The progesterone metabolite allopregnanolone and the deoxycorticosterone (DOC) metabolite allotetrahydrodeoxycorticosterone (alloTHDOC) are potent endogenous neuroactive steroids with anticonvulsant, anxiolytic and sedative/hypnotic properties. Acute systemic ethanol administration increases these neuroactive steroids in rodent plasma and brain, however no data are available for non-human primates. Eleven cynomologus monkeys were used to determine DOC levels following acute ethanol administration and modulation of the HPA axis by naloxone, dexamethasone, ACTH and CRF. DOC levels were measured by radioimmunoassay in plasma samples. Other studies have suggested that DOC levels are highly predictive of alloTHDOC levels in rodents. Intragastric administration of ethanol (1.0 and 1.5 g/kg) did not increase plasma DOC levels in monkey plasma. In fact, there was a tendency for a decrease in DOC levels, that was statistically significant 90 and 120 minutes following the administration of 1.0 g/kg ethanol (-44%, p<0.01). Naloxone administration (i.m.) increased DOC levels by 86% (p<0.01) at the dose of 125 ug/kg and by 97% (p<0.001) at the dose of 375 ug/kg; both effects were apparent after 60 minutes from the injection and DOC levels remained elevated at 120 minutes. This effect is likely due to activation of the HPA axis induced by this opioid antagonist. The administration of dexamethasone (130 ug/kg, i.m.) resulted in a 45% decrease in DOC levels (p<0.001), consistent with suppression of HPA axis function. Intravenous (i.v.) administration of ACTH (10 ng/kg) 4-6 hrs after 0.5 mg/kg dexamethasone, which shuts down the HPA axis, had no effect on DOC levels up to 30 min. Finally, administration of CRF (1 ug/kg, i.v.) increased DOC levels by about 50% at 30 minutes, however this increase was not statistically significant. These preliminary results show that DOC levels in non-human primates are regulated by the HPA axis. Ethanol, at the doses of 1.0 and 1.5 g/kg, does not activate the HPA axis in non-human primates and this is consistent with rodent data, where higher doses of ethanol are needed to activate the HPA axis and increase neuroactive steroid levels in plasma and brain.
Deoxycorticosterone levels after HPA axis modulation and ethanol administration in cynomolgus monkeys
Porcu P;
2005
Abstract
The progesterone metabolite allopregnanolone and the deoxycorticosterone (DOC) metabolite allotetrahydrodeoxycorticosterone (alloTHDOC) are potent endogenous neuroactive steroids with anticonvulsant, anxiolytic and sedative/hypnotic properties. Acute systemic ethanol administration increases these neuroactive steroids in rodent plasma and brain, however no data are available for non-human primates. Eleven cynomologus monkeys were used to determine DOC levels following acute ethanol administration and modulation of the HPA axis by naloxone, dexamethasone, ACTH and CRF. DOC levels were measured by radioimmunoassay in plasma samples. Other studies have suggested that DOC levels are highly predictive of alloTHDOC levels in rodents. Intragastric administration of ethanol (1.0 and 1.5 g/kg) did not increase plasma DOC levels in monkey plasma. In fact, there was a tendency for a decrease in DOC levels, that was statistically significant 90 and 120 minutes following the administration of 1.0 g/kg ethanol (-44%, p<0.01). Naloxone administration (i.m.) increased DOC levels by 86% (p<0.01) at the dose of 125 ug/kg and by 97% (p<0.001) at the dose of 375 ug/kg; both effects were apparent after 60 minutes from the injection and DOC levels remained elevated at 120 minutes. This effect is likely due to activation of the HPA axis induced by this opioid antagonist. The administration of dexamethasone (130 ug/kg, i.m.) resulted in a 45% decrease in DOC levels (p<0.001), consistent with suppression of HPA axis function. Intravenous (i.v.) administration of ACTH (10 ng/kg) 4-6 hrs after 0.5 mg/kg dexamethasone, which shuts down the HPA axis, had no effect on DOC levels up to 30 min. Finally, administration of CRF (1 ug/kg, i.v.) increased DOC levels by about 50% at 30 minutes, however this increase was not statistically significant. These preliminary results show that DOC levels in non-human primates are regulated by the HPA axis. Ethanol, at the doses of 1.0 and 1.5 g/kg, does not activate the HPA axis in non-human primates and this is consistent with rodent data, where higher doses of ethanol are needed to activate the HPA axis and increase neuroactive steroid levels in plasma and brain.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
