Histaminergic system of the lateral septum in the modulation of anxiety-like behaviour in rats Mohammad-Reza Zarrindast a,b,c, ⁎ , Farhad Valizadegan d , Parvin Rostami d , Ameneh Rezayof e a Department of Pharmacology and Iranian National Center for Addiction Studies, Tehran University of Medical Sciences, Tehran, Iran b School of Cognitive Science, Institute for Studies in Theoretical Physics and Mathematics, Tehran, Iran c Institute for Cognitive Science Studies, Tehran, Iran d Department of Biology, Tarbiat Moallem University, Tehran, Iran e Department of Animal Biology, School of Biology, College of Science, University of Tehran, Tehran, Iran Received 10 September 2007; received in revised form 18 December 2007; accepted 15 January 2008 Available online 26 January 2008 Abstract The central histaminergic system is known to have modulatory influence on anxiety-related behaviour both in animals and humans through histamine H 1 and/or H 2 receptors. In the present study, the effects of intra-lateral septal microinjections of histaminergic agents on anxiety-related behaviours in male Wistar rats have been investigated. As a model of anxiety, the elevated plus-maze which is a useful test to investigate the effects of anxiogenic or anxiolytic drugs in rodents was used. Intra-lateral septal administration of histamine (0.5 and 1 μg/rat) decreased the percentage of open arm entries and open arm time but not locomotor activity, showing an anxiogenic response. The intra-lateral septal injections of different doses of the histamine H1 receptor antagonist, pyrilamine (5, 10 and 20 μg/rat) or the histamine H2 receptor antagonist, ranitidine (5, 10 and 20 μg/rat) could not significantly alter the anxiety-like parameters in the plus-maze test. However, intra-lateral septal injections of different doses of pyrilamine (10 and 20 μg/rat) or ranitidine (10 and 20 μg/rat) significantly reversed histamine (1 μg/rat)-induced anxiogenic effect. The results may indicate that the histaminergic system of lateral septum modulate anxiety-like behaviour through histamine H1 and H2 receptors. © 2008 Elsevier B.V. All rights reserved. Keywords: Histamine; Pyrilamine; Ranitidine; Anxiety; Elevated plus-maze; (Rat) 1. Introduction Our previous studies indicate that histaminergic system in the central amygdala (Zarrindast et al., 2005b), the dorsal (Zarrindast et al., 2006) and ventral hippocampus (Rostami et al., 2006) are involved in mediating of anxiety-like behaviour. Moreover, several lines of evidence suggested that histaminer- gic system of the nucleus accumbens (Orofino et al., 1999), inferior colliculus, periaqueductal gray (Santos et al., 2003) and nucleus basalis magnocellularis (Privou et al., 1998) may have an important role in the modulation of anxiety. On the other hand, anxiety-related stress may release histamine (Yoshiotomi et al., 1985). Histamine acts through the interaction with pre- synaptic (H 3 ) and post-synaptic (H 1 ,H 2 , and H 4 ) receptors (For review see Brown et al., 2001). From the existing studies it may be concluded that different histamine receptors (H 1 ,H 2 and H 3 ) may be involved in mediating of anxiety-like behaviour. The impetus for the suggestion that the histamine H 1 receptors are involved in anxiogenic effects came from observations of Yanai and coworkers (1998). They have shown that mice lacking histamine H 1 receptors are significantly less anxious than wild- type mice in the elevated plus-maze. It has also been suggested that the stimulation of histamine H 1 receptors has an anxiogenic effect (Yuzurihara et al., 2000b). Furthermore, the anxiolytic effects have been reported by microinjection of chlorphenir- amine, the histamine H 1 receptor antagonist or ranitidine, the histamine H 2 receptor antagonist into the nucleus basalis magnocellularis region (Privou et al., 1998). In contrast, intra- nucleus accumbens administration of histamine decreased fear- Available online at www.sciencedirect.com European Journal of Pharmacology 583 (2008) 108 – 114 www.elsevier.com/locate/ejphar ⁎ Corresponding author. Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran. Tel.: +98 21 66402569; fax: +98 21 66402569. E-mail address: zarinmr@ams.ac.ir (M.-R. Zarrindast). 0014-2999/$ - see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2008.01.003