Site of Action of Acute Alcohol Administration in Stimulating the Rat Hypothalamic-Pituitary-Adrenal Axis: Comparison between the Effect of Systemic and Intracerebroventricular Injection of this Drug on Pituitary and Hypothalamic Responses

Abstract

The peripheral injection of alcohol stimulates the activity of the hypothalamic-pituitary-adrenal (HPA) axis, but the ready penetration of this drug in most bodily compartments has made it difficult to identify its specific sites of action. Here we determined whether alcohol can directly influence the corticotropes. We first determined whether alcohol acted within the brain to stimulate neurons in the paraventricular nucleus (PVN) of the hypothalamus, which synthesizes corticotropin-releasing factor (CRF) and vasopressin (VP). To test this hypothesis, we injected alcohol intracerebroventricularly (icv; 5 microl of 200-proof; 86 micromol) and compared these results with those obtained after its ip administration (3.0 g/kg). Although not causing neuronal damage and not leading to detectable levels of the drug in the general circulation, icv alcohol significantly up-regulated PVN CRF heteronuclear RNA levels and increased plasma ACTH levels, a change comparable to the one observed in the ip model. To determine whether alcohol stimulated the corticotropes independently of CRF and/or VP, we injected the drug ip or icv and measured changes in anterior pituitary proopiomelanocortin (POMC) transcripts and ACTH release in the presence or absence of endogenous CRF and/or VP. Intracerebroventricular and ip alcohol significantly increased POMC primary transcript levels, measured by ribonuclease protection assay, over a time-course that corresponded to ACTH release. Both the POMC and the ACTH responses were completely abolished by removal of CRF and VP. Collectively, these results indicate that alcohol-induced activation of the corticotropes does not represent a direct influence of the drug on the pituitary but requires CRF and VP.

Effect of Ethanol on Hypothalamic Opioid Peptides, Enkephalin, and Dynorphin: Relationship With Circulating Triglycerides

“…injection of ethanol combined with opioid peptide measurements, there is evidence that i.c.v. ethanol significantly increases the expression in the PVN of pro-opiomelanocortin and corticotrophin-releasing factor 1 (Lee et al, 2004). It also stimulates c-Fos-IR specifically in the PVN and NAc but not in other areas examined (Crankshaw et al, 2003).…”

Type 7 Adenylyl Cyclase-Mediated Hypothalamic-Pituitary-Adrenal Axis Responsiveness: Influence of Ethanol and Sex

“…However, significant increases in adrenocorticotropin release in vivo have been reported within minutes and reached a peak as early as 15 min after systemic ethanol injection (Thiagarajan et al, 1988;Ogilvie et al, 1997;Lee et al, 2004). These data suggest that the early in vivo effect of ethanol on adrenocorticotropin release may not depend on an increase in CRF release.…”

“…Thus, it was found that administration of anti-CRF serum totally abolished ethanol-induced release of adrenocorticotropin (Rivier et al, 1984). Whether ethanol was injected intraperitoneally or intracerebroventricularly, there was no increase in circulating adrenocorticotropin if hypothalamic CRF was absorbed by preinjection of CRF antibodies (Lee et al, 2004).…”

“…The mechanism by which ethanol increases circulating glucocorticoid levels has been traced to increases in adrenocorticotropin release (Rivier et al, 1984(Rivier et al, , 1996Lee et al, 2004), and corticotrophin-releasing factor (CRF) has also been shown to be important for ethanol's actions. Thus, it was found that administration of anti-CRF serum totally abolished ethanol-induced release of adrenocorticotropin (Rivier et al, 1984).…”

β-Endorphin and Alcoholism

“…Indeed, the physiological effects of alcohol are in part mediated by the HPA axis and dependent upon neuronal activation of the paraventricular nucleus, and the subsequent release of CRH, ACTH and, eventually, adrenal activation (Lee et al, 2004).…”