Article

Effects of A2A adenosine receptor blockade or stimulation on alcohol intake in alcohol-preferring rats

Psychopharmacology (Impact Factor: 3.99). 02/2012; 219(4):945-957. DOI: 10.1007/s00213-011-2430-1

ABSTRACT RationaleA2A adenosine receptors (A2AARs) have been proposed to be involved in drug addiction; however, preclinical studies about the effects of A2AAR ligands on alcohol consumption have provided inconsistent results.

ObjectivesThe present study evaluated the effect of intraperitoneal injections of the A2AAR antagonist ANR 94, and the A2AAR agonists CGS 21680 and VT 7 on voluntary drinking and operant self-administration of 10% ethanol in Marchigian Sardinian
alcohol-preferring (msP) rats.

ResultsVoluntary ethanol drinking was increased by ANR 94 in acute and subchronic experiments, while it was reduced by A2AAR agonists. The effect of CGS 21680 was abolished by a low dose of ANR 94, confirming its mediation by A2AARs. Ethanol self-administration was reduced by CGS 21680 and VT 7, while ANR 94 slightly but significantly increased it.
Blood alcohol levels were not modified by A2AAR agonists, indicating that their effect is not related to ethanol pharmacokinetics. The effect of VT 7 on ethanol drinking
was behaviourally selective; ethanol and food intake were reduced, but water intake was increased, and total fluid intake
was not different from that of controls. Moreover, VT 7 did not affect locomotor activity. CGS 21680 (0.1mg/kg) did not modify
total fluid intake, but 0.2 and 0.3mg/kg reduced total fluid intake and locomotor activity.

ConclusionThese results provide evidence that A2AAR agonists reduce ethanol consumption in msP rats, which represent an animal model of alcohol abuse related to stress, anxiety
and depression. A2AARs may represent a potential target for treatment of alcohol abuse.

KeywordsA2A Adenosine receptor–A2A Adenosine receptor agonist–A2A Adenosine receptor antagonist–Alcohol intake–Alcohol self-administration–Alcohol-preferring rats

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Available from: Maria Vittoria Micioni Di Bonaventura, Oct 08, 2014
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    • "The G-protein βγ dimers regulate alcohol consumption through a synergy of D2 and adenosine A2 receptor-stimulated PKA signaling [8] . It was reported that agonists of the adenosine A2A receptor reduce alcohol consumption in alcohol-preferring rats [9] . Other GPCRs are also involved in alcohol dependence. "
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    • "Conversely, administration of an A1R antagonist, DPCPX, had no effect (Arolfo et al. 2004). Interestingly, a recent study confirmed that the A2AR agonist CGS 21680 (0.1 mg/kg), at a dose devoid of any effect on total fluid self-administration and locomotion, reduced 10% ethanol-operant self-administration in Marchigian Sardinian ethanol-preferring rats (Micioni Di Bonaventura et al. 2011). However, the A2AR antagonists DMPX and SCH 58261 have been shown to reduce ethanol operant self-administration in rats (Thorsell, Johnson & Heilig 2007; Adams et al. 2008). "
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    • "Conversely, administration of an A1R antagonist, DPCPX, had no effect (Arolfo et al. 2004). Interestingly, a recent study confirmed that the A2AR agonist CGS 21680 (0.1 mg/kg), at a dose devoid of any effect on total fluid self-administration and locomotion, reduced 10% ethanol-operant self-administration in Marchigian Sardinian ethanol-preferring rats (Micioni Di Bonaventura et al. 2011). However, the A2AR antagonists DMPX and SCH 58261 have been shown to reduce ethanol operant self-administration in rats (Thorsell, Johnson & Heilig 2007; Adams et al. 2008). "
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    ABSTRACT: There is emerging evidence that the adenosinergic system might be involved in drug addiction and alcohol dependence. We have already demonstrated the involvement of A2A receptors (A2AR) in ethanol‐related behaviours in mice. Here, we investigated whether the A2AR agonist CGS 21680 can reduce ethanol operant self‐administration in both non‐dependent and ethanol‐dependent Wistar rats. To rule out a potential involvement of the A1R in the effects of CGS 21680, we also tested its effectiveness to reduce ethanol operant self‐administration in both heterozygous and homozygous A1R knockout mice. Our results demonstrated that CGS 21680 (0.065, 0.095 and 0.125 mg/kg, i.p.) had a bimodal effect on 10% ethanol operant self‐administration in non‐dependent rats. The intermediate dose was also effective in reducing 2% sucrose self‐administration. Interestingly, the intermediate dose reduced 10% ethanol self‐administration in dependent animals more effectively (75% decrease) when compared with non‐dependent animals (57% decrease). These results suggest that the A2AR are involved in CGS 21680 effects since the reduction of ethanol self‐administration was not dependent upon the presence of A1R in mice. In conclusion, our findings demonstrated the effectiveness of the A2AR agonist CGS 21680 in a preclinical model of alcohol addiction and suggested that the adenosinergic pathway is a promising target to treat alcohol addiction.
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