Tolerance to the anxiolytic effects of the triazolobenzodiazepines triazolam and alprazolam, as measured by the ingestion of a hypertonic sodium chloride solution in rats.

Rats were adapted to a water-deprivation regimen that allowed daily 1-hr drinking sessions of a single fluid, either 1.5% NaCl solution or water. Oral, presession, acute doses of triazolam (0.05-1.6 mg/kg) or alprazolam (0.4-6.4 mg/kg) produced dose-related increases in session NaCl solution ingestion. The relative potencies found for these two drugs approximated their relative Ki values reported in the literature. The increased ingestion produced in this and other experiments by anxiolytic agents is presented as an alternative way of evaluating punishment attenuation, and hence anxiolytic activity. Chronic oral dosing (every 2nd day) with triazolam (0.2 mg/kg) or alprazolam (1.2 mg/kg) led, after several weeks, to partial, but surmountable, tolerance to the increased NaCl solution ingestion produced by these drugs, which was confirmed by a rightward shift in the dose-effect relations. During chronic dosing, no corresponding declines in the independently evaluated increases in water intake produced by these drugs occurred. Abrupt drug discontinuation produced a precipitous decrease in NaCl solution intake, with subsequent recovery. For triazolam, the initial discontinuation decrease in intake to below the original base line suggested the possible accrual of a mild physiological dependence under this moderate chronic dose regimen.