EFFECTS OF PENTOBARBITAL TOLERANCE AND DEPENDENCE ON CONVULSANT AND GABA-A RECEPTOR ANTAGONIST BINDING

Experiments were performed which examined the effects of pentobarbital tolerance and dependence on GABA(A) receptor antagonist binding. In rats implanted with pentobarbital pellets for 7 days, followed by 24 hours of withdrawal, there was a significant decrease in the latency of TBPS-induced seizures and an increase in [S-35]TBPS binding in the frontal cortex. The pentobarbital tolerant rats had a significant increase in the low affinity K(D) of [H-3]SR95531 binding. Removal of the pellets for 24 hours caused a reversal of the effect on the low affinity K(D) and caused a decrease in the number of low affinity binding sites. In vitro addition of pentobarbital to binding assays produced a decrease in the number of high affinity [H-3]SR95531 binding sites without changing low affinity binding. In the cerebellum, the binding in none of the treatment groups was significantly different from placebo. These observations suggest that pentobarbital tolerance and withdrawal cause changes in the properties of the GABA(A) receptor antagonist binding site which are different from those caused by in vitro exposure to the drug.