Propofol modulates activation and desensitization of GABAA receptors in cultured murine hippocampal neurons

Abstract

Propofol (2,6 di-isopropylphenol) is an alkyphenol recently introduced for use as a general anesthetic. The modulation of GABAA receptor activation and desensitization by propofol was studied using a rapid perfusion system and whole-cell voltage-clamp recordings from mouse hippocampal neurons. The effects of concentrations of propofol used clinically on single-channel and synaptic currents were also examined. Propofol evoked current responses (EC50 = 61 microM) and shifted the dose-response curve of GABA-activated current to the left without altering the maximum of the GABA response. Preincubation with propofol and GABA led to desensitization of the GABA response (EC50 = 454 microM and 23 microM, respectively). Saturating concentrations of GABA (600 microM) evoked currents that peaked and then declined in a biexponential fashion with fast and slow time constants of tau f = 1.0 sec and tau s = 3.5 sec. Propofol (10 microM) did not change the amplitude of the peak response but decreased the rates of decay approximately 1.5-fold and enhanced the steady-state current proportionately. Recovery from desensitization was also biexponential (tau f = 11 sec, tau s = 69 sec) but not influenced by propofol. Single-channel recordings from outside-out patches demonstrated that both propofol and GABA activated channels with a 30 pS and 21 pS open state. Propofol increased the frequency but not the duration or conductance of GABA-activated events. Miniature inhibitory postsynaptic currents (mlPSCs) were evoked by the application of hypertonic sucrose to the cell soma. Propofol (2 microM) prolonged the decay time of mlPSCs to an extent similar to which it increased the open probability of GABA-activated channels (2.3- vs 3-fold). A sequential model, based on a previous scheme of GABA receptor gating (Weiss and Magelby, 1989), is presented to summarize propofol's actions on GABAA receptor function. We show through simulation that the model reliably reproduced the whole-cell tracings. Our results indicate that propofol's neurodepressive actions will be associated with enhancement of inhibitory synaptic transmission.

Retrograde Regulation of GABA Transmission by the Tonic Release of Oxytocin and Endocannabinoids Governs Postsynaptic Firing

“…Our results would seem to be consistent with these latter findings, but whether this increase in synaptic strength in facilitating trains is attributable to a relief from postsynaptic receptor desensitization as at auditory synapses (Brenowitz and Trussell, 2001;Wong et al, 2003) is unclear. A slow desensitization of GABA A receptors during repetitive activation has been described in other systems (Orser et al, 1994;Jones and Westbrook, 1996;Overstreet et al, 2000) and could conceivably contribute to the depression observed here when P r is high. It is also equally plausible that, by blocking CB 1 receptors, we may be relieving an eCB-driven, Ca 2ϩ -dependent inhibition of release machinery (Hsu et al, 1996;Bellingham and Walmsley, 1999) that is recruited selectively during repetitive synaptic activation.…”

Potentiation, activation and blockade of GABAA receptors of clonal murine hypothalamic GT1‐7 neurones by propofol

“…A similar phenomenon has been seen in experiments on chromaffin cells and dorsal root ganglion neurones (Robertson, 1989) with pentobarbitone and etomidate. More recently it has also been observed in experiments involving high concentrations of propofol in embryonic murine hippocampal neurones (Orser et al, 1994).…”

“…In addition, the general anaesthetic directly activates GABAA receptors at higher concentrations, relevant to total intravenous anaesthesia (Hales & Lambert, 1991;Hara et al, 1993;Orser et al, 1994). Numerous other compounds with general anaesthetic properties potentiate the actions of GABA and at higher doses directly activate GABAA receptors.…”

Inhibition by propofol (2,6 di‐isopropylphenol) of the N‐methyl‐D‐aspartate subtype of glutamate receptor in cultured hippocampal neurones

“…For example, the post-operative dreams, mood disturbances, and hallucinations observed following propofol anaesthesia, are more commonly associated with the dissociative anaesthetic ketamine (Young, 1988;Suresh, 1991;Oxorn et al, 1994). Propofol also blocks several non-ligand gated channels and exerts opposing actions on excitatory and inhibitory neurotransmitter receptors (Frenkel & Urban, 1991;Hales & Lambert, 1992;Magnelli et al, 1992;Veintemilla et al, 1992;Wachtel & Wegrzynowicz, 1992, Baum 1993Hara et al, 1993;Dilger et al, 1994;Olcese et al, 1994;Orser et al, 1994). Modulation of these receptors might also contribute to the clinical properties of propofol.…”