Deoxycorticosterone (DOC) is the precursor of the potent endogenous neuroactive steroids 3a,5a and 3a,5b-tetrahydrodeoxycorticosterone (THDOC) that exhibit GABA agonist-like properties including anticonvulsant, anxiolytic and sedative/hypnotic actions. Studies in rodents suggest that plasma DOC levels are highly predictive of THDOC levels. Eleven cynomologus monkeys were tested for plasma DOC levels following activation of the HPA axis by naloxone (375 microg/kg, i m.), adrenocorticotrophic hormone (ACTH, 10 ng/kg, i.v.) challenge, 4-6 hours after 0.5 mg/kg dexamethasone as well as suppression by dexamethasone alone (130 microg/kg, i.m.). Monkeys were induced to drink alcohol with scheduled pellet delivery that induced drinking up to 1.5 g/kg/day over the course of 3 months and were tested in the pharmacological challenges during scheduled drinking. DOC levels were measured by radioimmunoassay in plasma samples. Prior to induction of alcohol drinking, naloxone increased plasma DOC levels in a time dependent manner with a maximal increase of 97% at 60 minutes (p<0.001). Following the induction protocol, naloxone administration increased DOC levels by 218% at 60 minutes. ACTH administration had no effect on DOC levels prior to induction of ethanol drinking, but increased DOC levels by 45.8% following the induction process. The administration of dexamethasone alone resulted in a 45% decrease in DOC levels (p<0.001) prior to induction and decreased DOC levels by 72% (p<0.001) following induction, consistent with greater suppression of HPA axis function. These results show that DOC levels in non-human primates are regulated by the HPA axis and these effects are modulated by the induction of moderate levels of drinking. These results are consistent with previous data suggesting that alterations in HPA axis function may be related to alcohol drinking in monkeys. Supported by AA10564, AA13515 and AA13510.
Naloxone and ACTH stimulation of deoxycorticosterone levels are enhanced following the induction of drinking in cynomolgus monkeys
Porcu P;
2006
Abstract
Deoxycorticosterone (DOC) is the precursor of the potent endogenous neuroactive steroids 3a,5a and 3a,5b-tetrahydrodeoxycorticosterone (THDOC) that exhibit GABA agonist-like properties including anticonvulsant, anxiolytic and sedative/hypnotic actions. Studies in rodents suggest that plasma DOC levels are highly predictive of THDOC levels. Eleven cynomologus monkeys were tested for plasma DOC levels following activation of the HPA axis by naloxone (375 microg/kg, i m.), adrenocorticotrophic hormone (ACTH, 10 ng/kg, i.v.) challenge, 4-6 hours after 0.5 mg/kg dexamethasone as well as suppression by dexamethasone alone (130 microg/kg, i.m.). Monkeys were induced to drink alcohol with scheduled pellet delivery that induced drinking up to 1.5 g/kg/day over the course of 3 months and were tested in the pharmacological challenges during scheduled drinking. DOC levels were measured by radioimmunoassay in plasma samples. Prior to induction of alcohol drinking, naloxone increased plasma DOC levels in a time dependent manner with a maximal increase of 97% at 60 minutes (p<0.001). Following the induction protocol, naloxone administration increased DOC levels by 218% at 60 minutes. ACTH administration had no effect on DOC levels prior to induction of ethanol drinking, but increased DOC levels by 45.8% following the induction process. The administration of dexamethasone alone resulted in a 45% decrease in DOC levels (p<0.001) prior to induction and decreased DOC levels by 72% (p<0.001) following induction, consistent with greater suppression of HPA axis function. These results show that DOC levels in non-human primates are regulated by the HPA axis and these effects are modulated by the induction of moderate levels of drinking. These results are consistent with previous data suggesting that alterations in HPA axis function may be related to alcohol drinking in monkeys. Supported by AA10564, AA13515 and AA13510.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
