Regional neurochemical studies on the effect of β,β′ ‐iminodipropionitrile (IDPN) in the rat

Abstract

A permanent hyperkinetic syndrome, characterized by excitation, choreiform head and neck movements and circling, which has led to it being called collectively the "ECC-syndrome," is induced in rats by the daily IP administration of beta, beta'-iminodipropionitrile (IDPN), 300 mg/kg, for 7 days. The levels of the biogenic amines, norepinephrine (NE), dopamine (DA), serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA), were measured in the striatum, midbrain, medulla, cortex, and cerebellum on the day the syndrome appeared (day 7) and one week later (day 14). The biogenic amine most affected by IDPN administration was 5-HT. On day 7, striatal 5-HT levels increased and 5-HIAA levels decreased while in the medulla and midbrain, 5-HIAA levels increased. On day 14, significant reductions in both 5-HT, in the midbrain, striatum, and cortex, and 5-HIAA, in all regions except the cortex, were observed. NE was markedly increased in the medulla, midbrain, and striatum on day 7, whereas on day 14 it was found to be within the normal range in these same regions. With the exception of a slight, but significant, increase in the cortex on day 7, DA levels in all regions were found to be relatively unaffected by IDPN administration on both day 7 and day 14. In an attempt to detect degenerative changes which might be taking place in the brain and which might provide an explanation for the permanency of the behavioral disturbances, the uptake of [3H]-labeled NE, DA, and 5-HT into synaptosomal-rich preparations of striatum and the uptake of NE and 5-HT into the midbrain area were compared between normal and syndromized rats on both day 7 and day 14. Small changes were observed but they were not statistically significant. The alterations of 5-HT and 5-HIAA levels in several regions of the brain under the conditions examined may indicate that IDPN's neurotoxicity primarily affects 5-HT-containing neurones. The active membrane transporting system of the nerve endings studied, however, remained relatively intact. This latter finding eliminates the possibility that neuronal degeneration in these areas is responsible for the decreased 5-HT and 5-HIAA levels or is the pathology underlying the permanency of the syndrome. These results are evaluated in terms of a possible model for hyperkinetic disorders.

Central and peripheral effects of iminodipropionitrile on catecholamine metabolism in rats

“…These abnormalities bear some resemblance to the phenomena observed after acute injection of dopamine (DA) (Lewander, 1977) and serotonergic agonists (Green, 1984). The persistent changes seen after IDPN treatment can be blocked by drugs that are inhibitory to both the dopamine (Cadet et al, 1987b;Diamond et al, 1982b;Langlais et al, 1975;Schneider, 1984) and the norepinephrine system (Cadet et al, 1987a).…”

“…Very few studies have been carried out on the possible biochemical changes that may be associated with the IDPN-induced syndrome. In rats, it was reported that both serotonin (5-HT) and norepinephrine (NE) levels were increased on the day that the syndrome developed (7th day of injection); but while the level of NE returned to normal 1 week after the last injection of IDPN, that of 5-HT was significantly reduced at that time (Langlais et al, 1975). There was no change reported in the concentration of DA in the rat (Langlais et al, 1975) or mice brain (Gianutsos and Suzdak, 1985).…”

“…In rats, it was reported that both serotonin (5-HT) and norepinephrine (NE) levels were increased on the day that the syndrome developed (7th day of injection); but while the level of NE returned to normal 1 week after the last injection of IDPN, that of 5-HT was significantly reduced at that time (Langlais et al, 1975). There was no change reported in the concentration of DA in the rat (Langlais et al, 1975) or mice brain (Gianutsos and Suzdak, 1985). Diamond et al (1982a) reported a significant reduction in DA and homovanillic acid (HVA) concentration 3 months after the last injection of the drug.…”

Maternal exposure to 3,3’‐iminodipropionitrile targets late‐stage differentiation of hippocampal granule cell lineages to affect brain‐derived neurotrophic factor signaling and interneuron subpopulations in rat offspring

“…Within the brain, IDPN has been shown to increase glial fibrillary acidic protein (GFAP) expression in the cingulate cortex and hippocampus (Seoane et al, 1999). There also are studies to show neurochemical or oxidative stress-related effects in the brain by IDPN exposure (Langlais et al, 1975;Gianutsos and Suzdak, 1985;Perumal et al, 1991). IDPN also causes a loss of hearing and vestibular function acutely by hair cell degeneration (Crofton et al, 1994;Llorens and Demêmes, 1994).…”

Quipazine exacerbation of a hyperkinetic syndrome: Involvement of brain dopamine and serotonin

“…Despite these studies, the biochemical basis for this syndrome remains unknown. One study reported decreased levels of serotonin (5-HT) and its metabolite, 5-hydroxyindolacetic acid (5-HIAA), in the midbrain and striatum of rat brain 1 week after the appearance of the syndrome (Langlais et al, 1975). Although experimentally induced reductions in brain 5-HT have been associated with increased locomotor activity and a variety of behavioral disturbances, the delay (7 days) between the appearance of the syndrome and the reductions in 5-HT and 5-HIAA levels cast some doubt on the direct involvement of serotonergic systems in the production of the "ECC-Syndrome.…”