Etomidate blocks LTP and impairs learning but does not enhance tonic inhibition in mice carrying the N265M point mutation in the beta3 subunit of the GABA(A) receptor.

Enhancement of tonic inhibition mediated by extrasynaptic α5-subunit containing GABAA receptors (GABAARs) has been proposed as the mechanism by which a variety of anesthetics, including the general anesthetic etomidate, impair learning and memory. Since α5 subunits preferentially partner with ß3 subunits, we tested the hypothesis that etomidate acts through ß3-subunit containing GABAARs to enhance tonic inhibition, block LTP, and impair memory. We measured the effects of etomidate in wild type mice and in mice carrying a point mutation in the GABAAR ß3-subunit (ß3-N265M) that renders these receptors insensitive to etomidate. Etomidate enhanced tonic inhibition in CA1 pyramidal cells of the hippocampus in wild type but not in mutant mice, demonstrating that tonic inhibition is mediated by ß3-subunit containing GABAARs. However, despite its inability to enhance tonic inhibition, etomidate did block LTP in brain slices from mutant mice as well as in those from wild type mice. Etomidate also impaired fear conditioning to context, with no differences between genotypes. In studies of recombinant receptors expressed in HEK293 cells, α5ß1γ2L GABAARs were insensitive to amnestic concentrations of etomidate (1 µM and below), whereas α5ß2γ2L and α5ß3γ2L GABAARs were enhanced. We conclude that etomidate enhances tonic inhibition in pyramidal cells through its action on α5ß3-containing GABAA receptors, but blocks LTP and impairs learning by other means - most likely by modulating α5ß2-containing GABAA receptors. The critical anesthetic targets underlying amnesia might include other forms of inhibition imposed on pyramidal neurons (e.g. slow phasic inhibition), or inhibitory processes on non-pyramidal cells (e.g. interneurons).

Chlorpromazine prolongs the deactivation of N-methyl-D-aspartate-induced currents in cultured rat hippocampal neurons.

The effect of chlorpromazine (CPZ) on deactivation of N-methyl-D-aspartate (NMDA)-induced currents was studied in the whole-cell configuration of the patch-clamp technique in cultured rat hippocampal neurons. We report that CPZ (at 30-1000 microM) strongly slowed down the deactivation process in a dose-dependent manner. At high CPZ concentration (1 mM), the NMDA-elicited currents were insensitive to NMDA removal as long as CPZ was present and deactivated only when both NMDA and CPZ were washed out. CPZ by itself did not activate any current. These data indicate that one of CPZ actions is to stabilise the open conformation of NMDA receptors probably by fixing it in the bound state. This CPZ effect may be important as the synaptic currents represent mainly the deactivation process.

Differential effects of chlorpromazine on ionotropic glutamate receptors in cultured rat hippocampal neurons.

The effect of a widely used phenothiazine, chlorpromazine (CPZ) on ionotropic glutamate receptors was investigated using the patch-clamp technique in cultured rat hippocampal neurons. The non-N-methyl-D-aspartate (NMDA) receptors were insensitive to CPZ. The current responses to NMDA showed a wide range of variability of both the rate and the extent of desensitization. The responses characterized by fast and profound desensitization were strongly inhibited by 30 microM CPZ. The effectiveness of block of NMDA responses was clearly correlated with the apparent time constant of the desensitization onset. The extent of desenstitization was found to be increased by CPZ. We conclude that CPZ inhibits the NMDA receptors and propose that the sensibility to CPZ may depend both on the subunit composition and on the state of receptor modulation by intracellular factors.

Alkylresorcinols in fruit pulp and leaves of Ginkgo biloba L.

These studies were undertaken to characterise resorcinolic lipids (5-n-alk(en)ylresorcinols) composition and to determine their seasonal fluctuations in fruit pulp and leaves of Ginkgo biloba L. Resorcinolic lipid concentrations were consistently higher in fruit pulp than in leaves. In pulp, several mono- and di-unsaturated homologs of alkylresorcinols were the predominant group of analysed lipids. Contrary to the fruit pulp, only 5-n-pentadecylresorcinol was demonstrated in leaves. Initially, the alkylresorcinol's content both in pulp and leaves increased until June-July and decreased following seeds ripening. This trend continued until senescence of leaves in late September and October.