Chronic administration of iminodipropionitrile (IDPN), a neurotoxin, to rats produces a persistent behavioral syndrome characterized by lateral and vertical head twitching, random circling and hyperactivity. Conventionally, this IDPN-induced dyskinesia has been considered to be due to abnormalities in the serotonin neuronal system. However, the present study also demonstrated marked alterations in the dopamine (DA) and acetylcholine (ACh) neuronal systems. These were activation of DA neurons in the nucleus accumbens and thalamus + midbrain, decreased activity in the other brain areas and a decrease in D1 DA receptors. ACh contents were decreased in most brain areas while muscarinic ACh receptors were increased in the striatum, superior colliculus and geniculate nucleus. These alterations in the ACh neuronal system may be secondary to abnormalities in the DA neuronal system. IDPN-induced dyskinesia was enhanced by administration of L-dopa, which increases DA concentration, but was completely inhibited by ceruletide, which inhibits DA release. The dyskinesia was also inhibited by sulpiride, a central antagonist of D2 DA receptors. Interestingly, apomorphine and bromocriptine, which are DA receptor agonists, did not aggravate, but decreased dyskinesia in the IDPN-treated rats. These results strongly suggest that dyskinesia is caused not by abnormality of postsynaptic receptors in the DA neuronal system but by abnormally enhanced function of the presynaptic DA neurons themselves. In addition, ceruletide may be useful in the treatment of dyskinesia, and bromocriptine alone or in combination with L-dopa may be effective in Parkinson’s disease without the development of dyskinesia. Thus, the IDPN-treated rat model is useful for clarifying the biochemical pathophysiology of dyskinesia and developing drugs for its treatment.
Although neuronal death following brain ischemia was originally considered to be due to an energy deficiency resulting from an impaired respiratory chain, the observation of "delayed neuronal death" indicated some other factor. It is believed that delayed neuronal death after transient forebrain ischemia appears as a result of release of glutamate, an excitatory amino acid. In the present study, transient ischemia for 20 minutes in a rat four-vessel occlusion model was induced, and serial changes in histology and N-methyl-D-aspartate receptor (NMDA-R) binding were evaluated up to the chronic stage. Destruction of pyramidal cells and extensive astrocytic proliferation in the CA1 area of the hippocampus was completed by 10 days after cerebral ischemia followed by cerebral blood recirculation. However, the glutamate receptor subtype, NMDA-R, showed no change in all brain regions until after 10 days, but decreased in the hippocampus to 50% after 21 days despite no evidence of histological progression of neuronal death. The results show that the time course for appearance of light microscopic damage in the hippocampal region does not parallel that for depletion of NMDA-R binding sites.
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