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Varying magnitude of GABAergic recurrent inhibition enhancement by different sedative/anesthetic agents in dorsal and ventral hippocampus.

Georgopoulos P, Petrides T, Kostopoulos G, Papatheodoropoulos C

Department of Physiology, Medical School, University of Patras, 26 504 Patras, Greece.

The positive modulation of the GABA(A) receptor (GABA(A)R) is presumably one of the main mechanisms by which several sedatives mediate their actions in the central nervous system. This modulation appears to depend on the presence of alpha and beta GABA(A)R subunits, whose distinct expression in dorsal and ventral hippocampus has been recently shown. Using population spike recordings from the CA1 area of dorsal (DHS) and ventral (VHS) hippocampal slices we compared the effects of seven sedative/anesthetic drugs (diazepam, midazolam, phenobarbital, propofol, pentobarbital, thiopental and alfaxalone) on the GABAergic recurrent inhibition (RI) between the two hippocampal poles. The strength and duration of RI was quantified by measuring an antidromic stimulation-induced suppression of the orthodromic population spike at varying inter-pulse intervals. All drugs enhanced RI in both DHS and VHS but high concentrations of barbiturates and alfaxalone prolonged RI considerably more compared to benzodiazepines or low doses of barbiturates and propofol. Furthermore, the drug-induced prolongation of RI was significantly greater in DHS than in VHS. Thus, RI was enhanced by thiopental (50 microM), alfaxalone (2.5 microM) and pentobarbital (50 microM) up to 150 ms, 150 ms and 270 ms respectively in DHS, and up to 70 ms, 100 ms and 150 ms respectively in VHS. In addition, under GABA(B) receptor blockade, thiopental (100 microM) and alfaxalone (10 microM) prolonged GABA(A)R-mediated RI significantly more in DH (up to 900 ms) than in VH (up to 430 ms and 600 ms respectively). This finding provides support to the notion of diversification of intrinsic organization along the septotemporal axis of the hippocampus. Finally, an interesting link was revealed between the magnitude of drug-induced enhancement of RI and the reported sedative potency of the drugs used, suggesting that deep sedation and anesthesia may involve prolongation of GABAergic inhibition.

Published 18 April 2008 in Brain Res, 1207: 43-59.
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