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.