REDUCTION OF GABA-MEDIATED INHIBITORY POSTSYNAPTIC POTENTIALS IN HIPPOCAMPAL CA1 PYRAMIDAL NEURONS FOLLOWING ORAL FLURAZEPAM ADMINISTRATION

Oral administration of the benzodiazepine, flurazepam, for one week re sults in tolerance ill vivo and in vitro and in a reduction in recurre nt and feedforward inhibition in vitro in the CA1 pyramidal cell regio n of hippocampus. In the present study CA1 pyramidal cells were examin ed intracellularly in vitro in rat hippocampal slices (500 mu m) from rats sacrificed two or seven days after cessation of oral flurazepam t reatment. Following drug treatment, the membrane characteristics of CA 1 pyramidal cells were not significantly different from control neuron s. GABA(A)-mediated, early inhibitory postsynaptic potentials were sig nificantly reduced in amplitude (60%) in pyramidal neurons from rats k illed two days, but not in those killed seven days, after the end of d rug administration. The decrease in early inhibitory postsynaptic pote ntial amplitude was observed using just-subthreshold, threshold and su pramaximal orthodromic stimulation as well as following antidromic act ivation. The magnitude of the decrease in the early inhibitory postsyn aptic potential amplitude was similar in the presence of the GABA(B) a ntagonist, CGP 35348, and could not be attributed to differences in th e strength of afferent stimulation between flurazepam-treated and cont rol groups. The size of the GABA(B)-mediated, late inhibitory postsyna ptic potentials was also significantly decreased (45%) in comparison t o control cells. Reversal potentials for both the early (-72 mV) and l ate (-92 mV) hyperpolarizations were not significantly different betwe en groups. Following high intensity orthodromic stimulation, in the pr esence of an intracellular sodium channel blocker (QX-314) which also blocks the GABA(B)-mediated late hyperpolarization, a bicuculline-sens itive late depolarizing potential was unmasked in neurons from FZP-tre ated rats, but never from control cells. Excitatory postsynaptic poten tial amplitude was significantly increased in flurazepam-treated neuro ns and the threshold for the synaptically-evoked action potential was significantly increased. Following depolarizing current injection, the duration and frequency of pyramidal cell discharges and the action po tential threshold were not altered by oral flurazepam treatment. The a mplitude of the fast afterhyperpolarization was also not changed. Over all, the findings indicate an impairment of transmission at GABAergic synapses onto hippocampal CA1 pyramidal cell neurons after chronic ben zodiazepine treatment at a time when rats are tolerant to the anticonv ulsant effects of the benzodiazepines in vivo.