STABLE LOW-RATE MIDAZOLAM SELF-INJECTION WITH CONCURRENT PHYSICAL-DEPENDENCE UNDER CONDITIONS OF LONG-TERM CONTINUOUS AVAILABILITY IN BABOONS

The current research was undertaken to characterize intravenous midazo lam self-injection and the concurrent development of physical dependen ce under conditions of continuous drug availability. Baboons (n=6) IV self-injected midazolam under conditions of continuous availability un der a fixed-ratio 30 schedule of lever-pull responses with a 5-min tim e-out after each injection. Midazolam (1.0 mg/kg) maintained an orderl y spaced within-day pattern of injections and low but stable, daily ra tes of self-injection over 30 or more days (e.g. <20 injections/day). Sequential substitution of saline and then midazolam produced rapid ex tinction and then reinstatement of responding at the same stable rate. in subsequent manipulations, a range of lower doses of midazolam (0.0 156-0.25 mg/kg) were also shown to reinstate self-injection responding after extinction on saline; however, both chronic and acute dose mani pulations indicated that dose-regulation was poor. Chronic self-inject ion of the high dose (1.0 mg/kg) but not lower doses produced a suppre ssion in responding maintained by food pellet delivery. Chronic self-i njection of 1.0 and 0.25 mg/kg midazolam produced physical dependence as reflected in classic benzodiazepine spontaneous and flumazenil-prec ipitated withdrawal syndromes, including tremor, vomiting and, in one instance, seizure. The stable, low-rate self-injection of midazolam, w ith concurrent development of physical dependence, demonstrated in the present study may provide a useful model system for investigating fac tors which contribute to long-term inappropriate use of benzodiazepine s by physically dependent patients.