Rapid tolerance to benzodiazepine modifies rat hippocampal synaptic plasticity

Abstract

Glutamate antagonists to N-methyl- d-aspartate (NMDA) receptors blocks the development of ‘rapid’ tolerance to the sedative action of benzodiazepines (BZDs). This kind of glutamate receptors is closely related to synaptic plasticity in different areas of the brain such as hippocampus. In the present investigation, we studied the synaptic plasticity in dentate gyrus of the hippocampus during the development of tolerance to the hypomotility action induced by diazepam (DZ). The results show an increased hippocampal synaptic plasticity in slices from rats treated with diazepam (5 mg/kg per day) during 4 days, assessed as a decrease of the threshold in the stimulation frequency for long-term potentiation (LTP) elicitation. Thus, a single dose of DZ does not change the ease of induction of LTP but does change locomotor behavior; multiple DZ doses change LTP but not locomotor behavior. Our results reveal a positive correlation between the synaptic plasticity and development of BZD tolerance to locomotor activity.