Preexposure to drug administration context blocks the development of tolerance to sedative effects of diazepam.

The development of tolerance to benzodiazepine (BDZ) and other psychoactive agents such as morphine, alcohol, and barbiturates is thought to be a contingent or learning phenomenon. In a previous report, we demonstrated a positive correlation between the development of tolerance to the sedative effects of diazepam (DZ) and hippocampal synaptic plasticity. The results of the present work show that the development of tolerance to the hypolocomotor action of DZ (5 mg/kg) for 4 days and the associated increase in synaptic plasticity are context specific. Because animal preexposure to the drug administration context blocks both the tolerance sedative effects of DZ and the increased hippocampal synaptic plasticity, observed after 4 days of DZ administration, we propose the increased synaptic plasticity on hippocampal development as one of the biological substrates to the tolerance to DZ. Besides, the continuous administration of DZ did not induce a conditioning opponent response in these animals.