Xu M
Department of Cell Biology, Neurobiology and Anatomy, University of Cincinnati College of Medicine, Ohio 45267-0521, USA.
Ann N Y Acad Sci. 1998 May 30;844:27-39.
The dopamine D3 receptor is expressed mostly in the limbic regions of the brain that influence reward-related behaviors, including responses to psychostimulants. However, the lack of ligands with sufficient D3 receptor specificity has hampered our understanding of its possible involvement in mediating psychostimulant actions. To unravel dopamine D3 receptor function and underlying mechanisms in response to psychostimulants, we used a genetic approach and generated D3 receptor gene mutant mice. Our analysis indicates that the D3 mutant mice exhibit enhanced behavioral sensitivity to cocaine, amphetamine and combined injections of D1-and D2-class receptor agonists. By contrast, the combined electrophysiological effects of the same D1-and D2-class agonists on single neurons within the nucleus accumbens were not changed in the D3 mutant mice. We propose that the D3 receptor modulates responses to psychostimulants by inhibiting the cooperative effects of postsynaptic D1-and other D2-class receptors at systems level. The continuous use of the gene targeting approach will provide essential information regarding the molecular and cellular basis of psychostimulant actions and allow the development of new strategies in the prevention and cure of drug abuse.
多巴胺D3受体主要表达于大脑的边缘区域，这些区域影响与奖赏相关的行为，包括对精神兴奋剂的反应。然而，缺乏具有足够D3受体特异性的配体阻碍了我们对其可能参与介导精神兴奋剂作用的理解。为了阐明多巴胺D3受体在对精神兴奋剂反应中的功能及潜在机制，我们采用了遗传学方法，培育出了D3受体基因敲除小鼠。我们的分析表明，D3基因敲除小鼠对可卡因、苯丙胺以及D1和D2类受体激动剂联合注射表现出增强的行为敏感性。相比之下，在D3基因敲除小鼠中，相同的D1和D2类激动剂对伏隔核内单个神经元的联合电生理效应并未改变。我们推测，D3受体通过在系统水平上抑制突触后D1受体和其他D2类受体的协同作用来调节对精神兴奋剂的反应。持续使用基因靶向方法将为精神兴奋剂作用的分子和细胞基础提供重要信息，并有助于开发预防和治疗药物滥用的新策略。
