Neurotransmitter and Receptor Alterations in the Rat Persistent Dyskinesia Model Induced by Iminodipropionitrile

Abstract

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.

Chinese Medicine Formula “Jian-Pi-Zhi-Dong Decoction” Attenuates Tourette Syndrome via Downregulating the Expression of Dopamine Transporter in Mice

“…The IDPN-induced dyskinesia was considered due to activation of DA neurons and enhanced by administration of L-dopa, which increases DA concentration. Moreover, hyperfunction of DA neuronal system could be relieved by Tia [28]. …”

Effects of Acupuncture on Behavioral Stereotypies and Brain Dopamine System in Mice as a Model of Tourette Syndrome

“…The increase of DA is inhibited by sulpiride, a central antagonist of D2R. Therefore, dyskinesia of DA is caused by the abnormally enhanced function of presynaptic DA neurons (Ogawa et al, 1990). IDPN only needs to be injected intraperitoneally, which makes it easy to prepare and utilize, so we used IDPN to induce a model of TS in mice.…”

Pharmacokinetic and pharmacodynamic analyses, based on dopamine D2‐receptor occupancy of bromocriptine, of bromocriptine‐induced contralateral rotations in unilaterally 6‐OHDA‐lesioned rats

“…These results suggest that the effect of bromocriptine was due to stimulation of postsynaptic D 2 -receptors in the striatum and that there was a significant equilibration delay in the concentrations in the brain compared to those in plasma. The onset and duration of the effects of bromocriptine have been described in previous reports (Corrodi et al, 1973;Johnson et al, 1976;Schran et al, 1985;Ogawa et al, 1990). Corrodi et al (1973) reported that bromocriptine induced rotation in rats with 6-OHDA-induced lesions with a delay of 50 -60 min after administration, whereas ergocornine-induced rotation commenced within 5 min.…”

“…Johnson et al (1976) also reported that bromocriptine exhibited a time delay in the onset of effects such as stereotyped sniffing-licking and contralateral rotation in 6-OHDA-lesioned rats and that the drug had a sustained action in contrast to the actions of apomorphine, amphetamine, and L-dopa. Moreover, the duration of the effect in rats of bromocriptine has been studied with respect to suppression of iminodipropionitrail-induced head twitching (Ogawa et al, 1990) and bromocriptine-induced hypothermia (Schran et al, 1985). In some cases, active metabolites may cause a delay in the onset of the effect of a drug compared to plasma concentration.…”