Differential effects of trans-crotononitrile and 3-acetylpyridine on inferior olive integrity and behavioural performance in the rat.

The inferior olive climbing fibre projection is key to cerebellar contributions to motor control. Here we present evidence for a novel tool, trans-crotononitrile (TCN), to selectively inactivate the olive to study its functions. Anatomical, electrophysiological and behavioural techniques have been used in rats to assess the CNS effects of TCN, with a focus on the olivocerebellar projection. These findings were compared with those obtained with 3-acetylpyridine (plus nicotinamide administered 3.5 h later, 3AP + 3.5 h). Fluoro-Jade B cell labelling showed that TCN and 3AP + 3.5 h induce neurodegeneration primarily within the inferior olive, with no other targets in common. Recordings of evoked field potentials on the cerebellar cortical surface showed that both neurotoxins can reduce transmission in climbing fibre but not mossy fibre pathways. Both histological and electrophysiological differences suggest that TCN and 3AP have distinct mechanisms of action. Estimates of the numbers of surviving cells within individual subdivisions of the olive indicate that TCN and 3AP + 3.5 h cause different patterns of subtotal olivary lesion: most surviving neurons are present in the rostral (TCN) or caudal (3AP + 3.5 h) parts of the medial accessory olive, which are associated with two different cerebellar modules: the C2 and A modules, respectively. In behavioural studies, TCN and 3AP + 3.5 h produced differences in motor deficits consistent with the notion that these cerebellar modules have distinct functional responsibilities. Thus, studies using TCN as compared with 3AP + 3.5 h have the potential to shed light on the contributions of different cerebellar modules in motor control.

Behavioural disturbances and sensory pathology following allylnitrile exposure in rats.

Animals exposed to allylnitrile develop permanent abnormalities in motor behaviour, similar to those caused by 3,3'-iminodipropionitrile (IDPN) and crotononitrile. IDPN and crotononitrile effects have been attributed to vestibular hair cell degeneration, but allylnitrile has been suggested to modify behaviour through neuronal degeneration in the CNS. Adult male Long-Evans rats were exposed to allylnitrile (0, 20, 40, 60 mg/kg per day, for 3 days) and the changes in rearing activity and rating scores in tests of vestibular function were assessed. Surface preparations of the vestibular sensory epithelia and the organ of Corti were observed for hair cell loss by scanning electron microscopy. Corneal transparency and concentrations in retina and olfactory bulbs of glial fibrillary acidic protein (GFAP), a marker for reactive gliosis, were also determined, as they are known targets of IDPN toxicity. In a dose-dependent manner, allylnitrile caused corneal opacity and gliosis in the retina and olfactory bulbs, decreased rearing activity and increased the rating scores in tests of vestibular dysfunction, and induced hair cell loss in both the vestibular sensory epithelia and the organ of Corti. The behavioural deficits correlated well with the loss of vestibular hair cells. We conclude that allylnitrile causes permanent modifications in behaviour by loss of vestibular function as IDPN and crotononitrile do and that all these chemicals share other toxic targets, such as the cornea, the retina, and the olfactory system. Data reported here and elsewhere indicate that a number of nitriles show similar neurotoxic properties.