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

Abstract

Rationale Although abuse of benzodiazepines alone is uncommon, it is high in polydrug abusers, including those who abuse primarily opioids or stimulants. Objectives This study investigated whether drugs that are abused (e.g., amphetamine) or have mechanisms of action similar to abused drugs (e.g., morphine) alter the discriminative stimulus effects of the benzodiazepine midazolam. Methods 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 GABAB receptors). Results 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. Conclusions 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.

Mechanisms for the Specific Properties of γ‐Hydroxybutyrate in Brain

“…Other psychopharmacological properties reported for GHB (anxiolysis, euphoria, prosocial facilitation) have apparently never been reported for pure GABA‐B agonists . Baclofen is not a drug of abuse like GHB, which is self‐administered in monkeys and laboratory animals, with low reinforcing effects compared to benzodiazepines . Some cases of physical dependence and withdrawal syndromes have been reported for GHB, several reports have described a positive discrimination in pigeons between baclofen or GABA‐B receptor modulators and GHB …”

“…154 Baclofen is not a drug of abuse like GHB, which is self-administered in monkeys and laboratory animals, with low reinforcing effects compared to benzodiazepines. 155,156 Some cases of physical dependence and withdrawal syndromes have been reported for GHB, 157 several reports have described a positive discrimination in pigeons between baclofen or GABA-B receptor modulators and GHB. 154 A series of GHB analogs were synthetized in order to discriminate between GHB and GABA-B effects with substances that were not GABA precursors.…”

Quantitative pharmacological analyses of the interaction between flumazenil and midazolam in monkeys discriminating midazolam: Determination of the functional half life of flumazenil

“…The female monkeys (subjects HE, JA, LI and NI) had a history of discriminating midazolam from vehicle while responding under a schedule of stimulus-shock termination (Gerak and France, 2011; Zanettini et al, 2013). The male monkey (subject KI) discriminated midazolam from vehicle under a schedule of food presentation immediately before this experiment (Bai et al, 2011). All the animals used in these studies were maintained in accordance with the Institutional Animal Care and Use Committee, The University of Texas Health Science Center at San Antonio, Texas, USA, and the 2013 Guide for the Care and Use of Laboratory Animals (Institute of Laboratory Animal Resources on Life Science, National Research Council, National Academy of Sciences).…”

Acute tolerance to chlordiazepoxide qualitatively changes the interaction between flumazenil and pregnanolone and not the interaction between flumazenil and midazolam in rhesus monkeys discriminating midazolam11These studies were supported by United States Public Health Service Grant R01 DA009157 and a Senior Scientist Award [Grant K05 DA17918 (CPF)]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Drug Abuse or the

“…Two monkeys (HE and NI) were trained previously to discriminate midazolam while responding under a schedule of stimulus-shock termination (Gerak and France, 2011, 2012). Prior to this study, the third monkey (JA) discriminated midazolam while responding under a schedule of food presentation (Bai et al, 2011);the training dose was decreased and the schedule changed to stimulus-shock termination before this study. Animals used in these studies were maintained in accordance with the Institutional Animal Care and Use Committee, The University of Texas Health Science Center at San Antonio, Texas, USA, and with the 1996 Guide for the Care and Use of Laboratory Animals (Institute of Laboratory Animal Resources on Life Science, National Research Council, National Academy of Sciences).…”