Toxicology Letters 100 – 101 (1998) 217 – 224 General anaesthetics and their effects on GABA A receptor desensitization B.A. Orser *, L.C. McAdam, S. Roder, J.F. MacDonald The Anaesthesia Research Laboratory, Room 3318, Medical Sciences Building, Uniersity of Toronto, 1 King’s College Circle, Toronto, Ont. M5S IA8, Canada Accepted 7 May 1998 Abstract 1. Intravenous anaesthetics, including propofol and thiopental have at least three distinct effects on GABA A receptor function. 2. Low concentrations of these drugs enhance the amplitude of currents evoked by sub-saturating concentrations of GABA whereas higher concentrations directly activate the receptor in the absence of GABA. 3. Propofol and some barbiturates also decrease the rate and extent of desensitization as indicated by a prolongation in the decay of currents evoked by saturating concentrations of GABA. 4. In contrast, sedative benzodiazepines that lack general anaesthetic properties do not directly activate the GABA A receptor. 5. In addition, benzodiazepines such as midazolam, have no effect on desensitization when examined in the presence of saturating concentrations of GABA. 6. Here, we discuss the effects of intravenous general anaesthetic on desensitization of the GABA A receptor. © 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Desensitization; General anaesthetics; GABA A receptor function 1. Introduction Barbiturates, benzodiazepines and propofol are clinically important drugs that exert their neu- rodepressive effects, in part, by enhancing in- hibitory synaptic transmission (Tanelian et al., 1993). Although the GABA A receptor is likely the primary target for these drugs, differences in their clinical properties suggest dissimilar mechanisms of action. For example, propofol and barbiturates induce an anaesthetic state characterized by an inability to respond to noxious stimuli. In con- trast, it is nearly impossible to induce such surgi- cal anaesthesia with benzodiazopines. Thus, sedative benzodiazopines are not considered gen- eral anaesthetics. As well, tolerance develops to * Corresponding author. Present address: Department of Anaesthesia, Sunnybrook, Health Science Centre, 2075 Bayview Avenue, Toronto, Ont., Canada, M4N 3M5. Tel.: +1 416 9780574; fax: +1 416 9784940; e-mail: bever- ley.orser@utoronto.ca 0378-4274/98/$ - see front matter © 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S0378-4274(98)00188-X