This study investigated the effects of the pharmacological manipulation of noradrenergic activities on dopaminergic phenotypes in aged rats. Results showed that the administration of L-threo-3,4-dihydroxyphenylserine (L-DOPS) for 21 days significantly increased the expression of tyrosine hydroxylase (TH) and dopamine transporter (DAT) in the striatum and substantia nigra (SN) of 23-month-old rats. Furthermore, this treatment significantly increased norepinephrine/DA concentrations in the striatum and caused a deficit of sensorimotor gating as measured by prepulse inhibition (PPI). Next, old rats were injected with the α2-adrenoceptor antagonist 2-methoxy idazoxan or β2-adrenoceptor agonist salmeterol for 21 days. Both drugs produced similar changes of TH and DAT in the striatum and SN. Moreover, treatments with L-DOPS, 2-methoxy idazoxan, or salmeterol significantly increased the protein levels of phosphorylated Akt in rat striatum and SN. However, although a combination of 2-methoxy idazoxan and salmeterol resulted in a deficit of PPI in these rats, the administration of 2-methoxy idazoxan alone showed an opposite behavioral change. The in vitro experiments revealed that treatments with norepinephrine markedly increased mRNAs and proteins of ATF2 and CBP/p300 and reduced mRNA and proteins of HDAC2 and HDAC5 in MN9D cells. A ChIP assay showed that norepinephrine significantly increased CBP/p300 binding or reduced HDAC2 and HDAC5 binding on the TH promoter. The present results indicate that facilitating noradrenergic activity in the brain can improve the functions of dopaminergic neurons in aged animals. While this improvement may have biochemically therapeutic indication for the status involving the degeneration of dopaminergic neurons, it may not definitely include behavioral improvements, as indicated by using 2-methoxy idazoxan only.

本研究调查了去甲肾上腺素能活性的药理学操作对老年大鼠多巴胺能表型的影响。结果显示，给予 L-苏氨酸-3,4-二羟苯基丝氨酸 (L-DOPS) 21 天后，23 岁的纹状体和黑质 (SN) 中酪氨酸羟化酶 (TH) 和多巴胺转运蛋白 (DAT) 的表达显着增加。 - 个月大的老鼠。此外，这种治疗显着增加了纹状体中的去甲肾上腺素/DA 浓度，并导致通过前脉冲抑制 (PPI) 测量的感觉运动门控缺陷。接下来，给老年大鼠注射α2-肾上腺素受体拮抗剂2-甲氧基咪唑克生或β2-肾上腺素受体激动剂沙美特罗21天。两种药物在纹状体和 SN 中产生了相似的 TH 和 DAT 变化。此外，用 L-DOPS、2-甲氧基咪唑烷、或沙美特罗显着增加大鼠纹状体和 SN 中磷酸化 Akt 的蛋白水平。然而，虽然 2-甲氧基咪唑烷和沙美特罗的组合导致这些大鼠的 PPI 不足，但单独施用 2-甲氧基咪唑烷显示出相反的行为变化。这体外实验表明，去甲肾上腺素处理显着增加了 MN9D 细胞中 ATF2 和 CBP/p300 的 mRNA 和蛋白质，并减少了 HDAC2 和 HDAC5 的 mRNA 和蛋白质。ChIP 测定显示去甲肾上腺素显着增加 CBP/p300 结合或减少 HDAC2 和 HDAC5 对 TH 启动子的结合。目前的结果表明，促进大脑中的去甲肾上腺素能活动可以改善老年动物多巴胺能神经元的功能。虽然这种改善可能对涉及多巴胺能神经元退化的状态具有生化治疗指征，但它可能并不一定包括行为改善，如仅使用 2-甲氧基咪唑烷所示。