Ishida Y, Kuwahara I, Todaka K, Hashiguchi H, Nishimori T, Mitsuyama Y
Department of Psychiatry, Miyazaki Medical College, Japan.
Brain Res. 1996 Jul 15;727(1-2):205-11. doi: 10.1016/0006-8993(96)00381-2.
We examined the effects of MK-801, a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, and fetal ventral mesencephalic (VM) transplants on L-3,4-dihydroxyphenylalanine (L-DOPA)-induced Fos protein expression in the dopamine (DA)-depleted striatum. Unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal pathway were produced in young adult female rats and grafting was performed 3 weeks later. Methamphetamine-induced rotational behavior recovered significantly on the 4th week after grafting. Immunohistochemical examinations of c-Fos and tyrosine hydroxylase (TH) were performed 3-4 months after grafting. L-DOPA (100 mg/kg, i.p.) markedly induced Fos-like immunoreactivity (FLI) in the DA-depleted striatum. Pretreatment with a large dose of MK-801 (3-4.5 mg/kg, i.p.) dose-dependently suppressed L-DOPA-induced FLI in the striatum. The stimulatory effect of L-DOPA on c-Fos expression observed within the lesioned striatum was suppressed by fetal VM transplants. It seemed that the graft-induced effect on FLI extended over a considerably larger area than that covered by the graft-derived TH-immunoreactive innervation. Taken together, these findings suggest that glutamatergic modulation is involved in the L-DOPA-induced c-Fos expression in the denervated striatum which is normalized by fetal VM transplants. It also seems likely that VM grafts suppress the L-DOPA-induced expression of transcriptional factors which might be involved in the mechanisms underlying various side effects of chronic L-DOPA therapy.
我们研究了N-甲基-D-天冬氨酸（NMDA）受体的非竞争性拮抗剂MK-801以及胎儿腹侧中脑（VM）移植对L-3,4-二羟基苯丙氨酸（L-DOPA）诱导的多巴胺（DA）耗竭纹状体中Fos蛋白表达的影响。在年轻成年雌性大鼠中制作黑质纹状体通路的单侧6-羟基多巴胺（6-OHDA）损伤，并在3周后进行移植。移植后第4周，甲基苯丙胺诱导的旋转行为显著恢复。移植后3 - 4个月进行c-Fos和酪氨酸羟化酶（TH）的免疫组织化学检查。L-DOPA（100 mg/kg，腹腔注射）在DA耗竭的纹状体中显著诱导Fos样免疫反应性（FLI）。大剂量MK-801（3 - 4.5 mg/kg，腹腔注射）预处理可剂量依赖性地抑制纹状体中L-DOPA诱导的FLI。胎儿VM移植抑制了L-DOPA对损伤纹状体内c-Fos表达的刺激作用。似乎移植对FLI的影响扩展到比移植来源的TH免疫反应性神经支配所覆盖的区域大得多的区域。综上所述，这些发现表明谷氨酸能调节参与了L-DOPA诱导的去神经支配纹状体中的c-Fos表达，而胎儿VM移植可使其正常化。VM移植似乎也可能抑制L-DOPA诱导的转录因子表达，这些转录因子可能参与慢性L-DOPA治疗各种副作用的潜在机制。
