在伏隔核中刺激腺苷受体可逆转可卡因敏化和对多巴胺 D2 受体的交叉敏化在大鼠中的表达。
Stimulation of adenosine receptors in the nucleus accumbens reverses the expression of cocaine sensitization and cross-sensitization to dopamine D2 receptors in rats.
机构信息
Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado Boulder, USA.
出版信息
Neuropharmacology. 2012 Nov;63(6):1172-81. doi: 10.1016/j.neuropharm.2012.06.038. Epub 2012 Jun 28.
Adenosine receptors co-localize with dopamine receptors on medium spiny nucleus accumbens (NAc) neurons where they antagonize dopamine receptor activity. It remains unclear whether adenosine receptor stimulation in the NAc restores cocaine-induced enhancements in dopamine receptor sensitivity. The goal of these studies was to determine whether stimulating A(1) or A(2A) receptors in the NAc reduces the expression of cocaine sensitization. Rats were sensitized with 7 daily treatments of cocaine (15 mg/kg, i.p.). Following one-week withdrawal, the effects of intra-NAc microinjections of the adenosine kinase inhibitor (ABT-702), the adenosine deaminase inhibitor (deoxycoformycin; DCF), the specific A(1) receptor agonist (CPA) and the specific A(2A) receptor agonist (CGS 21680) were tested on the behavioral expression of cocaine sensitization. The results indicate that intra-NAc pretreatment of ABT-702 and DCF dose-dependently blocked the expression of cocaine sensitization while having no effects on acute cocaine sensitivity, suggesting that upregulation of endogenous adenosine in the accumbens is sufficient to non-selectively stimulate adenosine receptors and reverse the expression of cocaine sensitization. Intra-NAc treatment of CPA significantly inhibited the expression of cocaine sensitization, which was reversed by both A(1) and A(2A) receptor antagonism. Intra-NAc treatment of CGS 21680 also significantly inhibited the expression of cocaine sensitization, which was selectively reversed by A(2A), but not A(1), receptor antagonism. Finally, CGS 21680 also inhibited the expression of quinpirole cross-sensitization. Together, these findings suggest that adenosine receptor stimulation in the NAc is sufficient to reverse the behavioral expression of cocaine sensitization and that A(2A) receptors blunt cocaine-induced sensitization of postsynaptic D(2) receptors.
腺苷受体与多巴胺受体在伏隔核（NAc）神经元上共定位，拮抗多巴胺受体活性。目前尚不清楚 NAc 中的腺苷受体刺激是否能恢复可卡因诱导的多巴胺受体敏感性增强。这些研究的目的是确定刺激 NAc 中的 A1 或 A2A 受体是否能降低可卡因敏化的表达。大鼠用 7 天的可卡因（15mg/kg，ip）处理致敏。在一周的戒断后，测试了 NAc 内微注射腺苷激酶抑制剂（ABT-702）、腺苷脱氨酶抑制剂（脱氧胞苷；DCF）、特异性 A1 受体激动剂（CPA）和特异性 A2A 受体激动剂（CGS 21680）对可卡因敏化行为表达的影响。结果表明，ABT-702 和 DCF 的 NAc 预处理剂量依赖性地阻断了可卡因敏化的表达，而对急性可卡因敏感性没有影响，这表明伏隔核内源性腺苷的上调足以非选择性地刺激腺苷受体并逆转可卡因敏化的表达。NAc 内给予 CPA 显著抑制可卡因敏化的表达，该作用被 A1 和 A2A 受体拮抗所逆转。NAc 内给予 CGS 21680 也显著抑制可卡因敏化的表达，该作用被 A2A 受体选择性逆转，但不能被 A1 受体拮抗所逆转。最后，CGS 21680 还抑制了喹吡罗交叉敏化的表达。总之，这些发现表明，NAc 中的腺苷受体刺激足以逆转可卡因敏化的行为表达，而 A2A 受体使可卡因诱导的突触后 D2 受体敏化减弱。
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