Glucose and the insulin-releasing drug tolbutamide attenuate the effects of morphine and angiotensin on alcohol consumption

Abstract

Animal studies have shown that insulin injections reduce alcohol intake, implicating glucoregulatory processes in alcohol consumption. Angiotensin (ANG) II reduces alcohol intake and promotes glycogen breakdown in the liver but no studies have assessed the role of glucoregulatory processes in ANG II's effect. Similarly, glucose injections attenuate the analgesic and cognitive effects of opiates, yet no studies have assessed the effect of glucose on the well-documented ability of opiates to enhance alcohol consumption. The present experiments further examine the role of glucoregulatory processes in alcohol intake by assessing the effect of glucose injections on morphine-enhanced alcohol consumption and by evaluating the effect of the insulin-releasing drug, tolbutamide, on ANG II-reduced alcohol consumption. Adult male Wistar rats acquired alcohol drinking using the limited access procedure that offers daily 40-min access to both 6% w/v alcohol and water and ensures reliable alcohol drinking in bouts large enough to produce pharmacologically relevant intakes. Experiment 1: after intake stabilized, four groups of rats were first pretreated with vehicle injections and in the next phase, three of the four groups received either 50, 100, or 200 mg/kg glucose intraperitoneally (IP) prior to access to alcohol. Neither the vehicle injections nor any of the glucose doses had an effect on alcohol intake. In the final phase all groups continued to receive their respective glucose doses or vehicle but were now also treated with 5 mg/kg morphine sulphate IP prior to alcohol access. Morphine stimulated alcohol intake to a similar degree in all groups except the 200 mg/kg group, which showed a significant attenuation in morphine-enhanced alcohol intake. Experiment 2: after intake stabilized, different groups of rats were pretreated with vehicle injections and in the next phase received either 5, 25, 50, or 100 mg/kg tolbutamide or vehicle subcutaneously (SC) prior to alcohol access. The vehicle injections did not alter alcohol intake, and only the 100 mg/kg dose of tolbutamide produced a reduction in alcohol intake. In the final phase the groups continued to receive their respective doses of tolbutamide or vehicle but were also treated with 400 μg/kg ANG II SC immediately prior to alcohol access. ANG II reduced alcohol intake to a similar extent in the groups pretreated with 5–50 mg/kg tolbutamide. However, the 100 mg/kg dose of tolbutamide significantly attenuated ANG II's ability to reduce alcohol intake. These results demonstrate that manipulations that engage glucoregulatory processes can influence the mechanism(s) by which morphine and angiotensin respectively increase and decrease alcohol drinking.