Whole-cell patch-clamp recordings from acutely isolated CA1 pyramidal neurons showed that CBX exerts a selective dose-dependent inhibition of NMDA-evoked currents with an IC50 = 104 mu M. Thus the widely used gap junction uncoupler CBX acts as an antagonist at NMDA receptors and consequently impairs the induction of LTP. (C) 2008 Elsevier Ltd. find more All rights reserved.”
“Whereas advances in the molecular biology of GABA(A) receptor complex using knock-out and knock-in mice have been valuable in unveiling the structure, composition, receptor assembly, and several functions of different GABA(A) receptor subtypes, the mechanism(s) underlying benzodiazepine

(BZ) tolerance and withdrawal remain poorly understood. Studies using specific GABA(A) receptor subunit knock-in mice suggest that tolerance to sedative action of diazepam requires long-term activation of alpha EPZ5676 purchase 1 and alpha 5 GABA(A) receptor subunits. We investigated the role of long-term activation of these GABA(A) receptor subunits during anticonvulsant tolerance using high affinity and high intrinsic efficacy ligands for GABA(A) receptors expressing the alpha 5 subunit (imidazenil) or alpha 1 subunit (zolpidem), and a non-selective BZ recognition site ligand (diazepam). We report here that long-term activation of GABA(A) receptors by zolpidem

and diazepam but not by imidazenil elicits anticonvulsant tolerance. Although anticonvulsant cross-tolerance occurs between diazepam and zolpidem, there is no cross-tolerance between imidazenil and diazepam or zolpidem. Furthermore, PTK6 diazepam or zolpidem long-term treatment

decreased the expression of mRNA encoding the alpha 1 GABA(A) receptor subunit in prefrontal cortex by 43% and 20% respectively. In addition, diazepam but not zolpidem long-term treatment produced a 30% increase in the expression of the alpha 5 GABA(A) receptor subunit mRNA in prefrontal cortex. In contrast, imidazenil which is devoid of anticonvulsant tolerance does not elicit significant changes in the expression of alpha 1 or alpha 5 GABA(A) receptor subunit. These findings suggest that long-term activation of GABA(A) receptors containing the alpha 1 or other subunits but not the alpha 5 receptor subunit is essential for the induction of anticonvulsant tolerance. (C) 2008 Elsevier Ltd. All rights reserved.”
“Mitragynine is a major indole alkaloid isolated from the Thai medicinal plant Mitragyna speciosa that has opium-like properties, although its chemical structure is quite different from that of morphine. We attempted to develop novel analgesics derived from mitragynine, and thus synthesized the ethylene glycol-bridged and C10-fluorinated derivative of mitragynine, MGM-9 [(E)-methyl 2-(3-ethyl-7a,12a-(epoxyethanoxy)-9-fluoro-1,2,3,4,6,7,12,12b-octahydro-8-methoxyindolo[2,3-a]quinolizin-2-yl)-3-methoxyacrylate].