Negligible tolerance produced by chronic intravenous alprazolam administration: A low serum drug concentration effect

In 3-hr sessions, the authors investigated the onset, peak, and disappearance of the effects of alprazolam on performance under a differential reinforcement of low rate 45-S schedule in rats. Alprazolam was administered chronically as a daily bolus dose (2 mg/kg) via the intravenous route. Alprazolam decreased the reinforcement rate and increased the shorter response (nonreinforced) rate in a dose- and time-related fashion. Tolerance did not develop to the decreases in reinforcement rate; tolerance to increases in shorter response rate was negligible, occurring only at the low-concentration range. Clinically, an optimal dose regimen should be designed to avoid the tolerance development that occurs in the low serum benzodiazepine concentration range.