Quarta Davide, Borycz Janusz, Solinas Marcello, Patkar Kshitij, Hockemeyer Jörg, Ciruela Francisco, Lluis Carme, Franco Rafael, Woods Amina S, Goldberg Steven R, Ferré Sergi
Preclinical Pharmacology Section, Behavioral Neuroscience Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland 21224, USA.
J Neurochem. 2004 Nov;91(4):873-80. doi: 10.1111/j.1471-4159.2004.02761.x.
Adenosine, by acting on adenosine A(1) and A(2A) receptors, exerts opposite modulatory roles on striatal extracellular levels of glutamate and dopamine, with activation of A(1) inhibiting and activation of A(2A) receptors stimulating glutamate and dopamine release. Adenosine-mediated modulation of striatal dopaminergic neurotransmission could be secondary to changes in glutamate neurotransmission, in view of evidence for a preferential colocalization of A(1) and A(2A) receptors in glutamatergic nerve terminals. By using in vivo microdialysis techniques, local perfusion of NMDA (3, 10 microm), the selective A(2A) receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS 21680; 3, 10 microm), the selective A(1) receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT; 300, 1000 microm), or the non-selective A(1)-A(2A) receptor antagonist in vitro caffeine (300, 1000 microm) elicited significant increases in extracellular levels of dopamine in the shell of the nucleus accumbens (NAc). Significant glutamate release was also observed with local perfusion of CGS 21680, CPT and caffeine, but not NMDA. Co-perfusion with the competitive NMDA receptor antagonist dl-2-amino-5-phosphonovaleric acid (APV; 100 microm) counteracted dopamine release induced by NMDA, CGS 21680, CPT and caffeine. Co-perfusion with the selective A(2A) receptor antagonist MSX-3 (1 microm) counteracted dopamine and glutamate release induced by CGS 21680, CPT and caffeine and did not modify dopamine release induced by NMDA. These results indicate that modulation of dopamine release in the shell of the NAc by A(1) and A(2A) receptors is mostly secondary to their opposite modulatory role on glutamatergic neurotransmission and depends on stimulation of NMDA receptors. Furthermore, these results underscore the role of A(1) vs. A(2A) receptor antagonism in the central effects of caffeine.
腺苷通过作用于腺苷A(1)和A(2A)受体，对纹状体细胞外谷氨酸和多巴胺水平发挥相反的调节作用，A(1)受体激活会抑制，而A(2A)受体激活会刺激谷氨酸和多巴胺释放。鉴于A(1)和A(2A)受体优先共定位在谷氨酸能神经末梢的证据，腺苷介导的纹状体多巴胺能神经传递调节可能继发于谷氨酸神经传递的变化。通过使用体内微透析技术，局部灌注NMDA（3、10微摩尔）、选择性A(2A)受体激动剂2 - p -（2 - 羧乙基）苯乙胺基 - 5'- N - 乙基羧酰胺腺苷（CGS 21680；3、10微摩尔）、选择性A(1)受体拮抗剂8 - 环戊基 - 1,3 - 二甲基黄嘌呤（CPT；300、1000微摩尔）或体外非选择性A(1)-A(2A)受体拮抗剂咖啡因（300、1000微摩尔），均可引起伏隔核（NAc）壳部细胞外多巴胺水平显著升高。局部灌注CGS 21680、CPT和咖啡因时也观察到显著的谷氨酸释放，但灌注NMDA时未观察到。与竞争性NMDA受体拮抗剂dl - 2 - 氨基 - 5 - 膦酰戊酸（APV；100微摩尔）共同灌注可抵消NMDA、CGS 21680、CPT和咖啡因诱导的多巴胺释放。与选择性A(2A)受体拮抗剂MSX - 3（1微摩尔）共同灌注可抵消CGS 21680、CPT和咖啡因诱导的多巴胺和谷氨酸释放，且不改变NMDA诱导的多巴胺释放。这些结果表明，A(1)和A(2A)受体对NAc壳部多巴胺释放的调节主要继发于它们对谷氨酸能神经传递的相反调节作用，且依赖于NMDA受体的刺激。此外，这些结果强调了A(1)与A(2A)受体拮抗在咖啡因中枢效应中的作用。
