DEPRESSION OF EARLY AND LATE MONOSYNAPTIC INHIBITORY POSTSYNAPTIC POTENTIALS IN HIPPOCAMPAL CA1 NEURONS FOLLOWING PROLONGED BENZODIAZEPINE ADMINISTRATION - ROLE OF A REDUCTION IN CL- DRIVING-FORCE

GABAergic synaptic responses were studied by direct, monosynaptic acti vation of GABAergic interneurons in the CAI region of in vitro hippoca mpal slices from rats made tolerant to the benzodiazepine, flurazepam. Monosynaptic IPSPs were elicited in CA1 pyramidal neurons, following 1 week oral flurazepam administration, by electrical stimulation at th e stratum oriens/stratum pyramidale or stratum radiatum/stratum-lacano sum border less than or equal to 0.5 mm from the recording electrode p lane. Excitatory input to pyramidal cells and interneurons was elimina ted by prior superfusion of the glutamate receptor antagonists, APV (5 0 mu M) and DNQX (10 mu M). GABA(A) receptor-mediated early IPSPs were further isolated by perfusion of the GABA(B) antagonist, CGP 35348 (2 5 mu M) or by diffusion of Cs+ from the recording electrode. GABA(B) r eceptor-mediated late IPSPs were pharmacologically isolated by perfusi on of the GABA(A) antagonist, picrotoxin (50 mu M). There was a signif icant decrease in the amplitude of pharmacologically isolated early an d late IPSPs in FZP-treated neurons without a change in passive membra ne properties. A shift of the early IPSP, but not the late IPSP, rever sal potential in FZP-treated neurons suggested that a change in the dr iving force for anions, presumably Cl-, in CA1 neurons was one importa nt factor related to the decreased early IPSP amplitude after prolonge d activation of GABA(A) receptors by flurazepam. A decreased early IPS P amplitude accompanied by a decreased late IPSP amplitude suggested t hat presynaptic GABA release onto FZP-treated pyramidal cells may also be reduced. We conclude from these data that an impairment of GABAerg ic transmission in CAI pyramidal neurons associated with the developme nt of tolerance during chronic benzodiazepine treatment may be related to the regulation of both pre- and postsynaptic mechanisms at the GAB A synapse. (C) 1997 Wiley-Liss, Inc.