Adenosine A 2A receptors in the nucleus accumbens Bi-directionally alter cocaine seeking in rats

Abstract

Repeated cocaine administration enhances dopamine D 2 receptor sensitivity in the mesolimbic dopamine system, which contributes to drug relapse. Adenosine A 2A receptors are colocalized with D 2 receptors on nucleus accumbens (NAc) medium spiny neurons where they antagonize D 2 receptor activity. Thus, A 2A receptors represent a target for reducing enhanced D 2 receptor sensitivity that contributes to cocaine relapse. The aim of these studies were to determine the effects of adenosine A 2A receptor modulation in the NAc on cocaine seeking in rats that were trained to lever press for cocaine. Following at least 15 daily self-administration sessions and 1 week of abstinence, lever pressing was extinguished in daily extinction sessions. We subsequently assessed the effects of intra-NAc core microinjections of the A 2A receptor agonist, CGS 21680 (4-2-6-amino-9-(N-ethyl-b-D-ribofuranuronamidosyl)-9H-purin-2- ylaminoethylbenzenepropanoic acid hydrochloride), and the A 2A receptor antagonist, MSX-3 (3,7-dihydro-8-(1E)-2-(3-methoxyphenyl)ethenyl-7-methyl-3-3- (phosphonooxy)propyl-1-(2-propynyl)-1H-purine-2,6-dione disodium salt hydrate), in modulating cocaine- and quinpirole-induced reinstatement to cocaine seeking. Intra-NAc pretreatment of CGS 21680 reduced both cocaine- and quinpirole-induced reinstatement. These effects were specific to cocaine reinstatement as intra-NAc CGS 21680 had no effect on sucrose seeking in rats trained to self-administer sucrose pellets. Intra-NAc treatment with MSX-3 modestly reinstated cocaine seeking when given alone, and exacerbated both cocaine- and quinpirole-induced reinstatement. Interestingly, the exacerbation of cocaine seeking produced by MSX-3 was only observed at sub-threshold doses of cocaine and quinpirole, suggesting that removing tonic A 2A receptor activity enables behaviors mediated by dopamine receptors. Taken together, these findings suggest that A 2A receptor stimulation reduces, while A 2A blockade amplifies, D 2 receptor signaling in the NAc that mediates cocaine relapse. © 2012 American College of Neuropsychopharmacology. All rights reserved.