Substitution of temazepam and midazolam in pentobarbital-dependent rats

The ability of temazepam and midazolam to substitute for pentobarbital and thus maintain the physical dependence state was used to assess the potential dependence liability of these two benzodiazepine compounds. Male Sprague-Dawley rats, weighing 175-200 g and having ad lib access to food and water, were determined to be dependent on pentobarbital following 12 days of continuous, intraperitoneal infusion of pentobarbital using an escalating drug infusion schedule. On day 13 (substitution phase) the pentobarbital was replaced with either temazepam, midazolam or vehicle and the rats were infused for an additional 24 hours. This was followed on Day 14 (withdrawal phase) by a 24 hr saline infusion period. Rats were observed for changes in overt behavior and alterations of body weight during both Day 13 and Day 14. Preliminary potency estimation studies had indicated that both drugs were more potent and longer acting than was pentobarbital. Temazepam, in doses of 32.5, 65 and 130 mg/kg/24 hr, was demonstrated to substitute for pentobarbital and provided dose-dependent suppression of overt behavioral signs indicative of withdrawal. Temazepam also suppressed the weight loss typically observed during withdrawal. Substitution of saline for temazepam resulted in an increased incidence of withdrawal signs and an approximate 10% decline in body weight. Midazolam, in doses of 60 and 120 mg/kg/24 hr, also substituted for pentobarbital and suppressed both overt behavior and weight loss. Following saline substitution on Day 14, a mild withdrawal syndrome was evident although body weight was noted to remain near control values.(ABSTRACT TRUNCATED AT 250 WORDS)