Behavioral abnormalities and apoptotic changes in neurons in mice brain following a single administration of allylnitrile

A single dose of allylnitrile in mice might induce persistent behavioral ab normalities, of which the mechanism is not yet known. The present study was undertaken to explore the relationship between behavioral abnormalities an d pathological changes in the brain of mice following exposure to allylnitr ile. Exposure to allylnitrile (63, 84, and 112 mg/kg, p.o.) resulted in dos e-dependent changes in behavioral abnormalities, including increased locomo tor activity, circling, retropulsion, head twitching, and alteration in ref lexive behavior, which appeared at day 2 postdosing and were persistent thr oughout the experimental period (60 days) at the higher dose levels. Allyln itrile produced neuronal retraction including hyperchromasia of the nuclei in the raphe nuclei, cerebral cortex, hypothalamus, hippocampal CAI and den tate gyrus later than 30 days. No gliosis was observed in these regions. No t all but a significant number of neurons in the hippocampal CAI, medial ha benula and raphe nuclei were immunoreactive to CPP32 (Caspase-3) even at da y 2. These neurons were also positive to Hoechst 33258 staining, indicating allylnitrile caused apoptotic changes in specific neurons when neuronal be haviors became apparent. These apoptotic changes were persistent even in th e area without neuronal contraction such as medial habenula. However, almos t all neurons in these areas were also positive to terminal deoxynucleotidy l transferase mediated dUTP-biotin nick end labeling (TUNEL). It is conceiv able that allylnitrile caused apoptotic changes in neurons but did not alwa ys lead them to cell death immediately. Moreover, even when neuronal contra ction resulted in retention of behavioral abnormalities, onset of these abn ormalities seems to be associated with the impairment in the habenulo-raphe relay due to activation of apoptotic cascade in neurons.