Behavioural Pharmacology Sex-related effects of agmatine on caffeine-induced locomotor activity in Swiss Webster mice Tayfun Uzbay ⁎, Akin Kose, Hakan Kayir, Gokhan Ulusoy, Turgay Celik Gulhane Military Medical Academy, Department of Medical Pharmacology, Psychopharmacology Research Unit, Ankara, Turkey abstract article info Article history: Received 18 June 2009 Received in revised form 23 November 2009 Accepted 15 December 2009 Available online 24 December 2009 Keywords: Agmatine Caffeine Locomotor activity Sex difference Mice In mammalian brain, agmatine is an endogenous amine that is synthesized through the decarboxylation of L- arginine by arginine decarboxylase. It has been proposed as a new neurotransmitter and/or neuromodulator. It was shown that agmatine had some beneficial effects in animal models of opioid and alcohol addiction. Locomotor stimulant properties of drugs such as ethanol, caffeine, nicotine and amphetamine have been linked to their addictive properties. The present study investigates the effects of agmatine on caffeine- induced locomotor activity both in male and female mice. Adult Swiss Webster mice were used in the study. Locomotor activity was measured for 30 min immediately following caffeine (2.5, 5, 10 and 20 mg/kg, i.p.) or saline treatments. Agmatine (5, 10 and 20 mg/kg, i.p.) were injected 20 min before caffeine (2.5 and 5 mg/kg, i.p.) administration. In both sexes, agmatine (5–20 mg/kg) were also tested for ability to depress or stimulate locomotor activity in the absence of caffeine. Caffeine (5 mg/kg) induced a significant increase in locomotor activity of both male and female mice. There was no significant difference in the locomotor-activating effects of caffeine between male and female mice. Agmatine blocked the caffeine (5 mg/kg)-induced locomotor stimulation dose dependently in male but not female mice. Agmatine had not any effect on the lower dose (2.5 mg/kg) of caffeine in both sexes. These results suggest that agmatine has sex-related inhibitory effects on caffeine-induced locomotor activity in Swiss Webster mice, and male mice are more sensitive than the females to the effect of agmatine. © 2009 Elsevier B.V. All rights reserved. 1. Introduction The behavioral effects of caffeine in both humans and animals are biphasic in nature. Such as, in rodents, while low doses of caffeine stimulate locomotor activity, on the other hand it has depressant effects on motor activity and motor coordination at high doses (Nikodijević et al., 1993; Svenningson, et al. 1995; Daly and Fredholm, 1998). Psychostimulant properties of drugs such as ethanol, caffeine and nicotine can be assessed by open-field locomotor activity in rodents, and these psychostimulant effects have been linked to their addictive properties (Wise and Bozarth, 1987). Evans and Griffiths (1992) showed the development of tolerance to central effects of caffeine in humans. Chronic caffeine treatment also produces physical dependence, as characterized by a caffeine withdrawal syndrome in mice (Kaplan et al., 1993) and humans (Evans and Griffiths, 1999). Nevertheless, it is accepted that caffeine is an atypical substance that can cause addiction (Daly and Fredholm, 1998), and treatment of caffeine addiction may be important. Agmatine is a cationic amine formed by decarboxylation of arginine by the enzyme arginine decarboxylase (Tabor and Tabor, 1984). It is a biologically active substance and binds with high affinity to both imidazoline and α 2 -adrenergic receptors (Li et al., 1994; Piletz et al., 1995; Regunathan and Reis, 1996; Reis and Regunathan, 1998a). Agmatine also interacts with glutamate receptors (Yang and Reis, 1999). It is synthesized, and stored in neurons and released from axon terminals; interacts with cell specific receptors; and elicits biological actions within the central nervous system (Reis and Regunathan, 1998a,b). These findings suggest that agmatine may have functions of a novel neuromodulator (Reis and Regunathan, 2000). In experimental studies, agmatine exhibited anticonvulsant (Demehri et al., 2003; Su et al., 2004), anxiolytic (Gong et al., 2006) and antidepressant-like (Krass et al., 2008) actions. It potentiated the analgesic effect of morphine by an α 2 -adrenoceptor-mediated mechanism in mice (Yesilyurt and Uzbay, 2001). In addition, agmatine attenuates naloxone-precipitated morphine withdrawal signs in morphine-dependent rats (Aricioglu- Kartal and Uzbay, 1997) and some signs of ethanol withdrawal in ethanol-dependent rats (Uzbay et al., 2000a). These findings imply that agmatine may have a potential in treatment of substance abuse and addiction. However, the effects of agmatine on psychostimulant agents such as caffeine have not been investigated yet. There are links between the observed sex differences in various parameters related to brain function, such as the responsiveness of European Journal of Pharmacology 630 (2010) 69–73 ⁎ Corresponding author. Gulhane Military Medical Academy, Faculty of Medicine, Department of Medical Pharmacology, Psychopharmacology Research Unit, Etlik 06018 Ankara, Turkey. Tel.: +90 312 304 4764; fax: +90 312 304 2010. E-mail addresses: tuzbay@gata.edu.tr, uzbayt@yahoo.com (T. Uzbay). 0014-2999/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2009.12.020 Contents lists available at ScienceDirect European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar