Establishing benzodiazepines as oral reinforcers: midazolam and diazepam self-administration in rhesus monkeys. 1994

R B Stewart, and G A Lemaire, and J D Roache, and R A Meisch
Department of Psychiatry and Behavioral Sciences, University of Texas, Houston Health Science Center, Houston.

Oral benzodiazepine self-administration was examined in four adult male rhesus monkeys with histories of ethanol- and pentobarbital-reinforced behavior. Drug solutions and vehicle were concurrently available for 3-hr each day under fixed-ratio (FR) reinforcement schedules. Initially, the monkeys rejected a midazolam solution (0.1 mg/ml) after direct substitution of the drug for an 8% ethanol solution. However, midazolam self-administration was subsequently established by using a fading procedure in which increasing amounts of drug (0.0125-0.2 mg/ml) were gradually added to an 8% ethanol solution, followed by gradual reduction of the ethanol concentration to zero. Midazolam was an effective reinforcer for three of four monkeys tested, i.e., responding that was maintained by the drug solution exceeded that maintained by the drug vehicle. The fourth monkey also self-administered midazolam but drug-maintained responding was not consistently greater than vehicle-maintained responding. The responding maintained by the drug was an inverted-U-shaped or bitonic function of midazolam concentration. The midazolam intake (in milligrams per kilogram) increased as a function of increases in the drug concentration. At the higher concentrations, marked sedative intoxication was observed. There was an inverse relationship between FR size (varied from FR 8 to FR 32) and the amount of drug self-administered. The three monkeys in which midazolam functioned as a reinforcer were then tested with diazepam (0.2 mg/ml), which maintained drug self-administration behavior on direct substitution for 0.2-mg/ml midazolam. Diazepam-maintained responding usually exceeded water responding as the diazepam concentration was increased to 0.8 mg/ml. These data demonstrate robust reinforcing effects of both "short-" and "long-acting" benzodiazepines delivered by the oral route.

UI MeSH Term Description Entries
D008253 Macaca mulatta A species of the genus MACACA inhabiting India, China, and other parts of Asia. The species is used extensively in biomedical research and adapts very well to living with humans. Chinese Rhesus Macaques,Macaca mulatta lasiota,Monkey, Rhesus,Rhesus Monkey,Rhesus Macaque,Chinese Rhesus Macaque,Macaca mulatta lasiotas,Macaque, Rhesus,Rhesus Macaque, Chinese,Rhesus Macaques,Rhesus Macaques, Chinese,Rhesus Monkeys
D008297 Male Males
D008874 Midazolam A short-acting hypnotic-sedative drug with anxiolytic and amnestic properties. It is used in dentistry, cardiac surgery, endoscopic procedures, as preanesthetic medication, and as an adjunct to local anesthesia. The short duration and cardiorespiratory stability makes it useful in poor-risk, elderly, and cardiac patients. It is water-soluble at pH less than 4 and lipid-soluble at physiological pH. Dormicum,Midazolam Hydrochloride,Midazolam Maleate,Ro 21-3981,Versed,Hydrochloride, Midazolam,Maleate, Midazolam,Ro 21 3981,Ro 213981
D012054 Reinforcement, Psychology The strengthening of a conditioned response. Negative Reinforcement,Positive Reinforcement,Psychological Reinforcement,Reinforcement (Psychology),Negative Reinforcements,Positive Reinforcements,Psychological Reinforcements,Psychology Reinforcement,Psychology Reinforcements,Reinforcement, Negative,Reinforcement, Positive,Reinforcement, Psychological,Reinforcements (Psychology),Reinforcements, Negative,Reinforcements, Positive,Reinforcements, Psychological,Reinforcements, Psychology
D003975 Diazepam A benzodiazepine with anticonvulsant, anxiolytic, sedative, muscle relaxant, and amnesic properties and a long duration of action. Its actions are mediated by enhancement of GAMMA-AMINOBUTYRIC ACID activity. 7-Chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one,Apaurin,Diazemuls,Faustan,Relanium,Seduxen,Sibazon,Stesolid,Valium
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D006851 Hydrochloric Acid A strong corrosive acid that is commonly used as a laboratory reagent. It is formed by dissolving hydrogen chloride in water. GASTRIC ACID is the hydrochloric acid component of GASTRIC JUICE. Hydrogen Chloride,Muriatic Acid,Acid, Hydrochloric,Acid, Muriatic,Chloride, Hydrogen
D000284 Administration, Oral The giving of drugs, chemicals, or other substances by mouth. Drug Administration, Oral,Administration, Oral Drug,Oral Administration,Oral Drug Administration,Administrations, Oral,Administrations, Oral Drug,Drug Administrations, Oral,Oral Administrations,Oral Drug Administrations
D000431 Ethanol A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in ALCOHOLIC BEVERAGES. Alcohol, Ethyl,Absolute Alcohol,Grain Alcohol,Alcohol, Absolute,Alcohol, Grain,Ethyl Alcohol
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia

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