MIDAZOLAM INHIBITS LONG-TERM POTENTIATION THROUGH MODULATION OF GABA(A) RECEPTORS

Benzodiazepine drugs (BZ) are used for anxiety, insomnia, and seizures . They worsen memory, especially in large doses, but the mechanism of this action is uncertain. In micromolar concentrations, benzodiazepine s have been shown to reduce long-term potentiation (LTP), which could be a cellular basis for their amnesic action. We have found that the L TP-inhibiting effects of BZ occur in the nanomolar concentrations atta ined in humans, and that this effect occurs through modulation of GABA A receptor function. We recorded extracellular synaptic input/output ( I/O) curves for population spikes (PS) and EPSPs in rat hippocampal sl ices before and after induction of LTP. LTP increased maximal PS and E PSPs and shifted I/O curves for PS and EPSPs to the left, reflecting i ncreased synaptic responsiveness after LTP. Curves relating EPSPs to P S were also shifted, so that after LTP larger PS were elicited for the same size EPSP (ES potentiation). Midazolam (0.5 mu M) markedly inhib ited the left-shift in PS I/O curves due to E-S potentiation but did n ot significantly affect other parameters. 8-Phenyltheophylline (10 mu M), an adenosine receptor antagonist, did not prevent midazolam inhibi tion of LTP. Bicuculline, a GABAA receptor antagonist, caused a dose-d ependent antagonism of midazolam's LTP inhibition. Our results suggest that benzodiazepines reduce LTP primarily through reduction of E-S po tentiation, and that this effect occurs through modulation of GABAA re ceptor function. This could in part account for the ability of benzodi azepines to disturb new memory formation. Copyright (C) 1996 Elsevier Science Ltd.