This study investigate the effect of stimulation of glutamatergic afferents originating in the entorhinal cortex on possible changes of GABAergic transmission in the CA1 subregion of the hippocampus. Microdialysis was used to monitor extracellular GABA and in situ hybridization to measure levels of glutamic acid decarboxylase67 (GAD67) mRNA. A dose-dependent increase in extracellular levels of GABA in the dorsal CA1 subregion was detected following injection of 2.4 and 9.6 micrograms quisqualate into the lateral entorhinal cortex whereas 0.24 microgram had no effect. The GABA increase was attenuated by local administration of tetrodotoxin (TTX), indicating neuronal origin. A 60% decrease and a 160% increase were seen in levels of GAD67 mRNA in the CA1 following injection of 0.24 and 9.6 micrograms quisqualate, respectively. This study provides evidence of an entorhinal cortex influenced stimulatory effect on GABAergic activity in the CA1. However, no direct relationship was found between stimulated GABA release and subsequently measured GAD67 mRNA levels. The increased GABA release and the apparent adaptive increase in GAD67 mRNA levels by the strongest stimulation may be due to an endogenous inhibitory neuroprotective response to an excitotoxic influence.