Besret L, Caldwell M A, Torres E M, Dunnett S B
Centre for Brain Repair, University of Cambridge, Cambridge, UK.
Eur J Pharmacol. 2000 Nov 10;408(1):35-9. doi: 10.1016/s0014-2999(00)00747-0.
The effects of long-term administration of the dopamine D(2) receptor antagonist haloperidol on Parkinsonian symptoms have been shown to persist after cessation of the drug treatment. In order to determine whether the level of tyrosine hydroxylase could be affected by subchronic administration of haloperidol, we examined tyrosine hydroxylase-positive immunoreactive cells in the substantia nigra after blockade of dopaminergic receptors with this antipsychotic. Three weeks of injections with haloperidol (1.5 mg/kg, i.p.) caused a significant decrease in tyrosine hydroxylase-positive cell counts at 24 h (27%), 5 days (21%) and 2 weeks (10%) after the last administration, an effect that was blocked by concurrent administration of the antioxidant, vitamin C. The level of tyrosine hydroxylase returned to baseline after 4 weeks withdrawal, no change being observed at later time-points. Nissl staining demonstrated that no damage to the cell bodies was observed, suggesting that the decrease in tyrosine hydroxylase-positive cells was not due to dopaminergic cell loss. These results demonstrate a depleting action of a short course of haloperidol on nigral tyrosine hydroxylase that outlasts the period of application by 2-4 weeks. Moreover, the current study has shown the effect of the antioxidant vitamin C in protecting haloperidol effects on tyrosine hydroxylase-immunostaining.
长期给予多巴胺D(2)受体拮抗剂氟哌啶醇对帕金森症状的影响在停药后仍会持续。为了确定亚慢性给予氟哌啶醇是否会影响酪氨酸羟化酶水平，我们在用这种抗精神病药物阻断多巴胺能受体后，检查了黑质中酪氨酸羟化酶阳性免疫反应细胞。连续三周注射氟哌啶醇（1.5毫克/千克，腹腔注射）导致末次给药后24小时（27%）、5天（21%）和2周（10%）时酪氨酸羟化酶阳性细胞计数显著减少，同时给予抗氧化剂维生素C可阻断这一效应。停药4周后酪氨酸羟化酶水平恢复至基线，在随后的时间点未观察到变化。尼氏染色显示未观察到细胞体受损，这表明酪氨酸羟化酶阳性细胞减少并非由于多巴胺能细胞丢失。这些结果表明，短期使用氟哌啶醇对黑质酪氨酸羟化酶有耗竭作用，其持续时间比用药期长2至4周。此外，本研究显示了抗氧化剂维生素C对保护氟哌啶醇对酪氨酸羟化酶免疫染色的影响。
