Agmatine Potentiates Morphine-Induced Conditioned Place Preference in Mice: Modulation by Alpha(2)-Adrenoceptors

Abstract

The effects of agmatine, an endogenous polyamine metabolite formed by decarboxylation of L-arginine, and its combination with morphine on conditioned place preference (CPP) has been investigated in male mice. Our data show that subcutaneous administration of morphine (1-7.5 mg/kg) significantly increases the time spent in the drug-paired compartment in a dose-dependent manner. Intraperitoneal administration of agmatine (1-40 mg/kg) alone does not induce either CPP or conditioned place aversion, while combination of agmatine and subeffective doses of morphine leads to potent rewarding effects. Lower doses of morphine (0.1, 0.05, and 0.01 mg/kg) are able to induce CPP in mice pretreated with agmatine 1, 5, and 10 mg/kg, respectively. Concomitant intraperitoneal administration of UK 14 304 (0.5 mg/kg), a highly selective a 2 -agonist, with per se noneffective dose of morphine (0.5 mg/kg) and also its combination with noneffective doses of agmatine (1 mg/kg) plus morphine (0.05 mg/kg) produces significant CPP. UK 14 304 (0.05, 0.5 mg/kg) alone, or in combination with agmatine (1, 5 mg/kg) have had no effect. We have further investigated the possible involvement of the a 2 -adrenoceptors in the potentiating effect of agmatine on morphine-induced place preference. Selective a 2 -antagonists, yohimbine (0.005 mg/kg) and RX821002 (0.1, 0.5 mg/kg), block the CPP induced by concomitant administration of agmatine (5 mg/kg) and morphine (0.05 mg/kg). Yohimbine (0.001-0.05 mg/kg) or RX821002 (0.05-0.5 mg/kg) alone or in combination with morphine (0.05 mg/kg) or agmatine (5 mg/kg) fail to show any significant place preference or aversion. Our results indicate that pretreatment of animals with agmatine enhances the rewarding properties of morphine via a mechanism which may involve a 2 -adrenergic receptors.

Racemic gamma vinyl‐GABA (R,S‐GVG) blocks methamphetamine‐triggered reinstatement of conditioned place preference

“…Given this, it can be inferred that the previously neutral environmental stimuli have obtained a conditioned incentive value. These results are consistent with earlier studies in which many drugs of abuse, including METH, elicited a CPP (Mucha et al 1982; Hiroi and White 1991; Funada et al 2002; Sora et al 1998; Slusher et al 2001; Cunningham et al 2003; Roma and Riley 2005; Daza-Losada et al 2007; Tahsili-Fahadan et al 2006). Subsequently, repeated daily saline administrations successfully extinguished this CPP in all groups.…”

Melatonin enhances the rewarding properties of morphine: involvement of the nitric oxidergic pathway

“…administration of melatonin on the induction of place preference per se and also on the acquisition of morphine-induced place preference conditioning. Our data indicate that morphine induces a significant CPP in a dose-dependent manner in mice, which is consistent with our previous findings and results of others in this respect [12,28,37]. The present work shows that melatonin alone does not show any effect on place conditioning [35]; however, concomitant administration of melatonin with lower and per se noneffective dose of morphine induce a significant rewarding effect assessed by place preference conditioning paradigm.…”

Protective effects of agmatine on lipopolysaccharide-injured microglia and inducible nitric oxide synthase activity

“…Although it is an agonist for the α-2 -adrenergic and imidazoline receptors and an antagonist for the N-methyl-D-aspartic acid (NMDA) receptor (Reynolds, 1990;Piletz et al, 1995;Santos et al, 2005;Tahsili-Fahadan et al, 2006;Halaris and Plietz, 2007;Kotagale et al, 2010;Martinis et al, 2012), its precise working mechanisms are not yet fully understood. Several recent studies have reported that agmatine acts as a competitive inhibitor of nitric oxide synthase (NOS) (Auguet et al, 1995;Galea et al, 1996), suggesting that agmatine's neuroprotective effects may be associated with its interference with NO signaling.…”