Discrimination of ethanol and of diazepam: differential cross-tolerance

These experiments tested the hypothesis that cross-tolerance between ethanol (EtOH) and diazepam would occur in a drug discrimination paradigm. One group of rats (n = 28) was trained to discriminate EtOH (1.0g/kg, i.p.) from vehicle; another group of rats (n = 10) was trained to discriminate diazepam (5.6mg/kg, i.p.) from vehicle. Subjects were trained using a two-lever choice procedure where food was delivered under a fixed-ratio 10 schedule of reinforcement. In rats trained to detect EtOH, both EtOH (0.1-1.78g/kg) and diazepam (0.32-10mg/kg) dose dependently substituted for EtOH. Chronic administration of EtOH (6.8g/kg/12h for 7 days) resulted in 3-fold tolerance to EtOH and 6-fold cross-tolerance to the ability of diazepam to substitute for EtOH; chronic administration of diazepam (20mg/kg/8h for 7 days) failed to confer cross-tolerance to EtOH nor did it produce tolerance to the ability of diazepam to substitute for EtOH. In rats trained to detect diazepam, diazepam (0.56-10mg/kg) but not EtOH (0.1-1.78g/kg) substituted for diazepam. Chronic administration of diazepam (20mg/kg/8h for 7 days) produced 3-fold tolerance to diazepam; in contrast, chronic administration of EtOH (6.8g/kg/12h for 7 days) failed to confer cross-tolerance to diazepam. The dissociation of the cross-substitution and cross-tolerance patterns between EtOH and diazepam suggests that the population of benzodiazepine receptors that mediates substitution of diazepam for EtOH differs from the population of benzodiazepine receptors that mediates substitution of diazepam for diazepam.