The discriminative stimulus effects of midazolam are resistant to modulation by morphine, amphetamine, dizocilpine, and γ-butyrolactone in rhesus monkeys

Abstract

Although abuse of benzodiazepines alone is uncommon, it is high in polydrug abusers, including those who primarily use opioids or stimulants. This study investigated whether drugs that are abused (e.g., amphetamine) or drugs that have mechanisms of action similar to abused drugs (e.g., morphine) alter the discriminative stimulus effects of the benzodiazepine midazolam. Three rhesus monkeys discriminated 0.56 mg/kg of midazolam while responding under a fixed-ratio 10 schedule of food presentation. Dose-effect curves were determined for midazolam alone and in the presence of morphine (opioid receptor agonist), amphetamine (dopamine receptor indirect agonist), dizocilpine (N-methyl-D: -aspartic acid receptor antagonist), or γ-butyrolactone (prodrug of γ-hydroxybutyrate, which acts primarily at GABA(B) receptors). Doses of midazolam larger than 0.32 mg/kg produced ≥80% midazolam-lever responding. When administered alone, morphine, amphetamine, dizocilpine, and γ-butyrolactone did not produce midazolam-lever responding, although large doses of each drug eliminated responding; when administered in combination with midazolam, they did not alter the discriminative stimulus effects of midazolam up to doses that markedly decreased response rates. The current study demonstrates a lack of modulation of the discriminative stimulus effects of midazolam by morphine, amphetamine, dizocilpine, and γ-butyrolactone. Other effects of benzodiazepines, such as their reinforcing effects, might be altered by these other drugs, or benzodiazepines might modulate the discriminative stimulus or reinforcing effects of the other drugs, which might contribute to the relatively high incidence of benzodiazepine abuse among polydrug abusers.