Carta Anna R, Pinna Annalisa, Cauli Omar, Morelli Micaela
Department of Toxicology, University of Cagliari, 09124, Italy.
Synapse. 2002 Jun 1;44(3):166-74. doi: 10.1002/syn.10066.
Adenosine A2A receptor antagonists have been proposed as an effective therapy in the treatment of Parkinson's disease. In the present study, we compared the modifications on striatal glutamate decarboxylase (GAD67), enkephalin, and dynorphin mRNA levels produced by a chronic-intermittent administration of L-3,4-dihydroxyphenyl-alanine (L-dopa) (6 mg/kg) with those produced by the adenosine A2A receptor antagonist SCH 58261 (5 mg/kg) plus L-dopa (3 mg/kg) in unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats. As previously reported, L-dopa (6 mg/kg) and SCH 58261 (5 mg/kg) plus L-dopa (3 mg/kg) produced the same degree of turning behavior after the first administration. However, while L-dopa (6 mg/kg) induced a sensitized turning behavior response during the course of the treatment, which indicated a dyskinetic potential, SCH 58261 (5 mg/kg) plus L-dopa (3 mg/kg) produced a stable turning behavior response, which was predictive of absence of dyskinetic side effects. Unilateral 6-OHDA lesion produced an elevation in striatal GAD67 and enkephalin mRNA levels and to a decrease in dynorphin mRNA levels. Chronic-intermittent L-dopa (6 mg/kg) treatment increased the striatal levels of GAD67, dynorphin, and enkephalin mRNA in the lesioned side as compared to the vehicle treatment. Chronic-intermittent SCH 58261 (5 mg/kg) plus L-dopa (3 mg/kg) as well as L-dopa (3 mg/kg) or SCH 58261 (5 mg/kg) alone did not produce any significant modification in GAD67, dynorphin, or enkephalin mRNA levels in the lesioned striatum as compared to the striatum of vehicle-treated rats. The results show that combined SCH 58261 plus L-dopa did not produce long-term changes in markers of striatal efferent neurons activity and suggest that the lack of modifications in GAD67 and dynorphin mRNA after SCH 58261 plus L-dopa might correlate with the lack of turning behavior sensitization which predicts drug dyskinetic potential.
腺苷A2A受体拮抗剂已被提议作为治疗帕金森病的一种有效疗法。在本研究中，我们比较了在单侧6-羟基多巴胺（6-OHDA）损伤的大鼠中，慢性间歇性给予L-3,4-二羟基苯丙氨酸（L-多巴）（6毫克/千克）与腺苷A2A受体拮抗剂SCH 58261（5毫克/千克）加L-多巴（3毫克/千克）所引起的纹状体谷氨酸脱羧酶（GAD67）、脑啡肽和强啡肽mRNA水平的变化。如先前报道，L-多巴（6毫克/千克）和SCH 58261（5毫克/千克）加L-多巴（3毫克/千克）在首次给药后产生相同程度的旋转行为。然而，虽然L-多巴（6毫克/千克）在治疗过程中诱导了一种敏感的旋转行为反应，这表明有运动障碍的可能性，但SCH 58261（5毫克/千克）加L-多巴（3毫克/千克）产生了稳定的旋转行为反应，这预示着没有运动障碍的副作用。单侧6-OHDA损伤导致纹状体GAD67和脑啡肽mRNA水平升高，强啡肽mRNA水平降低。与溶剂处理相比，慢性间歇性L-多巴（6毫克/千克）治疗增加了损伤侧纹状体中GAD67、强啡肽和脑啡肽mRNA的水平。与溶剂处理大鼠的纹状体相比，慢性间歇性SCH 58261（5毫克/千克）加L-多巴（3毫克/千克）以及单独的L-多巴（3毫克/千克）或SCH 58261（5毫克/千克）在损伤的纹状体中未对GAD67、强啡肽或脑啡肽mRNA水平产生任何显著变化。结果表明，SCH 58261加L-多巴联合使用不会对纹状体传出神经元活动标志物产生长期变化，并表明SCH 58261加L-多巴后GAD67和强啡肽mRNA缺乏变化可能与缺乏预测药物运动障碍可能性的旋转行为敏感化有关。
