Neurotransmitter and receptor alterations in the rat persistent dyskinesia model induced by iminodipropionitrile.
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.
Ogawa
N
N
Institute for Neurobiology, Okayama University Medical School, Japan.
Mizukawa
K
K
Haba
K
K
Sato
H
H
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001345:Autoradiography; D001552:Benzazepines / Q000494:pharmacology; D001923:Brain Chemistry; D001971:Bromocriptine / Q000494:pharmacology; D002108:Ceruletide / Q000494:pharmacology; D004409:Dyskinesia, Drug-Induced / Q000473:pathology*; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D009498:Neurotoxins / Q000633:toxicity*; D018377:Neurotransmitter Agents / Q000032:analysis*; D009570:Nitriles / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000032:analysis*; D011976:Receptors, Muscarinic / Q000032:analysis*
D001552:Benzazepines; D009498:Neurotoxins; D018377:Neurotransmitter Agents; D009570:Nitriles; D011954:Receptors, Dopamine; D011976:Receptors, Muscarinic; D001971:Bromocriptine; C008110:3,3'-iminodipropionitrile; D007980:Levodopa; D002108:Ceruletide; D001058:Apomorphine