The role of oestradiol in sexually dimorphic hypothalamic-pituitary-adrenal axis responses to intracerebroventricular ethanol administration in the rat

Systemic ethanol (EtOH) administration activates the hypothalamic-pituitary-adrenal (HPA) axis of rats in a sexually dimorphic manner. The present studies tested the role played by the CNS in this phenomenon. In order to localize the effects of the drug to the brain, we utilized an EtOH administration paradigm whereby a small, non-toxic amount of the drug was delivered intracerebroventricularly (icv). Icv EtOH rapidly diffuses throughout the CSF and brain, and does not cause neuronal damage or have any long-term physiological or behavioral effects. Experimental groups included intact males, intact cycling females, and ovariectomized (OVX) animals with or without replacement estradiol (E2). Icv EtOH- induced HPA hormonal activation was determined by measuring plasma adrenocorticotropin (ACTH) levels. Activation of brain areas that both regulate HPA function and are responsive to gonadal hormones was determined using expression of the transcription factor c-fos (Fos) as a marker of neuronal activity. We observed sex- and estrous cycle- dependent differences in HPA activation by EtOH as measured by both these parameters. ACTH secretion was highest in females in proestrus or estrus, just prior to and after the endogenous peak of E2, as was Fos expression in the paraventricular nucleus of the hypothalamus (PVN) and the locus coreuleus (LC) of the brainstem. In OVX animals, E2 replacement caused an increase in PVN and LC Fos expression in response to icv EtOH as compared to OVX controls, but a decrease in ACTH secretion. Taken together these results indicate that at the level of the CNS, EtOH stimulates HPA activity more robustly at times when the effects of E2 are high, but that E2 alone is not responsible for the effect. The data further suggest that the LC plays an important role in the circuitry, which appears to be different from that activated following the systemic administration of EtOH.