NMDA-NR1 and -NR2B subunits mRNA expression in the hippocampus of rats tolerant to Diazepam.

The development of tolerance to the hypolocomotor effects of Diazepam (DZ) is thought to be a contingent or learning phenomenon. In previous reports, we demonstrated a positive correlation between the development of tolerance to the sedative effects of DZ and hippocampal synaptic plasticity. Furthermore, previous exposure to the drug administration context blocks both the tolerance to sedative effects of DZ and the increased hippocampal plasticity. The results of the present investigation show that the development of tolerance to hypolocomotor action of DZ (5 mg/kg/day) for 4 days results in a significant increase in the hybridization signals for mRNA for N-methyl-D-aspartate (NMDA) glutamatergic receptor NR1 and NR2B subunits in the hippocampal dentate gyrus. Furthermore, we have observed more benzodiazepine binding sites in the hippocampus of non-tolerant animals. We conclude that the increased hippocampal synaptic efficacy in DZ tolerant rats, may be NMDA receptor dependent due to an increased recombinant NR1-NR2B complex observed in the hippocampal formation of tolerant rats.