Short communication A possible participation of gonadotropin-releasing hormone in the neuroleptic and cataleptic effect of haloperidol S.N. Umathe a, * , M.M. Wanjari b , S.S.S. Manna a , N.S. Jain c a Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, Mahatma Jyotiba Fuley Shaikshanik Parisar, Amravati Road, Nagpur, Maharashtra 440 033, India b Central Research Institute (Ayurveda), Gwalior, Madhya Pradesh 474009, India c J.L.C. College of Pharmacy, Hingna Road, Nagpur, Maharashtra 440 009, India article info Article history: Received 5 January 2009 Accepted 16 March 2009 Available online 28 April 2009 Keywords: Luteinizing hormone-releasing hormone Antipsychotics Conditioned avoidance response Antide Leuprolide abstract Haloperidol, an antipsychotic agent, stimulates the release of gonadotropin-releasing hormone (GnRH), and this hormone is known to mimic some of the behavioral effects of haloperidol. Hence, the present study was carried out to find out the contribution of GnRH in the behavioral effects of haloperidol. The studies revealed that haloperidol (0.15, 0.25 and 0.5 mg/kg, i.p.) and leuprolide (GnRH agonist; 50, 100, 200 and 400 lg/kg, s.c.) dose-dependently inhibited conditioned avoidance response (CAR) in male Sprague–Dawley rats. In higher doses, haloperidol (0.5, 1 mg/kg, i.p.) and leuprolide (200, 400 lg/kg, s.c.) produced catalepsy in rats. Co-administration of sub-effective dose of leuprolide (50 or 100 lg/kg, s.c.) and haloperidol (0.15 or 0.5 mg/kg, i.p.) similarly inhibited CAR and induced catalepsy. Pre-treatment of rats with antide (GnRH antagonist; 10 lg/rat, s.c.), attenuated the inhibitory effect of both the agents on CAR; blocked leuprolide-induced catalepsy; and attenuated the intensity and reduced the duration of haloperidol-induced catalepsy. In conclusion, the studies suggest a possible role of GnRH in the neurolep- tic and cataleptic effect of haloperidol. Ó 2009 Published by Elsevier Ltd. 1. Introduction Haloperidol is a widely used antipsychotic agent. The neurolep- tic effect and extrapyramidal symptoms of haloperidol are attrib- uted to its ability to block dopamine D2 receptors (Baldessarini et al., 1988; Schlösser et al., 1997). Its interaction with D2 receptor and antagonism with dopamine is well demonstrated in several experimental studies (Arnt, 1982; Yurek and Randall, 1985). Literature documents that D2 receptors situated proximal to hypothalamus/pituitary exert inhibitory influence on the release of some tropic hormones. Therefore, haloperidol is known to stim- ulate the release of prolactin from anterior pituitary and gonado- tropin-releasing hormone (GnRH) from hypothalamus (Tasaka et al., 1985; Lacau-Mengido et al., 1993; Inoue et al., 1998; Mohan Kumar et al., 1998; Spitzer et al., 1998). While haloperidol-induced increased release of prolactin is known to cause hyperprolactemia, the consequences of increased release of GnRH are not known. The early studies established a key role of GnRH in endocrine system, while later studies indicated its direct influence on central nervous system. Immunocytochemical studies demonstrated the presence of GnRH and its receptors in various regions of rat brain (Reubi and Maurer, 1984; Leblanc et al., 1988). Moreover, arcuate nucleus projects its neurons to regions such as limbic system, ven- tral tegmental area, anterior cingulated gyrus, frontal cortex, cau- date, putamen and thalamus (Merchenthaler et al., 1984; Jennes et al., 1988). GnRH as well as GnRH agonists is reported to inhibit condi- tioned avoidance response (CAR) (Mora et al., 1991, 1998) and pro- duce catalepsy in experimental animals (Kádár et al., 1990, 1992). Pre-treatment with L-DOPA is known to reverse the inhibitory ef- fect of GnRH on CAR (Nasello et al., 1990). Moreover, GnRH has been shown to antagonize amphetamine-induced improvement in acquisition of CAR (Mora and Díaz-Véliz, 1983). Further, GnRH is also reported to inhibit the synthesis and release of dopamine from rat striatal tissues (Wang et al., 1982; Mora et al., 1987). Inci- dentally, Parkinson’s like syndrome is often evident in postmeno- pausal state (Alexander et al., 2007) that is characterized by low levels of estrogen (Erlik and Judd, 1982) and higher levels of GnRH released from hypothalamus (Kim et al., 2009). These evidences point towards the behavioral effects of GnRH that are probably mediated by its anti-dopaminergic action. Thus, it was speculated that GnRH released by haloperidol from hypothalamus, may be contributing to its neuroleptic and catalep- tic effect. We therefore, tested this possibility by studying the influence of GnRH antagonist pre-treatment on haloperidol-in- duced inhibition of conditioned avoidance response and catalepsy. The studies were carried out only in male Sprague–Dawley rats to 0143-4179/$ - see front matter Ó 2009 Published by Elsevier Ltd. doi:10.1016/j.npep.2009.03.002 * Corresponding author. Tel.: +91 712 2500324; fax: +91 712 2500355. E-mail address: umathesn@hotmail.com (S.N. Umathe). Neuropeptides 43 (2009) 251–257 Contents lists available at ScienceDirect Neuropeptides journal homepage: www.elsevier.com/locate/npep