title: Chronic benzodiazepine-induced reduction in GABA(A) receptor-mediated synaptic currents in hippocampal CA1 pyramidal neurons prevented by prior nimodipine injection.
abstract: One week oral flurazepam (FZP) administration in rats results in reduced GABA(A) receptor-mediated synaptic transmission in CA1 pyramidal neurons associated with benzodiazepine tolerance in vivo and in vitro. Since voltage-gated calcium channel (VGCC) current density is enhanced twofold during chronic FZP treatment, the role of L-type VGCCs in regulating benzodiazepine-induced changes in CA1 neuron GABA(A) receptor-mediated function was evaluated. Nimodipine (10 mg/kg, i.p.) or vehicle (0.5% Tween 80, 2 ml/kg) was injected 1 day after ending FZP treatment and 24 h prior to hippocampal slice preparation for measurement of mIPSC characteristics and in vitro tolerance to zolpidem. The reduction in GABA(A) receptor-mediated mIPSC amplitude and estimated unitary channel conductance measured 2 days after drug removal was no longer observed following prior nimodipine injection. However, the single nimodipine injection failed to prevent in vitro tolerance to zolpidem's ability to prolong mIPSC decay in FZP-treated neurons, suggesting multiple mechanisms may be involved in regulating GABA(A) receptor-mediated synaptic transmission following chronic FZP administration. As reported previously in recombinant receptors, nimodipine inhibited synaptic GABA(A) receptor currents only at high concentrations (>30 muM), significantly greater than attained in vivo (1 muM) 45 min after a single antagonist injection. Thus, the effects of nimodipine were unlikely to be related to direct effects on GABA(A) receptors. As with nimodipine injection, buffering intracellular free [Ca(2+)] with BAPTA similarly prevented the effects on GABA(A) receptor-mediated synaptic transmission, suggesting intracellular Ca(2+) homeostasis is important to maintain GABA(A) receptor function. The findings further support a role for activation of L-type VGCCs, and perhaps other Ca(2+)-mediated signaling pathways, in the modulation of GABA(A) receptor synaptic function following chronic benzodiazepine administration, independent of modulation of the allosteric interactions between benzodiazepine and GABA binding sites.
authors.affiliation: Department of Physiology and Pharmacology, and the Cellular and Molecular Neurobiology Program, University of Toledo College of Medicine, Health Science Campus, 3000 Arlington Avenue, Mailstop 1008, Toledo, OH 43614, USA.
authors.forename: K
authors.initials: K
authors.lastname: Xiang
authors.forename: E I
authors.initials: EI
authors.lastname: Tietz
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000378:metabolism / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects; D020013:Calcium Signaling / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005479:Flurazepam / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009553:Nimodipine / Q000378:metabolism / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D017729:Presynaptic Terminals / Q000187:drug effects*; D017966:Pyramidal Cells / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects*; D000077334:Zolpidem
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D002614:Chelating Agents; D018756:GABA Antagonists; D018757:GABA Modulators; D006993:Hypnotics and Sedatives; D011725:Pyridines; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D004533:Egtazic Acid; D009553:Nimodipine; D000077334:Zolpidem; D005479:Flurazepam; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid