Zhou Yan, Adomako-Mensah Johannes, Yuferov Vadim, Ho Ann, Zhang Jianhua, Xu Ming, Kreek Mary Jeanne
The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, New York 10021, USA.
Synapse. 2007 Jan;61(1):50-9. doi: 10.1002/syn.20340.
In humans, elevations of mu opioid receptor (MOP-r) binding potential (BP) in the frontal cortex (FC) are associated with cocaine craving during early abstinence. In rats, decreases in dopaminergic (DAergic) transmission in the medial FC are associated with increased cocaine-seeking behavior. DA D1 or D3 receptor homozygous knockout (D1-/- or D3-/-) mice offer the opportunity to test the roles of these specific receptors in regulating MOP-r gene expression in response to cocaine. In the present studies, we found an increase in basal MOP-r mRNA levels in the FC of both D1-/- and D3-/- mice compared to wild type controls, with no change in the nucleus accumbens (NAc) core or caudate-putamen (CPu). Acute "binge" cocaine (3 x 15 mg/kg for 2.5 h) returned FC MOP-r mRNA levels in D1-/- or D3-/- mice to those in wild type controls. In the NAc core, the MOP-r mRNA levels after acute "binge" cocaine were decreased in D1-/- mice while increased in D3-/- mice. In the CPu, however, the MOP-r mRNA levels after acute "binge" cocaine were increased in D1-/- mice while decreased in D3-/- mice. We also found a decrease in basal orexin mRNA levels in the lateral hypothalamus of the D3-/- mice, which was unaltered by acute "binge" cocaine. Together, our findings suggest that: (1) both D1 and D3 receptors are involved in FC MOP-r gene regulation; and (2) D1 and D3 receptors play opposite roles in the effects of cocaine on MOP-r gene regulation differentially in the NAc core or CPu.
在人类中，额叶皮质（FC）中μ阿片受体（MOP-r）结合潜力（BP）的升高与早期戒毒期间的可卡因渴求有关。在大鼠中，内侧FC中多巴胺能（DAergic）传递的减少与可卡因寻求行为的增加有关。多巴胺D1或D3受体纯合敲除（D1-/-或D3-/-）小鼠为测试这些特定受体在调节对可卡因反应的MOP-r基因表达中的作用提供了机会。在本研究中，我们发现与野生型对照相比，D1-/-和D3-/-小鼠的FC中基础MOP-r mRNA水平均升高，伏隔核（NAc）核心或尾状核-壳核（CPu）中无变化。急性“暴饮暴食”可卡因（3×15mg/kg，持续2.5小时）使D1-/-或D3-/-小鼠的FC中MOP-r mRNA水平恢复到野生型对照水平。在NAc核心中，急性“暴饮暴食”可卡因后，D1-/-小鼠的MOP-r mRNA水平降低，而D3-/-小鼠的则升高。然而，在CPu中，急性“暴饮暴食”可卡因后，D1-/-小鼠的MOP-r mRNA水平升高，而D3-/-小鼠的则降低。我们还发现D3-/-小鼠外侧下丘脑的基础食欲素mRNA水平降低，急性“暴饮暴食”可卡因对此无影响。总之，我们的研究结果表明：（1）D1和D3受体均参与FC中MOP-r基因的调节；（2）D1和D3受体在可卡因对NAc核心或CPu中MOP-r基因调节的影响中发挥相反作用。
