The hypothalamic-pituitary-adrenal (HPA) axis may play an important role in the pathology of alcoholism. Acute alcohol intake activates the HPA axis in healthy subjects. In contrast, a blunted HPA axis response has been found in both drinking and abstinent alcohol dependent patients. However, it is unknown if this is a trait or state effect of alcoholic disease. Pharmacological challenges to the HPA axis of adult male cynomolgus monkeys were conducted using naloxone, saline, CRF, dexamethasone, and ACTH after dexamethasone challenges prior to and following twelve consecutive months of ethanol self-administration. The neuroactive steroid precursor deoxycorticosterone (DOC) concentrations were measured by radioimmunoassay in plasma samples. Basal DOC levels and saline-induced DOC levels were elevated following long-term alcohol self-administration. The increase in basal DOC levels was 244% (p<0.005), while DOC levels following saline challenge showed a maximum increase of 328% (p<0.001). Furthermore, DOC responses to CRF (1 microg/kg, i.v.) and dexamethasone (130 microg/kg, i.m.) challenges were blunted, while responses to ACTH challenge were enhanced. In ethanol naïve monkeys, CRF elevated DOC levels by 111% (p<0.001) and dexamethasone suppressed DOC levels by 42% (p<0.001), but no effects of CRF or dexamethasone challenge on DOC levels were detected following ethanol exposure. ACTH challenge (10 ng/kg, i.v.) had no effect on plasma DOC levels prior to alcohol exposure, but increased DOC levels by 96% (p<0.001) following long-term ethanol drinking. The effect of naloxone challenge (375 microg/kg, i.m.) was not altered by long-term ethanol exposure. These data suggest that long-term ethanol self-administration alters baseline and HPA-mediated plasma DOC responses in monkeys. These adaptations might shed new light in understanding alcoholic disease.
Long-term voluntary alcohol consumption increases plasma deoxycorticosterone levels and alters hypothalamic-pituitary-adrenal axis modulation in cynomolgus monkeys
Porcu P;
2006
Abstract
The hypothalamic-pituitary-adrenal (HPA) axis may play an important role in the pathology of alcoholism. Acute alcohol intake activates the HPA axis in healthy subjects. In contrast, a blunted HPA axis response has been found in both drinking and abstinent alcohol dependent patients. However, it is unknown if this is a trait or state effect of alcoholic disease. Pharmacological challenges to the HPA axis of adult male cynomolgus monkeys were conducted using naloxone, saline, CRF, dexamethasone, and ACTH after dexamethasone challenges prior to and following twelve consecutive months of ethanol self-administration. The neuroactive steroid precursor deoxycorticosterone (DOC) concentrations were measured by radioimmunoassay in plasma samples. Basal DOC levels and saline-induced DOC levels were elevated following long-term alcohol self-administration. The increase in basal DOC levels was 244% (p<0.005), while DOC levels following saline challenge showed a maximum increase of 328% (p<0.001). Furthermore, DOC responses to CRF (1 microg/kg, i.v.) and dexamethasone (130 microg/kg, i.m.) challenges were blunted, while responses to ACTH challenge were enhanced. In ethanol naïve monkeys, CRF elevated DOC levels by 111% (p<0.001) and dexamethasone suppressed DOC levels by 42% (p<0.001), but no effects of CRF or dexamethasone challenge on DOC levels were detected following ethanol exposure. ACTH challenge (10 ng/kg, i.v.) had no effect on plasma DOC levels prior to alcohol exposure, but increased DOC levels by 96% (p<0.001) following long-term ethanol drinking. The effect of naloxone challenge (375 microg/kg, i.m.) was not altered by long-term ethanol exposure. These data suggest that long-term ethanol self-administration alters baseline and HPA-mediated plasma DOC responses in monkeys. These adaptations might shed new light in understanding alcoholic disease.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
