Although there is considerable uncertainty about the physiologic roles that neuronal nAChRs play in the central nervous system, their extraordinary sensitivity to general anesthetics, particularly the inhalational agents, suggests they may mediate some of the effects of general anesthetics at surgical, or even subanesthetic, concentrations.

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1 Glycine responses were studied under voltage clamp in Xenopus oocytes injected with cDNA encoding mammalian glycine receptor subunits and in rat medullary neurones. Bath application of glycine gave strychnine-sensitive currents which reversed close to the expected equilibrium potentials for chloride ions. The peak currents for the receptors expressed in oocytes fitted a Hill equation with EC50 = 215 + 5 uM and Hill coefficient nH= 1.70+0.05 (means+s.e.means). The peak currents from the receptors in medullary neurones fitted a Hill equation with EC50 = 30+1 gM and Hill coefficient nH= 1.76+0.08. The current-voltage relationship for the receptors expressed in oocytes showed strong outward rectification (with VV = -21+2 mV), while that for the glycine responses from the medullary neurones in symmetrical C1-was linear (with VrV= 3.2 + 0.6 mV). 2 Inhalational general anaesthetics, at concentrations close to their human minimum alveolar concentrations (MACs), potentiated responses to low concentrations of glycine. The potentiation observed with the recombinant receptors (between 60-220%) was approximately twice that found with the medullary neurones (between 40-80%). For both the recombinant receptors and the receptors in medullary neurones, the degree of potentiation increased in the order of methoxyfluranetsevoflurane

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1 The effects of ethanol, chloral hydrate and trichloroethanol upon the 5-HT3 receptor have been investigated by use of electrophysiological techniques applied to recombinant 5-HT3 receptor subunits (5-HT3R-A or 5-HT3R-As) expressed in Xenopus laevis oocytes. Additionally, the influence of tri-chloroethanol upon the specific binding of [3H]-granisetron to membrane preparations of HEK 293 cells stably transfected with the murine 5-HT3R-As subunit and 5-HT3 receptors endogenous to NG 108-15 cell membranes was assessed. 2 Ethanol (30-300mM), chloral hydrate (1-30mM) and trichloroethanol (0.3-10mM), produced a reversible, concentration-dependent, enhancement of 5-HT-mediated currents recorded from oocytes expressing either the 5-HT3R-A, or the 5-HT3R-As subunit. 3 Trichloroethanol (5 mM) produced a parallel leftward shift of the 5-HT concentration-response curve, reducing the ECm for 5-HT from 1 ± 0.04 M (n = 4) to 0.5 ± 0.01 gM (n = 4) for oocytes expressing the 5-HT3R-A. A similar shift, from 2.1 ± 0.05 gM (n = l1) to 1.3 ± 0.1 gM (n = 4), was observed in oocytes expressing the 5-HT3R-As subunit. Trichloroethanol (5 mM) had little or no effect upon the maximum current produced by 5-HT for either recombinant receptor. 4 Trichloroethanol (5 mM) similarly reduced the ECmo for 2-methyl-5-HT from 13 ± 0.4 gM (n = 4) to 4.6 ± 0.2 gM (n = 4) and from 15 ± 2 gM (n = 4) to 5 ± 0.4 gM (n = 4) for oocytes expressing the 5-HT3R-A and 5-HT3R-A, subunit respectively. Additionally, trichloroethanol (5 mM) produced a clear enhancement of the maximal current to 2-methyl-5-HT (expressed as a percentage of the maximal current to 5-HT) from 63 ± 0.7% (n = 4) to 101 ± 1.6% (n = 4) and from 9 ± 0.2% (n = 4) to 74 ± 2% (n = 4) for oocytes expressing the 5-HT3R-A and 5-HT3R-As subunit respectively. 5 Trichloroethanol (2.5 mM) had no effect upon the Kd, or B,., of specific [3H]-granisetron binding to membrane homogenates of NG 108-15 cells or HEK 293 cells. Similarly, competition for [3H]-granisetron binding by the 5-HT3 receptor antagonists ondansetron and tropisetron was unaffected. However, competition for [3H]-granisetron binding by the 5-HT3 receptor agonists, 5-HT, 2-methyl-5-HT and phenylbiguanide was enhanced by trichloroethanol (2.5 mM). 6 Unexpectedly, the competition for pH]-granisetron binding by the 5-HT3 receptor antagonist, quipazine, was enhanced by 2.5 mM trichloroethanol. Quipazine (1 nM-0.3 gM) antagonized 5-HT-evoked currents recorded from oocytes expressing the 5-HT3R-A subunit with an ICs of 18 ± 3 nM (n = 4). Additionally, quipazine (30 nM-0.3 jM) produced a small inward current which was greatly enhanced by 5 mM trichloroethanol and antagonized by 100 nM ondansetron. Collectively, these observations suggest that quipazine may act as a partial agonist. 7 The demonstration that a recombinant homo-oligomeric receptor, expressed in a foreign membrane, retains a sensitivity to alcohols, together with the sequencing of alcohol-insensitive 5-HT3 receptor subunits, may lead to a better definition of the alcohol binding sit...