Repeated agmatine treatment attenuates nicotine sensitization in mice: modulation by alpha2-adrenoceptors

Agmatine [2-(4-aminobutyl)guanidine] is an endogenous amine proposed as a neurotransmitter/neuromodulator that binds to multiple target receptors in brain. Besides, many central and peripheral functions, agmatine have been implicated in the process of drug addiction. The purpose of the present study was to examine the effects of centrally injected agmatine on nicotine induced locomotor sensitization in Swiss male mice. Our data shows that repeated injections of nicotine (0.4 mg/kg, sc, twice daily for 7 days) gradually increased locomotion during 7 days development period or after 3 days (nicotine) withdrawal phase challenged with nicotine (0.4 mg/kg, sc) on day 11. Mice were pretreated with agmatine (40-80 microg, icv) or agents known to increase endogenous brain agmatine levels [e.g. an agmatine biosynthetic precursor, L-arginine (80 microg, icv), ornithine decarboxylase inhibitor, difluoromethyl-ornithine (50 microg, icv), diamine oxidase inhibitor, aminoguanidine (25 microg, icv) and agmatinase inhibitor, arcaine (50 microg, icv)] 30 min before daily first nicotine injection or during nicotine withdrawal phase. All these treatments attenuated the development as well as incubation of locomotor sensitization to nicotine. Coadministration of agmatine (20 microg, icv) and alpha(2)-adrenoreceptors agonist, clonidine (0.1 microg, icv) evoked synergistic inhibition of nicotine sensitization. Conversely, prior administration of alpha(2)-adrenoceptor antagonist, yohimbine (5mg/kg, ip) or idazoxan (0.4 mg/kg, ip) reversed the inhibitory effect of agmatine on nicotine sensitization. There was no significant difference in activity between mice injected with any of these agents/saline alone and saline/saline groups. These data indicate that agmatine attenuates nicotine induced locomotor sensitization via a mechanism which may involve alpha(2)-adrenergic receptors. Thus, agmatine might have therapeutic implications in the treatment of nicotine addiction and deserve further investigations.