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 midazolam self-injection and the concurrent development of physical dependence under conditions of continuous drug availability. Baboons (n=6) i.v. self-injected midazolam under conditions of continuous availability under a fixed-ratio 30 schedule of lever-pull responses with a 5-min time-out after each injection. Midazolam (1.0 mg/kg) maintained an orderly spaced within-day pattern of injections and low, but stable, daily rates of self-injection over 30 or more days (e.g. <20 injections/day). Sequential substitution of saline and then midazolam produced rapid extinction and then reinstatement of responding at the same stable rate. In subsequent manipulations, a range of lower doses of midazolam (0.0156-0.25 mg/kg) were also shown to reinstate self-injection responding after extinction on saline; however, both chronic and acute dose manipulations indicated that dose-regulation was poor. Chronic self-injection of the high dose (1.0 mg/kg) but not lower doses produced a suppression in responding maintained by food pellet delivery. Chronic self-injection of 1.0 and 0.25 mg/kg midazolam produced physical dependence as reflected in classic benzodiazepine spontaneous and flumazenil-precipitated withdrawal syndromes, including tremor, vomiting and, in one instance, seizure. The stable, low-rate self-injection of midazolam, with concurrent development of physical dependence, demonstrated in the present study may provide a useful model system for investigating factors which contribute to long-term inappropriate use of benzodiazepines by physically dependent patients.
Weerts
E M
EM
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
Kaminski
B J
BJ
Griffiths
R R
RR
D000818:Animals; D014151:Anti-Anxiety Agents / Q000633:toxicity*; D005247:Feeding Behavior / Q000187:drug effects; D005442:Flumazenil; D008297:Male; D008874:Midazolam / Q000633:toxicity*; D010215:Papio; D012646:Self Administration; D013375:Substance Withdrawal Syndrome; D019966:Substance-Related Disorders
D014151:Anti-Anxiety Agents; D005442:Flumazenil; D008874:Midazolam