Zolpidem self-injection with concurrent physical dependence under conditions of long-term continuous availability in baboons

Abstract

Intravenous zolpidem self-injection, and the concurrent development of physical dependence under conditions of continuous drug availability, was characterized in three baboons. Previously, under similar conditions, 1.0 mg/kg midazolam maintained low, but stable, daily rates of self-injection (e.g. less than 20 injections/day) over 30 or more days and resulted in the development of physical dependence in baboons. In the current experiments, saline and zolpidem (1.0 mg/kg) were available for self-injection under a fixed-ratio (FR-30) schedule of lever-pull responses with a 5 min time-out after each injection. Saline maintained only low levels of responding (i.e. less than five injections per day). Zolpidem maintained an orderly spaced within-day pattern of injections and daily rates of self-injection were higher than saline (i.e. 10 or more injections per day). Daily rates of zolpidem self-injection were relatively stable in two baboons, and increased over time in the third baboon. Substitution of saline for zolpidem produced a rapid decrease in responding that remained low (i.e. less than five injections per day) in all three baboons. Chronic self-injection of zolpidem produced an increase in responding maintained by food pellet delivery and an increase in body weights. Administration of flumazenil (0.1-1.0 mg/kg, i.v.) after at least 35 days of zolpidem self-injection produced postures and behavioral signs typical of a classic flumazenil-precipitated benzodiazepine withdrawal syndrome. Substitution of saline after chronic zolpidem self-injection produced a time-limited spontaneous withdrawal syndrome. Behavioral signs and postures were similar to those observed during flumazenil-precipitated withdrawal and were most prominent during the first 8 days after zolpidem was discontinued. Therefore, like midazolam, zolpidem maintained self-injection and physical dependence developed under conditions of long-term continuous availability.