Agmatine, a metabolite of L-arginine, reverses scopolamine-induced learning and memory impairment in rats Tijen Utkan a, 1 , Semil S. Gocmez b, 2 , Soundararajan Regunathan c, 3 , Feyza Aricioglu d, 4, ⁎ a Kocaeli University Medical Faculty, Pharmacology Department and Experimental Medical Research and Application Unit, 41380 Kocaeli, Turkey b Namık Kemal University Medical Faculty, Pharmacology Department, 59100, Tekirdag, Turkey c The University of Mississippi Medical Center, Psychiatry and Human Behavior Department, Jackson, MS, USA d Marmara University, Faculty of Pharmacy, Pharmacology Department and Psychopharmacology Research Unit, 34668, Istanbul, Turkey abstract article info Article history: Received 7 June 2011 Received in revised form 26 June 2012 Accepted 7 July 2012 Available online 14 July 2012 Keywords: Agmatine Scopolamine Cognition Three panel runway Passive avoidance Agmatine (l-amino-4-guanidino-butane), a metabolite of L-arginine through the action of arginine decarbox- ylase, is a novel neurotransmitter. In the present study, effects of agmatine on cognitive functions have been evaluated by using one trial step-down passive avoidance and three panel runway task. Agmatine (20, 40, 80 mg/kg i.p.) was administered either in the presence or absence of a cholinergic antagonist, scopolamine (1 mg/kg i.p.). Scopolamine significantly impaired learning and memory in both passive avoidance and three panel runway test. Agmatine did not affect emotional learning, working and reference memory but significantly improved scopolamine-induced impairment of learning and memory in a dose dependent manner. Our results indicate that agmatine, as an endogenous substance, may have an important role in modulation of learning and memory functions. © 2012 Elsevier Inc. All rights reserved. 1. Introduction Agmatine (l-amino-4-guanidinobutane) is an endogenous poly- cationic amine synthesized by the decarboxylation of arginine by the enzyme arginine decarboxylase. Agmatine has been proposed to act as a novel neurotransmitter and/or neuromodulator in the mammalian brain (Raasch et al., 1995; Reis and Regunathan, 2000). Previous studies have shown that agmatine binds to imidazoline and alpha2- adrenoceptors and blocks N-methyl-D-aspartate (NMDA) receptor chan- nels (Reis and Regunathan, 1999; Yang and Reis, 1999) and other ligand-gated cationic channels, including nicotinic receptors. Although it was reported that agmatine inhibits all three isoforms of nitric oxide synthase (NOS) (Galea et al., 1996), recently Mun et al. (2010) showed that it stimulates endothelial NOS in the rat brain. Several studies indicat- ed that agmatine has a wide range of effects on central nervous system, such as its roles in morphine analgesia and morphine dependence (Aricioglu-Kartal and Uzbay, 1997; Aricioglu-Kartal and Regunathan, 2002; Aricioglu-Kartal et al., 2003; Aricioglu et al., 2004a, 2004b; Yananli et al., 2007), and antidepressant, anxiolytic (Aricioglu and Altunbaş, 2003; Zomkowski et al., 2002, 2004, 2005), antistress (Aricioglu et al., 2003a, 2003b, 2003c; Aricioglu and Regunathan, 2005), antinociceptive (Aricioglu et al., 2003a, 2003b, 2003c; Kolesnikov et al., 1996; Fairbanks et al., 2000; Santos et al., 2005), anticonvulsive (Aricioglu et al., 2003a, 2003b, 2003c; Demehri et al., 2003; Feng et al., 2005), antiproliferative, and neuroprotective (Gilad et al., 1996; Gilad and Gilad, 2000; Kim et al., 2004; Wang et al., 2006) effects in animal models. In contrast, the role of agmatine in learning and memory has not been extensively inves- tigated. It was shown that agmatine disrupts both the acquisition and early consolidation of conditioned contexual stimuli, suggesting that high levels of agmatine are able to inhibit NMDA receptor activity (Stewart and McKay, 2000). Agmatine was also examined for its roles in water maze place learning, contextual and auditory cued fear learning and conditioned taste aversion learning. It has been found that systemi- cally administered agmatine selectively impairs behavioral inferences of specific types of learning and memory (McKay et al., 2002). Agmatine has a facilitatory effect on memory consolidation in inhibitory avoidance task (Arteni et al., 2002). Agmatine given by intracerebroventricular microinfusion has shown to have an effect on working but not on refer- ence memory in radial arm maze in a dose dependent manner. A study Pharmacology, Biochemistry and Behavior 102 (2012) 578–584 ⁎ Corresponding author at: Marmara University, Faculty of Pharmacy, Department of Pharmacology and Psychopharmacology Research Unit, Haydarpasa,34668, Istanbul, Turkey. Tel.: +90 216 418 95 73; fax: +90 216 345 29 52. E-mail addresses: tijenutkan@hotmail.com (T. Utkan), selcengmez@yahoo.com (S.S. Gocmez), Sregunathan@umc.edu (S. Regunathan), feyza.aricioglu@gmail.com (F. Aricioglu). 1 Kocaeli University, Faculty of Medicine, Department of Pharmacology and Experi- mental Medical Research and Application Unit, Umuttepe, 41380, Kocaeli, Turkey. Tel.: +90 262 303 7460. 2 Namık Kemal University, Faculty of Medicine, Department of Pharmacology, Tekirdag,Turkey. Tel.: +90 542 647 2279. 3 The University of Mississippi Medical Center, Department of Psychiatry and Human Behavior, 2500 North State Street, Jackson, MS 39216-4505, USA. Tel.: +1 601 984 5896; fax: +1 601 984 5899. 4 Marmara University, Faculty of Pharmacy, Department of Pharmacology and Psychopharmacology Research Unit, Haydarpasa, 34668, Istanbul, Turkey. 0091-3057/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.pbb.2012.07.003 Contents lists available at SciVerse ScienceDirect Pharmacology, Biochemistry and Behavior journal homepage: www.elsevier.com/locate/pharmbiochembeh