Potentiation of muscimol-induced long-term depression by benzodiazepines and prevention or reversal by pregnenolone sulfate

We have recently reported a new protocol for inducing long-term depression through activation of GABA(A) receptors in the hippocampal slices. This long-term depression is reversed by bicuculline and potentiated by neurosteroids such as alphaxalone. It was also shown that glutamate receptor activity or extracellular calcium are not involved in the induction of this type of long-term depression. The present study investigated the possible relation between muscimol-induced long-term depression and barbiturates/benzodiazepine-induced amnesia and attempts to determine the possible effect of pregnenolone sulfate on muscimol-induced long-term depression. Extracellular recordings were made in the CA1 pyramidal cell layer of rat hippocampal slices following orthodromic stimulation of Schaffer collateral fibres in stratum radiatum (0.01 Hz). It was observed that pentobarbital, benzodiazepines and pregnanolone at concentrations that did not have any effect themselves on the population spike, potentiate the ability of muscimol to induce long-term depression. In addition to this, the long-term depression was either blocked or reversed by pregnenolone sulfate at concentrations (10 mu M) where pregnenolone sulfate did not induce any multiple burst or increase of spike size. The results suggest that the potentiation of this type of long-term depression by benzodiazepines and barbiturates can explain the main adverse effect of these drugs, amnesia and cognitive impairment. Moreover, the prevention or reversal of this type of long-term depression by pregnenolone sulfate, may suggest a clinical application of this agent in the management of amnesia or dementia. (C) 1998 The Italian Pharmacological Society.