NICOTINE TREATMENT COUNTERACTS PERINATAL ASPHYXIA-INDUCED CHANGES IN THE MESOSTRIATAL LIMBIC DOPAMINE SYSTEMS AND IN MOTOR BEHAVIOR IN THE 4-WEEK-OLD MALE-RAT

In the present study, the effects of nicotine treatment on the changes induced by perinatal asphyxia in exploratory and D-amphetamine-induced behaviour, and in the number of brain tyrosine hydroxylase-immunoreactive nerve cell bodies were investigated in four-week-old male rats. Asphyxia was induced in pups by placing the fetuses, still in their uterus horns removed by hysterectomy from full-term pregnant rats, in a 37 degrees C water bath for 15-16 min or 19-20 min. Surviving male pups were treated with nicotine via suckling from surrogate mothers implanted subcutaneously with Alzet minipumps containing nicotine (0.2 mu mol/kg per h) for four weeks. The minipumps implanted in the mothers of sham-treated animals contained saline only. After treatment, exploratory behaviour and D-amphetamine-induced behaviour was analysed in a computerized ''activity'' box. After the behavioural experiments, the rats were taken for tyrosine hydroxylase immunohistochemistry, and the total number of tyrosine hydroxylase immunoreactive cell bodies were counted in the A9 and A10 regions of the substantia nigra and the ventral tegmental area, respectively. Nicotine serum levels were measured using gas chromatography in selected asphyctic and control pups at different periods after delivery. During the exploratory phase, in saline-nurtured rats, 15-16 min of asphyxia slightly increased (approximate to 25%) locomotion, motility and rearing. In contrast, 19-20 min of asphyxia reduced the locomotion and rearing by approximate to 50%, as compared to controls. An increase in amphetamine-induced behaviours was observed after 15-16 min, but not after 19-20 min of asphyxia, as compared to controls. At the histochemical level, saline-nurtured 19-20 min, but not 15-16 min asphyctic rats showed a significant increase (approximate to 30%) in the number of tyrosine hydroxylase immunoreactive cell bodies in both A9 and A10 regions. The average of nicotine serum levels detected in pups nurtured for a four week period by nicotine-treated mothers was approximate to 5 ng/ml. The nicotine treatment did not significantly change the pattern of behaviour elicited by a new environment or by D-amphetamine in caesarean-delivered controls. However, nicotine counteracted the asphyxia-induced behavioural changes observed in the 19-20 min asphyctic group. Immunohistochemical analysis revealed that the nicotine treatment also counteracted the increase in the number of tyrosine hydroxylase immunoreactive neurons in the A9 and A10 regions observed following 19-20 min of perinatal asphyxia. In conclusion, nicotine treatment counteracted some of the long-term (four week) behavioural and histochemical consequences of perinatal asphyxia in rats. The possible clinical implications of using nicotine as a treatment of asphyxia are discussed.