Adaptive changes in the rat hippocampal glutamatergic neurotransmission are observed during long-term treatment with lorazepam

Abstract

Rationale: Chronic treatment with benzodiazepines induces tolerance to most of their pharmacological effects. The best-studied neurochemical correlation to this phenomenon involves GABAergic adaptive changes. However, some compensation by excitatory neurotransmission could also be postulated. Objective: The aim of this work was to investigate the effect of chronic treatment with benzodiazepines on several parameters of hippocampal glutamatergic neurotransmission. Methods: Rats were injected (IP) with a single dose or daily doses (21 days) of 1 mg/kg lorazepam (LZ) or vehicle. Thirty minutes after the last dose, animals were killed and parameters were measured in the dissected hippocampi. We determined one presynaptic parameter, in vitro glutamate release induced by a 60 mM K+ stimulus. [3H]MK-801 binding to postsynaptic NMDA receptors and the NMDA-stimulated efflux of cGMP were also evaluated. Results: While no changes were observed in any of the parameters after a single dose of the drug, we found an increase of 206% in in vitro glutamate release in chronically treated animals [two-way ANOVA: F(1,16)=6.22], together with an increment of 103% in the NMDA-stimulated cGMP efflux [two-way ANOVA: F(1,18)=14.05]. No changes either in KD or in Bmax values for [3H]MK-801 binding to hippocampal membranes were observed. Conclusions: Taken together, these changes strongly suggest that a compensatory increase in the glutamatergic response develops in the hippocampus during chronic treatment with LZ. Our findings might indicate a contribution of glutamatergic mechanisms to the tolerance to hippocampal-mediated effects of LZ, such as amnesic and anticonvulsant activities.