Yao Lina, McFarland Krista, Fan Peidong, Jiang Zhan, Ueda Takashi, Diamond Ivan
CV Therapeutics, Inc., 3172 Porter Drive, Palo Alto, CA 94304, USA.
Proc Natl Acad Sci U S A. 2006 May 16;103(20):7877-82. doi: 10.1073/pnas.0602661103. Epub 2006 May 9.
Relapse is the most serious limitation of effective medical treatment of opiate addiction. Opiate-related behaviors appear to be modulated by cannabinoid CB1 receptors (CB1) through poorly understood cross-talk mechanisms. Opiate and CB1 receptors are coexpressed in the nucleus accumbens (NAc) and dorsal striatum. These regions also have the highest density of adenosine A2a receptors (A2a) in the brain. We have been investigating the postsynaptic signaling mechanisms of mu-opiate receptors (MORs) and CB1 receptors in primary NAc/striatal neurons. In this article, we present evidence that MOR and CB1 act synergistically on cAMP/PKA signaling in NAc/striatal neurons. In addition, we find that synergy requires adenosine and A2a. Importantly, an A2a antagonist administered either directly into the NAc or indirectly by i.p. injection eliminates heroin-induced reinstatement in rats trained to self-administer heroin, a model of human craving and relapse. These findings suggest that A2a antagonists might be effective therapeutic agents in the management of abstinent heroin addicts.
复吸是阿片类药物成瘾有效医学治疗中最严重的限制因素。阿片类药物相关行为似乎通过尚未完全了解的相互作用机制，由大麻素CB1受体（CB1）进行调节。阿片类药物受体和CB1受体在伏隔核（NAc）和背侧纹状体中共同表达。这些区域在大脑中也具有最高密度的腺苷A2a受体（A2a）。我们一直在研究原代NAc/纹状体神经元中μ-阿片类受体（MORs）和CB1受体的突触后信号传导机制。在本文中，我们提供证据表明MOR和CB1在NAc/纹状体神经元中对cAMP/PKA信号传导具有协同作用。此外，我们发现协同作用需要腺苷和A2a。重要的是，直接注射到NAc中或通过腹腔注射间接给予的A2a拮抗剂，可消除在经过训练可自行注射海洛因的大鼠中，海洛因诱导的复吸行为，这是人类渴望和复吸的一种模型。这些发现表明，A2a拮抗剂可能是治疗戒断期海洛因成瘾者的有效治疗药物。
