title: Behavioral and toxicological effects of propofol.
abstract: There is increasing concern about abuse of propofol, a widely-used surgical anesthetic and sedative that is currently not a controlled substance. The purpose of this study was to establish a rat model of the psychoactive effect of subanesthetic doses of propofol that could be useful for confirming abuse liability and for studying mechanisms of propofol abuse. Sprague-Dawley rats were trained to discriminate propofol (10 mg/kg, intraperitoneally) from vehicle (2% methylcellulose). Carisoprodol (100 mg/kg), chlordiazepoxide (10 mg/kg), and dizocilpine (0.1 mg/kg) were tested for substitution for the discriminative-stimulus effects of propofol (10 mg/kg), whereas pentylenetetrazol (10 mg/kg) was tested for antagonism of the discriminative-stimulus effects. Propofol (10 mg/kg) was tested for substitution in rats trained to discriminate carisoprodol from vehicle. Carisoprodol produced 59% propofol-appropriate responding, chlordiazepoxide produced 65% propofol-appropriate responding, and dizocilpine produced 34% propofol-appropriate responding. Pentylenetetrazol decreased propofol-appropriate responding to 41%. Propofol produced 52% carisoprodol-appropriate responding. Mortality rate during training of propofol (10 mg/kg) was 38%. Postmortem examination revealed cardiovascular abnormalities similar to those observed in propofol-infusion syndrome in humans. The results demonstrate that propofol can be trained as a discriminative stimulus. Its discriminative-stimulus effects were more similar to compounds promoting γ-aminobutyric acid-A receptor activity than to a compound inhibiting N-methyl-d-aspartate receptor activity. As propofol has discriminative-stimulus effects similar to known drugs of abuse, and occasions a high-mortality rate, its potential for continued abuse is of particular concern.
authors.affiliation: Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX 76107-2699, USA. michael.gatch@unthsc.edu
authors.forename: Michael B
authors.initials: MB
authors.lastname: Gatch
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Forster
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002328:Carisoprodol / Q000494:pharmacology / Q000506:poisoning / Q000633:toxicity*; D002492:Central Nervous System Depressants / Q000494:pharmacology / Q000506:poisoning / Q000633:toxicity*; D004192:Discrimination, Psychological; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018756:GABA Antagonists / Q000494:pharmacology; D006993:Hypnotics and Sedatives / Q000494:pharmacology / Q000506:poisoning / Q000633:toxicity*; D008297:Male; D009043:Motor Activity; D009125:Muscle Relaxants, Central / Q000494:pharmacology / Q000506:poisoning / Q000633:toxicity*; D010433:Pentylenetetrazole / Q000494:pharmacology; D015742:Propofol / Q000494:pharmacology / Q000506:poisoning / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
chemical_list: D002492:Central Nervous System Depressants; D018756:GABA Antagonists; D006993:Hypnotics and Sedatives; D009125:Muscle Relaxants, Central; D016194:Receptors, N-Methyl-D-Aspartate; D002328:Carisoprodol; D016291:Dizocilpine Maleate; D010433:Pentylenetetrazole; D015742:Propofol