Abstract
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) IV 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.
Original language | English (US) |
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Pages (from-to) | 70-81 |
Number of pages | 12 |
Journal | Psychopharmacology |
Volume | 135 |
Issue number | 1 |
DOIs | |
State | Published - 1998 |
Keywords
- Anxiolytics
- Baboons
- Benzodiazepines
- Drug abuse
- Feeding
- Flumazenil
- Midazolam
- Physical dependence
- Reinforcement
- Self-administration
- Withdrawal
ASJC Scopus subject areas
- Pharmacology