Department of Psychology and Neuroscience, University of Colorado at Boulder, Boulder, CO 80309-0345, USA.
Neuropsychopharmacology. 2012 Apr;37(5):1245-56. doi: 10.1038/npp.2011.312. Epub 2011 Dec 14.
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-yl]amino]ethyl]benzenepropanoic 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.
反复可卡因给药会增强中脑边缘多巴胺系统中多巴胺 D2 受体的敏感性，从而导致药物复吸。腺苷 A2A 受体与伏隔核（NAc）中的中刺神经元上的 D2 受体共定位，在那里它们拮抗 D2 受体活性。因此，A2A 受体代表了降低导致可卡因复吸的增强的 D2 受体敏感性的靶点。这些研究的目的是确定 NAc 中腺苷 A2A 受体调节对接受可卡因自我给药训练的大鼠可卡因寻求的影响。在至少 15 次每日自我给药疗程和 1 周戒断后，在每日消退疗程中消退了按压杠杆的行为。随后，我们评估了 NAc 内核内微注射 A2A 受体激动剂 CGS 21680（4-[2-[[6-氨基-9-（N-乙基-β-D-呋喃核糖基氨基甲酰基）-9H-嘌呤-2-基]氨基]乙基]苯丙酸盐酸盐）和 A2A 受体拮抗剂 MSX-3（3,7-二氢-8-[[1E]-2-（3-甲氧基苯基）乙烯基]-7-甲基-3-[3-（膦酸氧基）丙基-1-（2-丙炔基）-1H-嘌呤-2,6-二酮二钠盐一水合物）对可卡因和喹吡罗诱导的可卡因寻求复吸的调制作用。NAc 内预处理 CGS 21680 减少了可卡因和喹吡罗诱导的复吸。这些作用是可卡因复吸特异性的，因为 NAc 内 CGS 21680 对接受蔗糖丸自我给药训练的大鼠的蔗糖寻求没有影响。当单独给予 NAc 治疗时，MSX-3 适度地重新引起可卡因寻求，并且加剧了可卡因和喹吡罗诱导的复吸。有趣的是，MSX-3 引起的可卡因寻求的加剧仅在亚阈值剂量的可卡因和喹吡罗时观察到，这表明去除紧张的 A2A 受体活性使多巴胺受体介导的行为成为可能。总之，这些发现表明，A2A 受体刺激减少，而 A2A 阻断放大，NAc 中的 D2 受体信号介导可卡因复吸。
