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The discriminative stimulus effects of midazolam are resistant to modulation by morphine, amphetamine, dizocilpine, and γ-butyrolactone in rhesus monkeys.
Psychopharmacology (Berl). 2011 Oct; 217(4):495-504.P

Abstract

RATIONALE

Although abuse of benzodiazepines alone is uncommon, it is high in polydrug abusers, including those who primarily use opioids or stimulants.

OBJECTIVES

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.

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 GABA(B) 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.

Authors+Show Affiliations

Department of Pharmacology, The University of Texas Health Science Center at San Antonio, Mail Code 7764, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

21503606

Citation

Bai, Xiang, et al. "The Discriminative Stimulus Effects of Midazolam Are Resistant to Modulation By Morphine, Amphetamine, Dizocilpine, and Γ-butyrolactone in Rhesus Monkeys." Psychopharmacology, vol. 217, no. 4, 2011, pp. 495-504.
Bai X, France CP, Gerak LR. The discriminative stimulus effects of midazolam are resistant to modulation by morphine, amphetamine, dizocilpine, and γ-butyrolactone in rhesus monkeys. Psychopharmacology (Berl). 2011;217(4):495-504.
Bai, X., France, C. P., & Gerak, L. R. (2011). The discriminative stimulus effects of midazolam are resistant to modulation by morphine, amphetamine, dizocilpine, and γ-butyrolactone in rhesus monkeys. Psychopharmacology, 217(4), 495-504. https://doi.org/10.1007/s00213-011-2302-8
Bai X, France CP, Gerak LR. The Discriminative Stimulus Effects of Midazolam Are Resistant to Modulation By Morphine, Amphetamine, Dizocilpine, and Γ-butyrolactone in Rhesus Monkeys. Psychopharmacology (Berl). 2011;217(4):495-504. PubMed PMID: 21503606.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The discriminative stimulus effects of midazolam are resistant to modulation by morphine, amphetamine, dizocilpine, and γ-butyrolactone in rhesus monkeys. AU - Bai,Xiang, AU - France,Charles P, AU - Gerak,Lisa R, Y1 - 2011/04/19/ PY - 2010/09/04/received PY - 2011/04/06/accepted PY - 2011/4/20/entrez PY - 2011/4/20/pubmed PY - 2012/2/14/medline SP - 495 EP - 504 JF - Psychopharmacology JO - Psychopharmacology (Berl) VL - 217 IS - 4 N2 - RATIONALE: Although abuse of benzodiazepines alone is uncommon, it is high in polydrug abusers, including those who primarily use opioids or stimulants. OBJECTIVES: 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. 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 GABA(B) 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. SN - 1432-2072 UR - https://www.unboundmedicine.com/medline/citation/21503606/The_discriminative_stimulus_effects_of_midazolam_are_resistant_to_modulation_by_morphine_amphetamine_dizocilpine_and_γ_butyrolactone_in_rhesus_monkeys_ L2 - https://dx.doi.org/10.1007/s00213-011-2302-8 DB - PRIME DP - Unbound Medicine ER -