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Benzodiazepine tolerance at GABAergic synapses on hippocampal CA1 pyramidal cells
Author(s) -
Zeng Xu J.,
Tietz Elizabeth I.
Publication year - 1999
Publication title -
synapse
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.809
H-Index - 106
eISSN - 1098-2396
pISSN - 0887-4476
DOI - 10.1002/(sici)1098-2396(19990315)31:4<263::aid-syn4>3.0.co;2-j
Subject(s) - flurazepam , gabaa receptor , hippocampal formation , postsynaptic current , bicuculline , gabaergic , excitatory postsynaptic potential , postsynaptic potential , neuroscience , chemistry , inhibitory postsynaptic potential , patch clamp , biophysics , electrophysiology , benzodiazepine , biology , receptor , biochemistry
Modulation of GABA function following 1 week oral administration of flurazepam (FZP) was investigated in chloride‐loaded, rat hippocampal CA1 pyramidal neurons. Rats were sacrificed 2 or 7 days after ending drug treatment, when anticonvulsant tolerance was present or absent in vivo , respectively . Spontaneous (s)IPSCs and miniature (m)IPSCs were recorded using whole‐cell voltage‐clamp techniques. s/mIPSCs were bicuculline‐sensitive, voltage‐dependent, and reversed their polarity at 0 mV, the predicted E Cl ‐. Comparisons of s/mIPSCs between FZP‐treated and control groups were made at V h = ‐90, ‐70, and ‐50 mV. The frequency of sIPSCs, but not mIPSCs, was significantly decreased in FZP‐treated neurons 2 days, but not 7 days, after FZP treatment, suggesting a decrease in interneuron activity. These conclusions were supported by the negative findings of additional studies of [ 3 H]GABA release from hippocampal slices and [ 3 H]GABA uptake from hippocampal synaptosomes. The lack of change in the paired‐pulse depression of GABA B ‐mediated IPSPs suggested that autoreceptor function was also not impaired following chronic FZP treatment. A large reduction in both sIPSC and mIPSC amplitude (60%) in FZP‐treated neurons, the absence of mIPSCs in one‐third of FZP‐treated cells, and a measurable reduction in synaptic and unitary conductance confirmed that postsynaptic GABA A receptor function was profoundly impaired in FZP‐treated CA1 neurons. Zolpidem, an α1‐selective benzodiazepine receptor ligand, enhanced mIPSC amplitude and decay, but its ability to prolong mIPSC decay was reduced in FZP‐treated neurons. Several pre‐ and postsynaptic changes at GABAergic synapses on CA1 pyramidal cells might be related to the decreased tonic GABA inhibition in FZP‐treated CA1 neurons associated with the expression of benzodiazepine anticonvulsant tolerance. Synapse 31:263–277, 1999. © 1999 Wiley‐Liss, Inc.