Interaction Between Alcohol and Nitric Oxide on ACTH Release in the Rat

Background: This work was designed to determine whether alcohol increased nitric oxide (NO) levels within the hypothalamic‐pituitary (HP) axis, whether endogenous NO participated in the known ability of alcohol to release ACTH and, conversely, whether prior alcohol treatment altered the ACTH response to NO. Methods: In a first group of experiments, intact adult male rats were injected with the vehicle or alcohol intragastrically (4.5 g/kg). The effect of alcohol on NO was studied by measuring nitrite + nitrate levels, as well as NOS activity, as indexes of formation of this gas. The role of endogenous NO then was studied by blocking the activity of NO synthase, the enzyme responsible for formation of this gas, and determining whether this treatment altered the ACTH response to alcohol. Finally, we investigated the influence of alcohol on the ACTH response to NO. These studies were done in rats exposed to alcohol vapors (4 hr/day for 1–5 days) to avoid the confounding influence of HP axis stimulation by acutely injected alcohol. Results: The acute intragastric injection of alcohol significantly (p < 0.01) increased NO levels in the paraventricular nucleus of the hypothalamus, the anterior pituitary, and peripheral blood. The ACTH response to acute intragastric alcohol injection was significantly (p < 0.01) decreased by the arginine derivative Nω‐nitro‐L‐arginine‐methylester, which nonspecifically blocks NOS activity, as well as by the specific neuronal NOS antagonist 7‐nitroindazole. A 5 but not 1 or 3 day exposure to intermittent alcohol vapors interfered with the ACTH response to the intracerebroventricular injection of the NO donor 3‐morpholino‐sydnonimine. Conclusion: Acute alcohol injection increases NO levels in blood and the HP axis, and these responses seem to facilitate the ACTH response to alcohol. Reciprocally, prolonged (5 days) exposure to ethanol vapors blunts the HP axis response to centrally administered NO.