サルの L-Dopa 誘発不随意運動に関する実験的研究

Hypokinesia in the unilateral limbs was induced in 8 monkeys (Macaca fuscata fuscata) by a lesion in the contralateral mesencepahlic ventromedial tegmentum (VMT). Daily oral administration of L-Dopa/carbidopa (40mg/kg, 4mg/kg) relieved the hypokinesia and thereafter induced continuous abnormal (choreo-athetoid) involuntary movements (AMI) in upper and lower limbs contralateral to the lesion. These movements were always uniform and continued for a few hours. The author performed a series of pharmacological studies using these VMT-lesioned monkeys. 1) Direct injection of dopamine (500-1000μg/10μl) and apomorphine (500-1500μg/10μl)into the dorsomedial part of the head of the caudate nucleus ipsilateral to the VMT lesion induced the same AIM as those induced by oral administration of L-Dopa/carbidopa. However, intraputaminal injection of these agents induced AIM in bucco-lingual region only. 2) After oral administration of L-Dopa/cabidopa, direct injection of methionine-enkephalin (300μg/10μl), GABA (500-1000μl/10μl) and serotonin (100-200μg/10μl) into the dorsomedial part of the head of the caudate nucleus (HCN) slightly decreased the AIM. However, substance p(200-400μg/10μl) or atropine (100-200μg/10μl) had no effect on the AIM. Neither the direct injection of GABA (500-1000μg/10μl) nor substance P (200-400μg/10μl) into the internal segment of the globus pallidus had any effect of the AIM. 3) The dopaminergic receptor (DA-2) binding study was performed on caudate tissues which were removed 5 weeks after creating the lesion in the unilateral VMT. DA-2 receptor binding of the dorsomedial part of the caudate nucleus, ipsilateral to the lesion, had a higher affinity than that of the ipsilateral ventrolateral part or the contralateral caudate tissue. These results suggest that denervation supersensitivity of the post-synaptic DA-2 receptors in the dorsomedial part of the caudate nucleus is a basic condition for the development of L-Dopa induced AIM, and the postdopaninergic neuronal systems in the caudate nucleus are slightly suppressed by the intra-caudate neurons, of which transmitter substances are methionine-enkephalin, GABA and serotonin.

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