Leuprolide – A luteinizing hormone releasing hormone agonist attenuates ethanol withdrawal syndrome and ethanol-induced locomotor sensitization in mice S.N. Umathe a, * , P.S. Bhutada a , P.V. Dixit a , N.S. Jain b a Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur 440 033, Maharashtra, India b J.L.C. College of Pharmacy, New Nandanvan Layout, Nagpur 440 009, Maharashtra, India Received 4 October 2007; accepted 27 December 2007 Available online 15 February 2008 Abstract 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 impli- cate in ethanol dependence. Hence, it was contemplated that LHRH agonist such as leuprolide may influence the behavioral con- sequences 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 leu- prolide 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 hyperlo- comotor 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, indi- cated 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. Ó 2008 Elsevier Ltd. All rights reserved. Keywords: Gonadotropin-releasing hormone; Alcoholism; Substance dependence; Swiss mice; Castration; Neuromodulator; Neuropeptides; Locomotor activity 1. Introduction Besides endocrine effect, LHRH analogues are dem- onstrated to exhibit variety of effects such as antidepres- sant, antianxiety, analgesic, anticonvulsant, catalepsy, drug discrimination learning, and inhibition of condition avoidance response, apomorphine/amphet- amine-induced stereotypic behavior, and cage climbing behavior in rodents (Ka ´da ´r et al., 1990, 1992; Jain and Subhedar, 1993; De Beun, 1999; Bobyntsev et al., 2006). These non-endocrine effects are probably because LHRH neurons are projected to some of the brain regions such as amygdala, ventral tegmental area (VTA), hippocampus, cerebral cortex, anterior 0143-4179/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.npep.2007.12.006 * Corresponding author. Tel.: +91 712 2500324; fax: +91 712 2500355. E-mail address: umathesn@hotmail.com (S.N. Umathe). www.elsevier.com/locate/npep Available online at www.sciencedirect.com Neuropeptides 42 (2008) 345–353 Neuropeptides