背景:L-3,4-二羟基苯丙氨酸诱导的运动障碍,左旋多巴(LID),是帕金森病药物治疗的主要并发症。LID诱导谷氨酸能皮质纹状体投射的过度活性,减少谷氨酸能过度活性的药物发挥抗运动障碍作用。长期服用immepip,组胺H3受体激动剂(H3R),减少LID,减少纹状体透析液中的GABA和谷氨酸含量(Avila-Luna等人。,精神药理学236:1937-1948,2019)。
目的:在黑质致密部(SNc)中被6-羟基多巴胺单侧损伤的大鼠中,我们检查了长期服用immepip及其戒断是否会改变LID,左旋多巴对谷氨酸和GABA含量的影响,以及大脑皮层和纹状体中多巴胺D1受体(D1R)和H3Rs的mRNA水平。
结果:给予左旋多巴21天诱导LID。这种效应伴随着大脑皮层同侧和受损SNc的GABA和谷氨酸水平的增加,和immepip给药阻止(GABA)或减少(谷氨酸)这些作用。在纹状体,同侧核中GABA含量增加,immepip阻止的效果。左旋多巴给药对纹状体谷氨酸水平没有显著影响。在病变和左旋多巴治疗的动物中,D1RmRNA在同侧纹状体中降低,immepip给药阻止的效果。
结论:我们的结果表明,慢性H3R激活减少了LID和谷氨酸能皮质纹状体投射的过度活性,为正常和病理条件下皮质和纹状体中D1R和H3Rs之间的相互作用提供了进一步的证据。
BACKGROUND: Dyskinesias induced by L-3,4-dihydroxyphenylalanine, L-Dopa (LIDs), are the major complication in the pharmacological treatment of Parkinson\'s disease. LIDs induce overactivity of the glutamatergic cortico-striatal projections, and drugs that reduce glutamatergic overactivity exert antidyskinetic actions. Chronic administration of immepip, agonist at histamine H3 receptors (H3R), reduces LIDs and diminishes GABA and glutamate content in striatal dialysates (Avila-Luna et al., Psychopharmacology 236: 1937-1948, 2019).
OBJECTIVE: In rats unilaterally lesioned with 6-hydroxydopamine in the substantia nigra pars compacta (SNc), we examined whether the chronic administration of immepip and their withdrawal modify LIDs, the effect of L-Dopa on glutamate and GABA content, and mRNA levels of dopamine D1 receptors (D1Rs) and H3Rs in the cerebral cortex and striatum.
RESULTS: The administration of L-Dopa for 21 days induced LIDs. This effect was accompanied by increased GABA and glutamate levels in the cerebral cortex ipsi and contralateral to the lesioned SNc, and immepip administration prevented (GABA) or reduced (glutamate) these actions. In the striatum, GABA content increased in the ipsilateral nucleus, an effect prevented by immepip. L-Dopa administration had no significant effects on striatal glutamate levels. In lesioned and L-Dopa-treated animals, D1R mRNA decreased in the ipsilateral striatum, an effect prevented by immepip administration.
CONCLUSIONS: Our results indicate that chronic H3R activation reduces LIDs and the overactivity of glutamatergic cortico-striatal projections, providing further evidence for an interaction between D1Rs and H3Rs in the cortex and striatum under normal and pathological conditions.