crotononitrile and 2-pentenenitrile

Brainstem auditory and visual evoked-potentials were studied in male Sprague-Dawley rats during subchronic oral treatment with three unsaturated aliphatic nitriles. The rats were given, by gastric intubation, doses of 10, 20 and 40 mg x kg(-1) 3-butenenitrile (allyl cyanide) and 25, 50 and 100 mg x kg(-1) of either cis/trans-2-butenenitrile (crotononitrile) or cis-2-pentenenitrile once a day, 5 days per week for 12 weeks. Oral administration of the three unsaturated nitriles produced deafness and absence of reaction when the animals were subject to droptest. Rats in the high dosage groups exhibited a complete disappearance of the five waves of the auditory evoked-potentials. There was a decrease in the amplitudes of the 2nd component of the auditory evoked-potentials. Those changes were not reversible at the 8th week of the recovery period. A dose-dependent effect on inner and outer hair cells was observed in the organ of Corti. The basal part of the cochlea was the most affected. Though no measurements were made of systemic exposure, a tentative ranking of decreasing ototoxicity of these three unsaturated nitriles might be proposed based on the electrophysiological deficiencies and histological losses observed: 3-butenenitrile >cis-2-pentenenitrile >cis/trans-2-butenenitrile. Moreover, rats treated with those nitriles showed a corneal opacity as well as a decrease in the amplitude and lengthening of the peak latencies of the visual evoked-potentials. These latter changes were reversible by the end of the 8th week of the recovery period and appeared to be related to the opacity of the cornea.

Topics: Administration, Oral; Animals; Dose-Response Relationship, Drug; Evoked Potentials, Auditory, Brain Stem; Evoked Potentials, Visual; Male; Nitriles; Rats; Rats, Sprague-Dawley; Solvents

A single oral administration of allylnitrile, crotononitrile or 2-pentenenitrile in rats induced behavioral abnormalities, such as head-twitching, head weaving, hindlimb abduction, backward pedaling and pivoting. The head-twitching, which was most consistently observed, was suppressed by serotonin (5-HT) antagonists, cyproheptadine or methysergide or by the 5-HT depleter, dl-p-chlorophenylalanine but was accentuated by the 5-HT releaser, dl-p-chloroamphetamine. The results suggest that the 5-HT system is involved in producing the behavioral abnormalities. To discover the effects of allylnitrile, crotononitrile and 2-pentenenitrile on the metabolism of 5-HT and dopamine, 6 areas of the brain of the rat were examined on days 1, 6, 15 and 30 after injection. Each of the nitriles caused significant increases in the level of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) and in the ratio of 5-HIAA/5-HT, one day after injection. The increase in 5-HIAA was most remarkable, suggesting an enhancement of the serotonergic system. The three nitriles had no effect on the metabolism of dopamine, over a period of 30 days.

Topics: Animals; Behavior, Animal; Brain; Cyproheptadine; Fenclonine; Hydroxyindoleacetic Acid; Male; Methysergide; Movement Disorders; Nitriles; p-Chloroamphetamine; Rats; Rats, Inbred Strains; Receptors, Serotonin; Serotonin

The effect of crotononitrile (4.22 mmol/kg, CRN) or 2-pentenenitrile (2.00 mmol/kg, 2-PN), which exhibit long-term dyskinesia, was examined on the metabolism of serotonin (5-HT) and dopamine (DA) in five brain regions of mice 1, 5, 12 and 35 days after dosing with CRN or 2-PN or vehicle (0.1 ml/25 g). One day after injection, CRN increased the level of the following substances and the ratio of 5-hydroxyindoleacetic acid (5-HIAA)/5-HT: 5-HT in medulla oblongata plus pons (144% of control); 5-HIAA in cortex (162%), striatum (166%), medulla oblongata plus pons (212%), hypothalamus (146%) and mid-brain (167%); 5-HIAA/5-HT in medulla oblongata plus pons (148%) and midbrain (133%). The changes caused by 2-PN were as follows: DA levels in cortex (176% of control, 35 days after dosing); HVA levels in striatum (136%, 1 day); 5-HT levels in hypothalamus (141%, 35 days); 5-HIAA levels in striatum (150%, 1 day), medulla oblongata plus pons (159%, 1 day) and midbrain (146%, 1 day); 5-HIAA/5-HT in striatum (153%, 1 day) and midbrain (134%, 1 day). The results suggest that changes in the 5-HT system are involved in the appearance of the dyskinetic syndrome which was seen in mice 1-2 days after dosing with CRN or 2-PN.

Topics: Animals; Brain; Dopamine; Dyskinesia, Drug-Induced; Male; Mice; Mice, Inbred Strains; Nitriles; Serotonin

A single oral dose of crotononitrile or 2-pentenenitrile induced behavioral abnormalities such as circling, hyperactivity and head twitching. Crotononitrile induced the abnormalities in both olive oil- and CCl4 pretreated mice, whereas 2-pentenenitrile induced the abnormalities only in CCl4-pretreated mice. Seven related compounds induced no behavioral abnormality. The head twitching by crotononitrile and 2-pentenenitrile was either reduced by treatment with serotonin and dopamine antagonists, or enhanced by a serotonin releaser, suggesting that both the serotonin and dopamine systems are involved in the behavioral abnormalities induced by these two nitriles.

Topics: Animals; Behavior, Animal; Carbon Tetrachloride; Dopamine; Drug Interactions; Male; Mice; Mice, Inbred Strains; Nitriles; Psychotropic Drugs; Serotonin