long-Evans rats w ere trained to discriminate either 1.0 g/kg ethanol (n=8) or 2.0 g/kg ethan ol (n=9) from water under a fixed-ratio (FR) 20 schedule of food presentati on. Following training, ethanol substitution tests were conducted with cumu lative 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, nifedi pine, 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 alterati ons in the ethanol-like discriminative stimulus effects of DZP in animals t rained 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 p resence of the VGCC antagonists and attenuated in the presence of the agoni st in animals trained with 2.0 g/kg ethanol. Conclusions: Overall, these da ta show that VGCC modulation is not a robust component of ethanol-like disc riminative 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 hig her training doses, appear to be modulated by dihydropyridine-sensitive VGC Cs.