CHANGES IN STRIATAL IMMEDIATE-EARLY GENE-EXPRESSION FOLLOWING NEONATAL DOPAMINERGIC LESION AND EFFECTS OF INTRASTRIATAL DOPAMINERGIC TRANSPLANTS

To evaluate the functional integration of neonatal dopaminergic transp lants within host brain we studied the postsynaptic effects induced by their stimulation by following the expression of immediate early gene s c-fos, c-jun and egr-1. This study was conducted nine months after t he intrastriatal implantation of embryonic mesencephalic neurons to ra t pups having sustained a unilateral lesion of the nigrostriatal dopam inergic system. We examined whether, when challenged with d-amphetamin e: (1) dopaminergic grafts transplanted into the previously denervated neonatal neostriatum lead to a normal activation of postsynaptic stri atal neurons in term of immediate early genes activation; and (2) whet her this activation is related to the action of the dopamine released from the grafts using a dopaminergic D-1 antagonist. Following a mild stress-injection of saline--c-fos expression was high in the lesioned neostriatum when compared with control animals. This effect was only p artially counteracted by a pre-treatment with the D-1 antagonist SCH 2 3390, but was abolished by the graft. Administration of d-amphetamine increased c-fos expression in the neostriatum and the globus pallidus of the control group. This activation was partially blocked by the les ion. The transplant reversed the effect of the lesion and, moreover, l ed to a c-fos over-expression in the dorsolateral neostriatum and the globus pallidus. These overcompensations positively correlated with th e abnormal rotation induced by d-amphetamine in the same animals. Pre- treatment with SCH 23390 blocked the effect of d-amphetamine on c-fos expression in control and grafted animals. Similar results were found for egr-1 but not c-jun expression. It is concluded that the neonatal lesion of the nigrostriatal dopaminergic pathway, in contrast to the a dult-stage lesion, modifies the reactivity of c-fos in the neostriatum to stress, presumably in relation with compensatory reorganizations o ccurring following the neonatal lesion. Grafts made into neonates, whe n challenged with amphetamine, induce an abnormal c-fos expression whi ch can predict the degree of overshoot observed for rotation activity. This over-expression, which depends upon the stimulation of D-1 recep tors, indicate an abnormal activation of postsynaptic target cells by the grafts. (C) 1996 IBRO. Published by Elsevier Science Ltd.