Md. Wang et al., The interaction between ethanol and pregnanolone at induction of anaesthesia investigated with a threshold method in male rats, BR J PHARM, 134(7), 2001, pp. 1393-1402
1 An anaesthesia threshold was used to investigate the pharmacodynamic and
pharmacokinetic interactions between ethanol and pregnanolone in male rats.
2 The criterion to determine threshold doses of pregnanolone was the first
burst suppression of 1 s in the EEG. Ethanol (0.5, 1.0, 1.5 and 2.0 g kg(-1
)) was injected i.p. 15 min before pregnanolone infusion. Trunk blood, seru
m, cortex, cerebellum, hippocampus, striatum, brain stem, fat and muscle ti
ssues obtained at criterion were used to determine ethanol (blood) and preg
nanolone.
3 Ethanol reduced threshold doses in a dose dependent linear manner. A simi
lar reduction of pregnanolone tissue concentrations was only found in brain
stem and striatum. Deviations consisted of larger decreases in serum, cere
bellum and hippocampus after 0.5 g kg(-1) ethanol and in cerebellum, cortex
and hippocampus after 2.0 g kg(-1) of ethanol. Positive correlations betwe
en dose and concentration of pregnanolone was recorded in brain stem, hippo
campus, cerebellum and cortex. A kinetic component influenced the concentra
tion in cortex. There was a correlation between dose and serum concentratio
n of pregnanolone only after ethanol. In the muscle 0.5 g kg(-1) ethanol ha
d no influence on pregnanolone concentration.
4 The linear, additive pharmacodynamic interaction could involve the GABA i
onophore. A pharmacokinetic interaction was found in cortex. The retained h
igh uptake of pregnanolone in muscle (after 0.5 g kg(-1)) corresponded to l
osses in other tissues (including serum). The reduced uptake of pregnanolon
e in cerebellum, cortex and hippocampus (after 2.0 g kg(-1)) was not due to
a corresponding change in serum concentration. It was probably due to a re
duced blood flow.