PHENOTYPE OF STRIATAL CELLS EXPRESSING C-FOS FOLLOWING AMPHETAMINE TREATMENT OF RATS WITH INTRASTRIATAL DOPAMINERGIC GRAFTS

Activation of the nigrostriatal dopaminergic system by psychostimulant s such as amphetamine increases c-Fos expression in the striatum, most ly in the striatonigral substance P-ergic pathway. This effect is grea tly reduced in the neostriatum deprived of dopaminergic afferents. Dop aminergic grafts implanted into the denervated neostriatum restore the reactivity of the striatum to amphetamine. However, the number of str iatal neurons expressing c-Fos is greatly increased in the graft-beari ng striatum compared with the normal striatum. We examined whether thi s increase in the number of c-fos-expressing neurons corresponds to th e recruitment of a new neuronal population, or whether it reflects an increase in the proportion of substance P-ergic neurons exhibiting act ivation of c-Fos. Adult rats received a unilateral 6-hydroxydopamine l esion of the ascending dopaminergic mesotelencephalic pathway, and a s uspension of embryonic mesencephalic neurons was subsequently implante d into the denervated neostriatum. Three months after implantation, an imals were injected with d-amphetamine (5 mg/kg) and killed 2 h later. in the first experiment, striatal sections were processed to visualiz e both c-Fos protein, by immunohistochemistry, and preproenkephalin A or substance P, by in sift, hybridization. in the second experiment, c -Fos and neuropeptide Y were visualized on the same sections. in addit ion, some sections incubated with anti-c-fos antibody were counterstai ned with toluidine blue in order to determine whether cholinergic neur ons were expressing c-Fos following amphetamine treatment. The density of neurons expressing c-Fos following amphetamine treatment was three -fold higher in the graft-bearing striata than in the striata of contr ol animals. Approximately 75% of the c-Fos expressing cells were subst ance P-ergic in control animals whereas 6% were enkephalinergic and on ly a few were neuropeptide Y-ergic or cholinergic. Similar proportions were found in the graft-bearing striatum, signifying that the pattern of activation of c-fos following amphetamine administration is not ch anged by the graft. Thus, the increased expression of c-Fos predominan tly reflects a graft-induced increase in the proportion of neurons exp ressing c-Fos within the same population of neurons which normally exp resses c-Fos in the striatum, i.e. the striatonigral substance P-ergic neurons; there is no recruitment of a new neuronal population. This i ncreased activation of the striatonigral substance P-ergic pathway may underlie the abnormal behavioural reactions brought about by amphetam ine-induced stimulation of the implanted dopaminergic neurons.