Pickering Chris, Chau Pei Pei, Söderpalm Bo, Ericson Mia
Addiction Biology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg Gothenburg, Sweden.
Front Behav Neurosci. 2010 Jun 10;4:32. doi: 10.3389/fnbeh.2010.00032. eCollection 2010.
Executive dysfunction is a common symptom among alcohol-dependent individuals. Phencyclidine (PCP) injection induces dysfunction in the prefrontal cortex of animals but little is known about how PCP affects the response to ethanol. Using the in vivo microdialysis technique in male Wistar rats, we investigated how systemic injection of 5 mg/kg PCP would affect the dopamine release induced by local infusion of 300 mM ethanol into the nucleus accumbens. PCP given 60 min before ethanol entirely blocked ethanol-induced dopamine release. However, when ethanol was administered 60 min before PCP, both drugs induced dopamine release and PCP's effect was potentiated by ethanol (180% increase vs 150%). To test the role of prefrontal cortex dysfunction in ethanol reinforcement, animals were pretreated for 5 days with 2.58 mg/kg PCP according to previously used 'PFC hypofunction protocols'. This, however, did not change the relative response to PCP or ethanol compared to saline-treated controls. qPCR illustrated that this low PCP dose did not significantly change expression of glucose transporters Glut1 (SLC2A1) or Glut3 (SLC2A3), monocarboxylate transporter MCT2 (SLC16A7), glutamate transporters GLT-1 (SLC1A2) or GLAST (SLC1A3), the immediate early gene Arc (Arg3.1) or GABAergic neuron markers GAT-1 (SLC6A1) and parvalbumin. Therefore, we concluded that PCP at a dose of 2.58 mg/kg for 5 days did not induce hypofunction in Wistar rats. However, PCP and ethanol do have overlapping mechanisms of action and these drugs differentially affect mesolimbic dopaminergic transmission depending on the order of administration.
执行功能障碍是酒精依赖个体的常见症状。苯环己哌啶（PCP）注射会导致动物前额叶皮质功能障碍，但关于PCP如何影响对乙醇的反应知之甚少。我们使用雄性Wistar大鼠的体内微透析技术，研究了全身注射5mg/kg PCP如何影响向伏隔核局部输注300mM乙醇所诱导的多巴胺释放。在乙醇注射前60分钟给予PCP可完全阻断乙醇诱导的多巴胺释放。然而，当在PCP注射前60分钟给予乙醇时，两种药物均诱导多巴胺释放，且乙醇可增强PCP的作用（增加180%，而单独PCP增加150%）。为了测试前额叶皮质功能障碍在乙醇强化中的作用，根据先前使用的“前额叶皮质功能减退方案”，用2.58mg/kg PCP对动物进行5天预处理。然而，与盐水处理的对照组相比，这并未改变对PCP或乙醇的相对反应。定量聚合酶链反应表明，这种低剂量的PCP并未显著改变葡萄糖转运蛋白Glut1（SLC2A1）或Glut3（SLC2A3）、单羧酸转运蛋白MCT2（SLC16A7）、谷氨酸转运蛋白GLT-1（SLC1A2）或GLAST（SLC1A3）、即早基因Arc（Arg3.1）或GABA能神经元标志物GAT-1（SLC6A1）和小白蛋白的表达。因此，我们得出结论，以2.58mg/kg的剂量给予PCP 5天不会在Wistar大鼠中诱导功能减退。然而，PCP和乙醇确实具有重叠的作用机制，并且这些药物根据给药顺序不同地影响中脑边缘多巴胺能传递。
