Agmatine Inhibits Behavioral Sensitization to Ethanol Through Imidazoline Receptors

Abstract

Background: Locomotor sensitization to repeated ethanol (EtOH) administration is proposed to play a role in early and recurring steps of addiction. The present study was designed to examine the effect of agmatine on EtOH-induced locomotor sensitization in mice.Methods: Mice received daily single intraperitoneal injection of EtOH (2.5 g/kg, 20 v/v) for 7 consecutive days. Following a 3-day EtOH-free phase, the mice were challenged with EtOH on day 11 with a single injection of EtOH. Agmatine (10 to 40 lg/mouse), endogenous agmatine enhancers (L-arginine [80 lg/mouse], arcaine [50 lg/mouse], aminoguanidine [25 lg/mouse]), and imidazoline receptor agonist/antagonists were injected (intracerebroventricular [i.c.v.]) either daily before the injection of EtOH during the 7-day development phase or on days 8, 9, and 10 (EtOH-free phase). The horizontal locomotor activity was determined on days 1, 3, 5, 7, and 11.Results: Agmatine (20 to 40 lg/mouse) administration for 7 days (development phase) significantly attenuated the locomotor sensitization response of EtOH challenge on day 11. Further, the agmatine administered only during EtOH-free period (days 8, 9, and 10) also inhibited the enhanced locomotor activity on the 11th day to EtOH challenge as compared to control mice indicating blockade of expression of sensitization. Daily treatment (i.c.v.) with endogenous agmatine enhancers like L-arginine (80 lg/mouse) or arcaine (50 lg/mouse) and aminoguanidine (25 lg/mouse) restrained the development as well as expression of sensitization to EtOH. Imidazoline I 1 receptor agonist, moxonidine, and I 2 agonist, 2-BFI, not only decreased the development and expression of locomotor sensitization but also potentiated the effect of agmatine when employed in combination. Importantly, I 1 receptor antagonist, efaroxan, and I 2 antagonist, idazoxan, blocked the effect of agmatine, revealing the involvement of imidazoline receptors in agmatine-mediated inhibition of EtOH sensitization.Conclusions: Inhibition of EtOH sensitization by agmatine is mediated through imidazoline receptors and project agmatine and imidazoline agents in the pharmacotherapy of alcohol addiction.

Effects of imidazoline agents in a rat conditioned place preference model of addiction

“…The involvement of the imidazoline system in a drug abuse behavior has been intensively studied. The imidazoline compound which received the greatest attention in being evaluated was AG, while IDZ and EFR were used to demonstrate that the effects of AG were via imidazoline receptors (Wei et al 2005 ; Su et al 2008 ; Thorn et al 2012 ; Sameer et al 2013 ; Taksande et al 2019a , b ).…”

“…The administration of IDZ and EFR prevented the inhibition of ethanol-induced locomotor sensitization by AG in Albino male Swiss mice (Taksande et al 2019a ). EFR reversed the effect of pretreatment with AG (40 mg/kg ip ) or moxonidine, an imidazoline receptor agonist (0.4 mg/kg) or a combination of sub-effective doses of both of them on ethanol (1.25 g/kg ip )-induced preference in Swiss albino male mice (Sameer et al 2013 ).…”

“…The same doses of AG and drugs are known to raise its endogenous levels like l -arginine, aminoguanidine, and arcaine, attenuated the ethanol consumption in a two-bottle choice paradigm on Wistar rats. The effect of AG on ethanol intake was potentiated by moxonidine ( agonist) and 2-BFI ( agonist) and blocked by IDZ ( antagonist) and EFR ( antagonist), suggesting the implication of imidazoline receptors in the regulation of brain dopaminergic signaling in the ventral tegmentum area (Taksande et al 2019a , b ). AG attenuated the development of morphine physical dependence, regulated long-term reward memory, and inhibited the expression of the transcription factor FosB that is a physical dependence indicator.…”

“…The spontaneous motor activity in rats was decreased by the treatment with IDZ than EFR, more for the former (Rusu et al 2015 ). IDZ and EFR reversed the inhibitory influence in ethanol consumption (Taksande et al 2019b ), withdrawal-induced depression (Chimthanawala et al 2020 ), and locomotor sensitization (Taksande et al 2019a ) exerted by AG. IDZ was tested in a preliminary double-blind, cross-over, randomized human laboratory study with ten social drinkers included.…”

Agmatine Attenuates Oxidative Stress In Alcohol-Related Neurodevelopmental Disorder In Prenatal Ethanol Exposure Rat Model

“…( Yananlı et al 2007). The molecule efficiently reduced self-administration associated with ethanol (Taksande et al 2019). Additionally, treatment with agmatine in ethanol addiction and withdrawal period has been found to improve performance in numerous behavioral tasks (Chimthanawala et al 2020;Uzbay et al 2000).…”