Sotty Florence, Montezinho Liliana P, Steiniger-Brach Björn, Nielsen Jacob
Department of Neurophysiology, H. Lundbeck A/S, Copenhagen-Valby, Denmark.
J Neurochem. 2009 May;109(3):766-75. doi: 10.1111/j.1471-4159.2009.06004.x. Epub 2009 Feb 19.
Phosphodiesterase (PDE) 10A is highly expressed in medium spiny neurons of the striatum, at the confluence of the corticostriatal glutamatergic and the midbrain dopaminergic pathways, both believed to be involved in the physiopathology of schizophrenia. There is a growing body of evidence suggesting that targeting PDE10A may be beneficial for the treatment of positive symptoms in schizophrenia. The aim of the present study was to investigate how PDE10A inhibition modulates mesolimbic dopaminergic neurotransmission. We found that the selective PDE10A inhibitor, MP-10, blocked D-amphetamine-induced hyperactivity as well as D-amphetamine-induced dopamine efflux in the nucleus accumbens in a dose-dependent manner. We further investigated the mechanism by which PDE10A inhibition affects dopaminergic neurotransmission. We report that MP-10 potentiated the effect of a high but not a low dose of D-amphetamine on the mean firing rate of dopaminergic neurons recorded from the ventral tegmental area. Similarly, the effect of a high, but not a low dose of D-amphetamine, was completely reversed by the selective D(1) antagonist, SCH23390. These data suggest that the D(1)-regulated feedback control of midbrain dopamine neurons is a critical pathway involved in the modulation of the response of mesolimbic dopamine neurons to D-amphetamine by PDE10A inhibition.
磷酸二酯酶（PDE）10A在纹状体的中等棘状神经元中高度表达，位于皮质纹状体谷氨酸能通路和中脑多巴胺能通路的交汇处，这两条通路均被认为与精神分裂症的病理生理学有关。越来越多的证据表明，靶向PDE10A可能对治疗精神分裂症的阳性症状有益。本研究的目的是探究PDE10A抑制如何调节中脑边缘多巴胺能神经传递。我们发现，选择性PDE10A抑制剂MP-10以剂量依赖性方式阻断了D-苯丙胺诱导的多动以及伏隔核中D-苯丙胺诱导的多巴胺释放。我们进一步研究了PDE10A抑制影响多巴胺能神经传递的机制。我们报告称，MP-10增强了高剂量而非低剂量D-苯丙胺对腹侧被盖区记录的多巴胺能神经元平均放电率的影响。同样，高剂量而非低剂量D-苯丙胺的作用被选择性D(1)拮抗剂SCH23390完全逆转。这些数据表明，中脑多巴胺神经元的D(1)调节反馈控制是一条关键通路，参与了PDE10A抑制对中脑边缘多巴胺神经元对D-苯丙胺反应的调节。
