The role of L-type voltage-gated calcium channels in hippocampal CA1 neuron glutamate and GABA-A receptor-mediated synaptic plasticity following chronic benzodiazepine administration
Clinicians require caution prescribing benzodiazepines for a prolonged period of time because of the development of functional tolerance and dependence. The objective of these dissertation studies was to evaluate the role of L-type VGCC in mediating glutamate receptors and GABAA receptor functional changes in the expression of benzodiazepine tolerance and dependence following a 1-week FZP oral treatment regimen in rats. Initially, AMPA receptor-mediated mEPSC amplitude in hippocampal CA1 neurons was evaluated in rats withdrawn from 1-week FZP administration, using whole-cell electrophysiological recordings, and was found to correlate with benzodiazepine withdrawal-anxiety in rats measured using an elevated plus-maze. A compensatory role of NMDA receptor functional down-regulation was further identified as a counterbalance to AMPA receptor-mediated neuronal hyper-excitation. Following pharmacological antagonism of NMDA receptor and VGCC function, a role for regulation of L-type VGCCs, but not NMDA receptors, in mediating enhanced AMPA receptor function and benzodiazepine withdrawal anxiety was identified. Further studies concentrated on the regulation of L-type VGCC function following chronic benzodiazepine administration using whole-cell voltage-clamp method. The temporal pattern of L-type VGCC functional regulation was evaluated following chronic benzodiazepine administration. The direct concentration- and use-dependent effect of the benzodiazepines to affect L-type VGCC currents was also investigated. Based on the evidence of L-type VGCC function changes and its role in mediating AMPA receptor synaptic plasticity following chronic FZP administration, the relation between L-type VGCC and GABA receptor was further explored. Pharmacological antagonism was again applied for investigating the role of L-type VGCC in mediating GABAA receptor function using whole-cell ctrophysiological recordings of GABAA receptor-mediated currents. GABAA receptor channel kinetics and single channel conductance was evaluated after L-type VGCC antagonist application both in vivo and in vitro. In all, these studies would give the insight of an L-type VGGG-dependent Ca2+ signaling mechanism in differentially mediating specific glutamate receptors and GABAA receptor synaptic changes that are associated with benzodiazepine tolerance and dependence. To serve as the foundation for more mechanistic studies, a model of the cellular mechanisms underlying benzodiazepine tolerance and dependence was proposed in these dissertation studies based on the present findings, and on past evidence from our laboratory and others.
School:University of Toledo Health Science Campus
School Location:USA - Ohio
Source Type:Master's Thesis
Keywords:benzodiazepine l vgccs hippocampus ampa receptor dependence tolerance gaba
Date of Publication:01/01/2007