Research Report Effect of agmatine on brain L-citrulline production during morphine withdrawal in rats: A microdialysis study in nucleus accumbens Hasan Yananlı a , M. Zafer Gören a , Kemal Berkman a, ⁎ , Feyza Arıcıoğlu b a Marmara University, Department of Pharmacology and Clinical Pharmacology, School of Medicine, Haydarpaşa, Istanbul, 34668, Turkey b Marmara University, Department of Pharmacology, Faculty of Pharmacy, Haydarpaşa, Istanbul, 34668, Turkey ARTICLE INFO ABSTRACT Article history: Accepted 10 November 2006 Available online 19 December 2006 Agmatine, an endogenous nitric oxide (NO) synthase inhibitor and ligand for imidazoline receptors, has been previously shown to prevent morphine dependence in rats. The present study was designed to investigate NO formation in nucleus accumbens core region (NAcc) during naloxone (NL)-precipitated morphine withdrawal in rats treated with agmatine or L-NAME by using intracerebral microdialysis in freely moving rats, through measuring extracellular L-citrulline concentrations, an indirect sign of NO production since equal amounts of L-citrulline and NO are produced from L-arginine. L-Citrulline levels in the NAcc core did not change following administration of agmatine (40 mg/kg i.p.) or L-NAME (100 mg/kg i.p.) in control rats. Both agmatine and L-NAME attenuated withdrawal symptoms of morphine in NL (2 mg/kg i.p.)-precipitated withdrawal. L-Citrulline levels showing the release of NO increased in morphine-dependent rats during NL-precipitated withdrawal. Agmatine and L-NAME treatments significantly suppressed the increase in L- citrulline levels compared to physiological saline-treated rats in this setting. The results suggest that the release of L-citrulline in NAcc may be involved in the processes of morphine withdrawal and agmatine as an endogenous inhibitor of NO synthase may be one of the factors involved in the changes in the physiology and behavioral state during opioid withdrawal and may have pharmacological importance. © 2006 Elsevier B.V. All rights reserved. Keywords: Agmatine Morphine withdrawal NO (nitric oxide) Microdialysis L-NAME Nucleus accumbens 1. Introduction The mechanisms involved in morphine tolerance, depen- dence and withdrawal are still being intensely investigated and not definitely described yet. There is considerable evidence demonstrating the involvement of the nitric oxide (NO) pathways in the development of opioid tolerance and the onset of morphine withdrawal symptoms (Vaupel et al., 1995). It is long known that NO synthase (NOS) inhibitors were shown to attenuate the development of tolerance and inhibit or abolish some aspects of the naloxone (NL)-precipitated withdrawal (Vaupel et al., 1997). In recent years, agmatine, a newly isolated substance in NO pathway, has been reported to play an important role in the onset of opiate dependence and withdrawal in rodents. Agmatine has shown to inhibit NOS (Galea et al., 1996). It is an amine produced by the enzyme arginine decarboxylase (ADC) and formed through the decarboxylation of L-arginine. It was first recognized as being synthesized and stored in plants, bacteria and invertebrates but agmatine and its biosynthetic BRAIN RESEARCH 1132 (2007) 51 – 58 ⁎ Corresponding author. Fax: +90 216 347 55 94. E-mail address: berkmank@gmail.com (K. Berkman). 0006-8993/$ – see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2006.11.028 available at www.sciencedirect.com www.elsevier.com/locate/brainres