Leuprolide – A luteinizing hormone releasing hormone agonist attenuates ethanol withdrawal syndrome and ethanol-induced locomotor sensitization in mice

Ethanol inhibits the synthesis, content and release of hypothalamic luteinizing hormone releasing hormone (LHRH), and LHRH modulates the activity of several neurotransmitters that experience adaptive changes on chronic exposure to ethanol, and also implicate in ethanol dependence. Hence, it was contemplated that LHRH agonist such as leuprolide may influence the behavioral consequences of withdrawing ethanol in dependent state. In the present study, ethanol dependence was produced in mice by providing ethanol liquid diet for 10 days; and its withdrawal on day 11 led to physical signs of hyperexcitability with its peak at 6th h. Acute treatment with leuprolide (20 ng/mouse, i.c.v.), 10 min prior to peak, significantly attenuated hyperexcitability. Such effect of leuprolide was evident even in castrated mice, and castration significantly increased the hyperexcitability in ethanol withdrawal state. Chronic treatment with leuprolide (10 ng/mouse, twice daily, i.c.v.) till day 10 significantly reduced the signs of hyperexcitability in ethanol withdrawal state. In another set of experiment, ethanol (2.4 g/kg, i.p.) was administered on day 1, 4, 7, 10 and 15, which caused gradual increase in locomotor activity indicating ethanol-induced sensitization. Leuprolide (20 ng/mouse, i.c.v.), 10 min prior to the challenge dose of ethanol (2.4 g/kg, i.p.) on day 15 significantly attenuated the expression of sensitization to hyperlocomotor effect of ethanol. Similarly, administration of leuprolide (20 ng/mouse, i.c.v.), 10 min prior to ethanol on day 1, 4, 7 and 10 not only reduced the gradual increase in locomotor activity but also attenuated the sensitized locomotor response on day 15, indicated attenuation of development of sensitization. Leuprolide per se did not affect physical signs and locomotor activity in control group. In conclusion, the present study demonstrated that leuprolide treatment attenuates expression and development of ethanol dependence and sensitization in mice.