Discriminative stimulus effects of flumazenil in untreated and in diazepam-treated rhesus monkeys

Rationale: Long-term use of benzodiazepine agonists can have adverse effect s (e.g., development of dependence), thereby limiting their clinical useful ness. Objectives: The goal of the current study was to examine the discrimi native stimulus effects of flumazenil in untreated and diazepam-treated mon keys to determine whether this type of procedure could be used to examine b enzodiazepine dependence. Methods: Flumazenil (0.32 mg/kg s.c.) was establi shed as a discriminative stimulus in eight monkeys receiving 5.6 mg/kg/day of diazepam (p.o.); four responded under a fixed ratio (FR)5 schedule of st imulus-shock termination (SST) and four responded under a FR5 schedule of f ood presentation. For comparison, 1.0 mg/kg flumazenil (s.c.) was establish ed as a discriminative stimulus in four untreated monkeys responding under a FR5 schedule of SST. Results: Flumazenil dose-dependently increased respo nding on the flumazenil-appropriate lever in all monkeys. In diazepam-treat ed monkeys, Ro 15-4513, ethyl beta-carboline-3-carboxylate and bretazenil s ubstituted for flumazenil with pentylenetetrazole substituting in some monk eys; other drugs failed to substitute for flumazenil. Acute administration of 10.0 mg/kg diazepam (s.c.) shifted the flumazenil dose-effect curve thre efold to the right of the control dose-effect curve. Temporary suspension o f diazepam treatment produced a time-related increase in flumazenil-lever r esponding that was reversed by diazepam. In untreated monkeys, midazolam su bstituted for flumazenil, with other drugs, including those with primary me chanisms of action at non-gamma-aminobutyric acid(A) receptors, substitutin g in some monkeys. Ro 15-4513 did not substitute in any untreated monkey. C onclusions: The flumazenil discriminative stimulus appears to be pharmacolo gically selective in treated monkeys with only negative and low efficacy po sitive modulators substituting for flumazenil; in contrast, a variety of dr ugs substitute for flumazenil in untreated monkeys. This apparent differenc e in selectivity suggests that diazepam treatment modifies the flumazenil d iscriminative stimulus perhaps due to the development of dependence.