Dynamic aspects of acute tolerance to allopregnanolone evaluated using anaesthesia threshold in male rats.

Abstract

It is unclear if allopregnanolone (AlloP) anaesthesia can induce tolerance. Acute tolerance is defined as altered sensitivity to a drug during a single continuous exposure. Induction of acute tolerance to AlloP was studied in male rats using a threshold technique of deep anaesthesia. AlloP was infused at a dose rate of 4.0 mg kg(-1) min(-1). The infusion was stopped when a burst suppression of 1 s or more (the "silent second", SS) occurred in the EEG. To maintain anaesthesia, the infusion was restarted when no SS had been seen in the EEG for 1 min. This interrupted targeted infusion towards an EEG end-point (SS) was continued until 30, 60 or 90 min of anaesthesia had been reached. At these times the rats were killed and AlloP concentrations in serum, muscle, fat and different brain regions were determined by radioimmunoassay. Maintenance dose rate (MDR) was calculated using 20-min intervals. During anaesthesia the MDR increased (P<0.001) from 0.67 (sem 0.03) mg kg(-1) min(-1) (in the interval 10-30 min) to 0.98 (0.04) mg kg(-1) min(-1) (in the interval 65-85 min). After 60 min a slight increase in MDR was observed. After 90 min of anaesthesia the AlloP concentrations in the hippocampus and brainstem had increased by more than 50% compared with control values of 25.2 (1.13) and 52.7 (5.81) nmol g(-1) respectively, and after 60 min to around 40%. At 30 min no increase was seen in any brain region analysed. Measurements in vivo and in vitro record acute tolerance to AlloP occurring with a delay.