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.