crotononitrile and allyl-cyanide

Konzo and lathyrism are associated with consumption of cassava and grass pea, respectively. Cassava consumption has also been associated with a third disease, tropical ataxic neuropathy (TAN). This review presents a new unifying hypothesis on the causative agents for these diseases: namely, that they are nitriles, compounds containing cyano groups. The diseases may be caused by different but similar nitriles through direct neurotoxic actions not mediated by systemic cyanide release. Both cassava and Lathyrus contain nitriles, and other unidentified nitriles can be generated during food processing or in the human body. Available data indicate that several small nitriles cause a variety of neurotoxic effects. In experimental animals, 3,3'-iminodipropionitrile (IDPN), allylnitrile and cis-crotononitrile cause sensory toxicity, whereas hexadienenitrile and trans-crotononitrile induce selective neuronal degeneration in discrete brain regions. IDPN also induces a neurofilamentous axonopathy, and dimethylaminopropionitrile is known to cause autonomic (genito-urinary) neurotoxicity in both humans and rodents. Some of these actions depend on metabolic bioactivation of the parental nitriles, and sex- and species-dependent differences in susceptibility have been recorded. Recently, neuronal degeneration has been found in rats exposed to acetone cyanohydrin. Taken together, the neurotoxic properties of nitriles make them excellent candidates as causative agents for konzo, lathyrism and TAN.

Topics: Aminopropionitrile; Animals; Brain; Cyanides; Humans; Lathyrism; Lathyrus; Manihot; Molecular Structure; Nerve Degeneration; Neurotoxins; Nitriles

Nitriles are widely used in industry as plastics, solvents, and synthetic intermediates. It has been shown that the thermal degradation of acrylonitrile-based plastics leads to the emission of a great variety of nitriles. Exposure of humans and experimental animals to some nitriles has been shown to lead to disorders of the central nervous, hepatic, cardiovascular, renal, and gastrointestinal systems. Iminodipropionitrile has long been known to induce in experimental animals behavioral syndromes that other nitriles have not been reported to induce. Recently, we have found that a single administration of allylnitrile, an analog of acrylonitrile, induces in rodents behavioral abnormalities including head twitching, head weaving, random circling, increased locomotor activity, backward pedaling, pivoting, and somersaulting. The induced abnormalities were persistent. Crotononitrile and 2-pentenenitrile also are able to produce behavioral abnormalities. Thus, the nitriles appear as a new class of neurotoxic compounds with potential relevance to the human health. The mechanism by which allylnitrile induces and maintains the behavioral abnormalities is summarised below. 1. Allylnitrile activates the serotonin (5-HT) system in the central nervous system, and as a consequence activation of 5-HT-2 receptors due to increased 5-HT may lead to induction of head twitching. 2. Although the data available indicate that the dopamine (DA) system may be involved in allylnitrile-induced behavioral abnormalities, it remains unknown how the DA system relates to the abnormalities. 3. Allylnitrile decreases the noradrenaline level in the central nervous system, which is thought to be secondary to the 5-HT system activation mentioned above. The allylnitrile-induced head twitching, however, may occur in consequence to both enhanced beta-adrenoceptor stimulation and to the removal of tonic inhibitory control by alpha-2-adrenoceptors. 4. The neuropathological data indicate an important role of the medial habenular and raphe nuclei in allylnitrile-induced behavioral abnormalities. Onset of the behavioral abnormalities appears to be associated with the impairment in the medial habenulo-raphe relay owing to activation of apoptotic cascade in neurons. 5. On the basis of the findings with iminodipropionitrile and crotononitrile, allylnitrile might produce pathological changes in the vestibular sensory hair cells. Further studies are needed to explore the mechanism underlying the allylnitr

Topics: Animals; Behavior, Animal; Brain; Dopamine; Humans; Mice; Nitriles; Norepinephrine; Rats; Serotonin; Vestibule, Labyrinth

Several nitriles, including allylnitrile and cis-crotononitrile, have been shown to be ototoxic and cause hair cell degeneration in the auditory and vestibular sensory epithelia of mice. However, these nitriles can also be lethal due in large part to the microsomal metabolic release of cyanide, which is mostly dependent on the activity of the 2E1 isoform of the cytochrome P450 (CYP2E1). In this study, we co-administered mice with a nitrile and, to reduce their lethal effects, a selective CYP2E1 inhibitor: diallylsulfide (DAS) or trans-1,2-dichloroethylene (TDCE). Both in female 129S1/SvImJ (129S1) mice co-treated with DAS and cis-crotononitrile and in male RjOrl:Swiss/CD-1 (Swiss) mice co-treated with TDCE and allylnitrile, the nitrile caused a dose-dependent loss of vestibular function, as assessed by a specific behavioral test battery, and of hair cells, as assessed by hair bundle counts using scanning electron microscopy. In the experiments, the CYP2E1 inhibitors provided significant protection against the lethal effects of the nitriles and did not diminish the vestibular toxicity as assessed by behavioral effects in comparison to animals receiving no inhibitor. Additional experiments using a single dose of allylnitrile demonstrated that TDCE does not cause hair cell loss on its own and does not modify the vestibular toxicity of the nitrile in either male or female 129S1 mice. In all the experiments, high vestibular dysfunction scores in the behavioral test battery predicted extensive to complete loss of hair cells in the utricles. This provides a means of selecting animals for subsequent studies of vestibular hair cell regeneration or replacement.

Topics: Allyl Compounds; Animals; Behavior, Animal; Cell Death; Cytochrome P-450 CYP2E1 Inhibitors; Deafness; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Hair Cells, Vestibular; Male; Mice; Mice, 129 Strain; Microscopy, Electron, Scanning; Nitriles; Sulfides; Vestibular Function Tests; Vestibule, Labyrinth

IDPN (3,3'-iminodipropionitrile) causes a neurofilamentous proximal axonopathy. This study addressed the hypothesis that the butenenitriles (allylnitrile, cis-crotononitrile and trans-crotononitrile) have an IDPN-like axonopathic potential. First, male adult rats were exposed (i.p.) to IDPN, allylnitrile, cis-crotononitrile or trans-crotononitrile at 3.25 mmol/kg/day, 0.89 mmol/kg/day, 1.79 mmol/kg/day, or 3.75 mmol/kg/day for 3 consecutive days, respectively; lumbar dorsal root ganglia were examined for axonal swelling eight days after dosing. IDPN caused axonal swelling, a few swollen axons were recorded in one trans-crotononitrile animal, and no axonal abnormalities were observed following cis-crotononitrile or allylnitrile. To further evaluate trans-crotononitrile, additional rats were given this nitrile through a 10-day i.p. dosing schedule (2.5 mmol/kg/day, 2.75 mmol/kg/day, 3.0 mmol/kg/day or 3.25 mmol/kg/day) or a 9-week drinking water exposure (12.3, 24.6 and 49.1mM, three weeks each), and examined by light and electron microscopy. Semithin sections revealed no overt swelling in axons from several locations of the nervous system after trans-crotononitrile; quantitative analysis in the L5 dorsal root ganglion showed no increase in proximal axon diameter in comparison to control animals. At the transmission electron microscopy level, pathological effects were mild; they were mostly found in the animals submitted to the 10-day dosing regimen, and did not include evidence of significant axonal swelling. Although an axonopathic potential for the three unsaturated 4-carbon nitriles cannot be excluded, the present data indicated that this potential is significantly lower than that of IDPN.

Topics: Animals; Axons; Behavior, Animal; Ganglia, Spinal; Indicators and Reagents; Male; Microscopy, Electron; Motor Activity; Nitriles; Rats; Rats, Long-Evans

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

The effects on embryonic development of a series of eight saturated (acetonitrile, propionitrile, and n-butyronitrile) and unsaturated (acrylonitrile, methacrylonitrile, allylnitrile, cis-2-pentenenitrile, and 2-chloroacrylonitrile) nitriles were compared in vitro using the whole embryo culture system. Day 10 rat embryos were cultured for 46 h in rat serum in the presence of either of these chemicals. All the tested chemicals produced concentration-dependent decreases in growth and differentiation and increases in the incidences of morphologically abnormal embryos. A wide range of embryotoxic potency was observed, with 2-chloroacrylonitrile and acetonitrile at the extremes (lowest effect levels of 50 microM and 40 mM, respectively). No common pattern could be drawn for all the eight nitriles tested in vitro, although there were some similarities between the malformations elicited by propionitrile and n-butyronitrile or between those elicited by the five unsaturated nitriles. Presence of a rat hepatic microsomal fraction and NADPH in the culture medium enhanced the embryotoxic effects of the five unsaturated nitriles tested but had no effects on saturated nitriles embryotoxicity. In addition to these in vitro experiments, pregnant rats were given a single oral dose of each compound on Day 10 of gestation and the embryos were evaluated on Day 12 of gestation, i.e., at a time of development corresponding to the developmental stage at the end of the whole embryo culture. All the nitriles investigated produced the characteristic defects developed by embryos exposed to sodium cyanide in utero or in culture. Our results provide further evidence that maternal production of cyanide may contribute to the developmental toxicity of saturated and unsaturated nitriles and suggest that distinct metabolites derived from microsomal metabolism of unsaturated nitriles may also play a role.

Topics: Abnormalities, Drug-Induced; Acetonitriles; Acrylonitrile; Animals; Culture Techniques; Dose-Response Relationship, Drug; Embryo, Mammalian; Embryonic and Fetal Development; Female; Gestational Age; Methacrylates; Microsomes, Liver; NADP; Nitriles; Pregnancy; Rats; Rats, Sprague-Dawley; Sodium Cyanide; Structure-Activity Relationship

Allylnitrile and crotononitrile induce behavioral abnormalities in mice. To explore the possible involvement of the vestibular system in these behavioral abnormalities, the expression of Fos protein, used as an indicator of neuronal activity, was examined within various brain structures in allylnitrile-, crotononitrile- and vehicle-treated mice. In each nitrile-treated mouse, Fos expression was observed in brain structures, which were divided into two groups. The structures in group 1 showed Fos expression between 1.5 h and 2 days postdosings, and in those in group 2 expression remained for up to 30 days postdosing. As most of these structures, especially in group 2, were identical to some Fos-positive structures observed after unilabyrinthectomy, the present results indicate that each nitrile induces Fos expression by causing a change in the peripheral vestibular system, resulting in behavioral abnormalities.

Topics: Animals; Behavior, Animal; Brain Chemistry; Dyskinesia, Drug-Induced; Male; Mice; Nitriles; Proto-Oncogene Proteins c-fos; Vestibular Nuclei

A single dose of allylnitrile in mice might induce persistent behavioral abnormalities, of which the mechanism is not yet known. The present study was undertaken to explore the relationship between behavioral abnormalities and pathological changes in the brain of mice following exposure to allylnitrile. Exposure to allylnitrile (63, 84, and 112 mg/kg, p.o.) resulted in dose-dependent changes in behavioral abnormalities, including increased locomotor activity, circling, retropulsion, head twitching, and alteration in reflexive behavior, which appeared at day 2 postdosing and were persistent throughout the experimental period (60 days) at the higher dose levels. Allylnitrile produced neuronal retraction including hyperchromasia of the nuclei in the raphe nuclei, cerebral cortex, hypothalamus, hippocampal CA1 and dentate gyrus later than 30 days. No gliosis was observed in these regions. Not all but a significant number of neurons in the hippocampal CA1, medial habenula and raphe nuclei were immuno-reactive to CPP32 (Caspase-3) even at day 2. These neurons were also positive to Hoechst 33258 staining, indicating allylnitrile caused apoptotic changes in specific neurons when neuronal behaviors became apparent. These apoptotic changes were persistent even in the area without neuronal contraction such as medial habenula. However, almost all neurons in these areas were also positive to terminal deoxynucleotidyl transferase mediated dUTP-biotin nick end labeling (TUNEL). It is conceivable that allylnitrile caused apoptotic changes in neurons but did not always lead them to cell death immediately. Moreover, even when neuronal contraction resulted in retention of behavioral abnormalities, onset of these abnormalities seems to be associated with the impairment in the habenulo-raphe relay due to activation of apoptotic cascade in neurons.

Topics: Animals; Apoptosis; Behavior, Animal; Bisbenzimidazole; Brain; Caspase 3; Caspases; DNA Fragmentation; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Histocytochemistry; Immunohistochemistry; In Situ Nick-End Labeling; Male; Mice; Motor Activity; Neurons; Nitriles; Time Factors

3,3'-Iminodipropionitrile (IDPN) exposure causes a neurofilamentous axonopathy and olfactory, audiovestibular and visual toxicity. Many events relevant to these effects and the neurotoxic properties of nitriles as a class remain to be elucidated. We characterized the gliosis associated with the IDPN-induced retinal degeneration in comparison to other effects on the visual and central nervous systems. Gliosis was quantified using an ELISA for the intermediate filament protein, glial fibrillary acidic protein (GFAP). IDPN (0-400 mg kg-1 day-1x3 days, i.p.) caused corneal opacity and dose- and time-dependent increases in retinal GFAP, up to 26-28 fold of control values at 4 weeks post-exposure; a second peak occurred at 16 weeks. In contrast, GFAP peaked at 1 week in olfactory bulbs (OB), cingulate cortex and hippocampus. Cerebellum and striatum showed no gliosis. Retinal dopamine decreased within 2 weeks. Delayed GFAP increases occurred in superior and inferior colliculi. Retina and superior colliculi also showed increased [3H]PK-11195 binding. Histological analysis demonstrated progressive degeneration and gliosis in retina and colliculi. Taken together, the data indicate that primary and secondary degenerative events occur in the retina, and that this retinal degeneration induces GFAP increases in retina and superior colliculus. In addition, GFAP assays demonstrated that the retinal toxicity of IDPN is enhanced by CCl4 hepatotoxicity and blocked by methimazole inhibition of flavin-mono-oxygenases, similarly to its ototoxicity. GFAP assays also indicated that neither vestibulotoxic doses of crotononitrile nor olfatotoxic doses of dichlobenil damage the retina. The data support the use of GFAP assays for assessing the retinal toxicity of IDPN and other nitriles.

Topics: Animals; Antineoplastic Agents; Auditory Cortex; Benzamides; Cerebral Cortex; Glial Fibrillary Acidic Protein; Gliosis; Herbicides; Inferior Colliculi; Isoquinolines; Male; Neuroglia; Neurons, Afferent; Neurotoxins; Nitriles; Olfactory Pathways; Rats; Rats, Long-Evans; Retina; Retinal Degeneration; Superior Colliculi; Tritium; Visual Cortex

N-Alkylation of 17-azasteroid lactams (16-oxo-17-azaandrost-5-en-3 beta-ol acetate 3 and its D-homo analog 4) was studied. It has been found that both lactams are readily alkylated with iodomethane or iodoethane. In contrast to this there was no reaction with 2-iodo-6-methylheptane due to the steric hindrance. 1,4-Addition of lactam to the conjugated systems was also studied. The addition to acrylonitrile proved to be easy compared to crotononitrile. However the efficient addition to the latter compound was also attained by using potassium t-butoxide as a base in t-butanol.

Topics: Acrylonitrile; Alkylation; Androstenols; Azasteroids; Hydrocarbons, Iodinated; Indicators and Reagents; Nitriles

Allylnitrile induces in rats persistent behavioral abnormalities, including head twitching, following a single administration. We studied the role of 5-hydroxytryptamine (5-HT) and noradrenaline (NA) systems in the brain of rats in inducing and maintaining the head twitching. Allynitrile (1.49 mmol/kg) induced 5-HT system activation in all areas of the brain studied 1-4 days after oral administration, and a reduction in the content of NA in the hippocampus, cortex and hypothalamus 1 day after dosing, in the hippocampus, cortex, hypothalamus and midbrain 2 days after dosing, and in the hypothalamus 4 days after dosing. Allylnitrile induced no change in the content of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA) or NA 7-28 days after dosing. Pretreatment with 5,7-dihydroxytryptamine (5,7-DHT) suppressed the allylnitrile-induced head twitching, and decreased the contents of 5-HT and 5-HIAA in almost all areas of the brain throughout the observation period, as well as the ratio of 5-HIAA/5-HT in the medulla oblongata plus pons from 1 to 30 days after dosing with allylnitrile. No change in NA was observed in any areas of the brain. Pretreatment with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) increased the head twitching induced by allylnitrile, and decreased the content of NA in all areas of the brain throughout the observation period, without any change in the contents of 5-HT or 5-HIAA or in the ratio of 5-HIAA/5-HT. The present results suggest the involvement of 5-HT and NA systems in allylnitrile-induced head twitching.

Topics: 5,7-Dihydroxytryptamine; Animals; Benzylamines; Dyskinesia, Drug-Induced; Head; Hydroxyindoleacetic Acid; Male; Nitriles; Norepinephrine; Rats; Rats, Wistar; Serotonin

In liver fractions from male Sprague-Dawley rats, the metabolism of allylnitrile (ALN) to cyanide (CN-) was localized in the microsomal fraction and required NADPH and oxygen for maximal activity. The biotransformation of ALN to CN- was characterized with respect to time, microsomal protein concentration, pH and temperature. Metabolism of ALN was increased in microsomes obtained from phenobarbital-treated rats (160% of control) and decreased with cobaltous chloride and beta-diethyl aminoethyl-2,2-diphenyl pentanoate (SKF 525-A) treatments (48% of control). Addition of SKF 525-A to the incubation mixtures inhibited ALN metabolism to CN-. Addition of the epoxide hydrolase inhibitor, 1,1,1-trichloropropane 2,3-oxide, decreased the formation of CN- from ALN. Addition of glutathione, cysteine, D-penicillamine, and 2-mercaptoethanol enhanced the release of CN- from ALN. These findings indicate that ALN is metabolized to CN- via a cytochrome P-450-dependent mixed-function oxidase system.

Topics: Animals; Biotransformation; Cyanides; Hydrogen-Ion Concentration; Magnesium Chloride; Male; Microsomes, Liver; NADP; Nitriles; Phenobarbital; Rats; Rats, Sprague-Dawley; Sulfhydryl Compounds

Animals exposed to 3,3'-iminodipropionitrile (IDPN) or to several similar nitriles develop a permanent syndrome of behavioral abnormalities. The present work addressed the hypothesis that this syndrome is caused by a toxic effect of these nitriles on the peripheral vestibular system. Male Long-Evans rats were given acute doses of IDPN (0, 200, 400, 600, or 1000 mg/kg, ip) and assessed for a number of behaviors indicative of vestibular function at postdosing times ranging from 1 day to 9 weeks. The pathological effects of IDPN on the morphology of the vestibular sensory epithelia were studied by scanning electron microscopy at 1,2,4, and 21 days after exposure. The behavioral study revealed dose-dependent deficits in vestibular function after IDPN. Alterations in vestibular morphology occurred at the same doses of IDPN that induced behavioral changes (400-1000 mg/kg). The pathological alterations after IDPN consisted of degeneration of the vestibular sensory hair cells, and no hair cells remained in the vestibular receptors 3 weeks after the 1000 mg/kg dose. A good correlation was also found for the time-course characteristics of the behavioral and the morphopathological effects of IDPN. The vestibular sensory epithelia displayed a regional pattern of differential sensitivity to the toxic effect of IDPN. Both intraepithelial and interepithelial differences in sensitivity were found. Crotonitrile (250 mg/kg, ip), which induces the same behavioral syndrome, was found to induce also degeneration of the vestibular hair cells. We conclude that IDPN and the similar nitriles that cause the same behavioral abnormalities are toxic to the peripheral vestibular system.

Topics: Animals; Behavior, Animal; Body Weight; Dose-Response Relationship, Drug; Hair Cells, Vestibular; Male; Neurotoxins; Nitriles; Rats

Allylnitrile is known to induce head twitching in rats and mice. Carbon tetrachloride (CCl4) impairs the hepatic mixed function oxidase system and lowers acute toxicity of nitriles. In the present study we examined the effect of CCl4 on the allylnitrile-induced head twitching to elucidate the mechanism of the abnormal behavior. In rats, CCl4 pretreatment inhibited the head twitching induced by allylnitrile (1.49 mmole/kg, po), the maximal and dose-dependent inhibition occurring when CCl4 was given just prior to the nitrile administration, while CCl4 post-treatment had no effect on the head twitching. A dose-dependent inhibition of cyanide formation arising from allylnitrile in the liver and a dose-dependent attenuation of acute toxicity of allylnitrile were observed when CCl4 was given just prior to the nitrile administration in rats and mice. Intracerebroventricular injection of allylnitrile (2.0 to 18 mumole/brain) induced no head twitching in rats. The results suggest that active metabolites of allylnitrile are responsible for the head twitching, and that CCl4 prevents the metabolic process in the liver by forming conjugates with allylnitrile, resulting in the inhibition of the head twitching.

Topics: Animals; Behavior, Animal; Carbon Tetrachloride; Cyanides; Dose-Response Relationship, Drug; Liver; Male; Mice; Mice, Inbred Strains; Nitriles; Rats; Rats, Wistar; Tic Disorders

The developmental toxicities of eight aliphatic mononitriles were studied in Sprague-Dawley rats after inhalation exposure for 6 hr/day, during Days 6 to 20 of gestation. The range of exposure concentrations for acetonitrile was 900 to 1800 ppm; for propionitrile and n-butyronitrile, 50 to 200 ppm; for isobutyronitrile, 50 to 300 ppm; for acrylonitrile and methacrylonitrile, 12 to 100 ppm; for allylnitrile 12 to 50 ppm; and for 2-chloroacrylonitrile, 1 to 12 ppm. Embryolethality was observed after exposure to 1800 ppm acetonitrile, 200 ppm propionitrile, 300 ppm isobutyronitrile; fetotoxicity was observed after exposure to 200 ppm propionitrile, n-butyronitrile, or isobutyronitrile, or to 25 ppm acrylonitrile in the presence of overt signs of maternal toxicity. In the absence of significant maternal toxicity, allylnitrile caused embryolethality, fetotoxicity, and clear teratogenicity at 50 ppm, and n-butyronitrile and methacrylonitrile caused fetotoxicity at 200 ppm and 100 ppm, respectively. While maternal toxicity was observed for 2-chloroacrylonitrile, it did not cause significant embryonal or fetal toxicity up to 12 ppm.

Topics: Acetonitriles; Administration, Inhalation; Animals; Body Weight; Embryo, Mammalian; Female; Fetus; Male; Nitriles; Pregnancy; Rats; Rats, Sprague-Dawley; Reproduction; Teratogens

The effects of allylnitrile (ALN), which induces a long-term dyskinesia in mice, on the metabolism of serotonin (5-HT) and dopamine (DA) were studied after a single administration. One day after injection, ALN produced a significant increase in the levels of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA): 5-HT in the brain cortex, medulla oblongata plus pons, hypothalamus and midbrain; 5-HIAA in the cortex, medulla oblongata plus pons, striatum, hypothalamus and midbrain; the ratio of 5-HIAA/5-HT in the medulla oblongata plus pons, striatum and midbrain; HVA in the cortex and midbrain. These changes were not seen 10 and 35 days after injection when the animals were showing behavioral abnormalities. The present findings suggest that changes in 5-HT and DA metabolism are involved in the appearance of the dyskinetic syndrome.

Topics: Administration, Oral; Animals; Brain; Chromatography, High Pressure Liquid; Dopamine; Dyskinesia, Drug-Induced; Hydroxyindoleacetic Acid; Male; Mice; Nitriles; Serotonin

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

Topics: Animals; Cyanides; Cytosol; Glutathione; Glutathione Transferase; In Vitro Techniques; Male; Methacrylates; Mitochondria, Liver; Nitriles; Rats; Rats, Inbred Strains

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

A single oral dose of allylnitrile (ALN) in mice pretreated with CCl4 induced behavioral abnormalities such as circling, hyperactivity, and head twitching, which lasted for a 4-month observation period. Histopathologically hemorrhage, demyelinated fibers and necrotic neurons were observed in the midbrain and pons 40 to 50 days after the administration of ALN. The head twitching was either reduced by treatment with serotonin and dopamine antagonists or enhanced by a serotonin releaser, suggesting that both serotonin and dopamine systems are involved in the behavioral abnormalities by ALN. These disorders by ALN may be used as an animal model of the dyskinetic syndrome.

Topics: Animals; Behavior, Animal; Brain; Carbon Tetrachloride; Cerebral Hemorrhage; Male; Mice; Movement Disorders; Nitriles; Time Factors