Agmatineproducesantidepressant-likee¡ects intwomodelsofdepressioninmice Andrea D. E. Zomkowski, Luciana Hammes, Jaime Lin, Joa ì o Batista Calixto, 1 Adair Roberto S. Santos 2 and Ana Lu¤ cia S. Rodrigues CA 1 Departamento de Bioqu|¤mica and Departamento de Farmacologia,CCB,Universidade Federal de Santa Catarina, 88040-900,Floriano¤ polis; 2 Nu¤ cleo de Investigac° o ì es Qu|¤mico-Farmace“ uticas,CCS,Universidade doVale de Itaja|¤,Itajai, SC, Brazil CA Corresponding Author Received17 December 2001; accepted10 January 2002 Agmatineproduces an antidepressant-like e¡ect when assessedin the forced swimming test (FST) and in the tail suspension test (TST)inmice(doserange0.01^50mg/kg,i.p.),withoutaccompany- ing changes in ambulation in an open-¢eld. I.c.v. injection of agma- tine (1^100nmol/site) also reduced the immobility time in the FST. Agmatine signi¢cantly enhanced the anti-immobility e¡ect of imi- pramine, butdidnot a¡ect that of MK-801.The anti-immobility ef- fect of agmatine assessed in the FST was not a¡ected by pre- treatment with prazosin. In contrast, agmatine’s antidepressant- like e¡ect was completely prevented by pre-treatment of animals with yohimbine,GMP or L-arginine.Taken together these data de- monstrate that agmatine elicited a signi¢cant antidepressant-like e¡ect through a mechanism that seems to involve an interaction with NMDA receptors, the L-arginine-nitric oxide pathway and a 2 -adrenoceptors. NeuroReport 13:387^391  c 2002Lippincott Williams & Wilkins. Keywords: a 2 -Adrenoceptors; Agmatine; Depression; Forced swimming test; Imipramine; MK-801; NMDA; Nitric oxide;Tail suspension test INTRODUCTION Agmatine is an amine formed by the enzymatic decarbox- ylation of L-arginine by arginine decarboxylase [1]. Agma- tine has been discovered recently in mammals, where it is expressed in the CNS [2]. Agmatine meets most of the criteria for it to be established as a novel neurotransmitter/ neuromodulator in the CNS. It is synthesized in the brain, stored in synaptic vesicles in a large number of neurons with selective distribution in the CNS, accumulated by uptake, released by depolarization, and inactivated by selective re-uptake or enzymatically degraded by agmati- nase. Agmatine binds with high affinity to a 2 -adrenergic and imidazoline receptors [3–5]. In addition, agmatine blocks the ligand-gated NMDA receptor channel and inhibits all isoforms of nitric oxide synthase (NOS) [3–5]. A growing amount of experimental data indicates that NMDA receptors may be involved in the mechanism of action of some antidepressant drugs, and, by implication, in the pathogenesis of depression. Both preclinical and clinical studies now indicate that compounds which reduce transmission at NMDA receptors are antidepressants [6]. Moreover, it has been demonstrated that NOS inhibitors exert antidepressant-like effects in animal models of depression [7,8]. Since agmatine is know to inhibit both NMDA receptors and NOS, the present study was designed to investigate whether agmatine produces antidepressant- like effects in the forced swimming test (FST) and in the tail suspension test (TST) in mice. These behavioral tests have good predictive value for antidepressant potency in man [9,10]. We also investigated the participation of NMDA receptors, nitric oxide inhibition and adrenergic pathways in the antidepressant like-effect of agmatine in mice. MATERIALS ANDMETHODS Animals, drugs and treatment: Swiss mice of either sex, weighing 30–40 g were maintained at 22–271C with free access to water and food, under a 12:12 h light:dark cycle. All manipulations were carried out between 9:00 and 16:00h, with each animal used only once. Agmatine, GMP, L-arginine, imipramine, prazosin, yohimbine (Sigma, USA) and MK-801 (RBI, USA) were dissolved in saline and administered i.p. in a volume of 10 ml/kg body weight. Agmatine was administered by i.p. 30 min before the FST or TST. Alternatively, in order to assess its central effect, agmatine was administered i.c.v. 15min before the FST or open-field test. I.c.v. injections were given under light ether anesthesia, directly into the lateral ventricle as described previously [11], with the bregma fissure as a reference. Saline or agmatine was injected in a volume of 5 ml, given over 30 s, and the cannula remained in place for a further 30 s. In the experiments that investigated the effects of agmatine, MK-801 and imipramine, alone or in combination, on the immobility time in the FST, MK-801 was injected 15 min before, whereas the other drugs were injected 30 min before the test. 0959-4965  c Lippincott Williams & Wilkins Vol 13 No 4 25 March 2002 387 COGNITIVE NEUROSCIENCE AND NEUROPSYCHOLOGY NEUROREPORT