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 transplants within host brain we studied the postsynaptic effects induced by their stimulation by following the expression of immediate early genes c-fos, c-jun and egr-1. This study was conducted nine months after the intrastriatal implantation of embryonic mesencephalic neurons to rat pups having sustained a unilateral lesion of the nigrostriatal dopaminergic system. We examined whether, when challenged with d-amphetamine: (1) dopaminergic grafts transplanted into the previously denervated neonatal neostriatum lead to a normal activation of postsynaptic striatal neurons in term of immediate early genes activation; and (2) whether this activation is related to the action of the dopamine released from the grafts using a dopaminergic D1 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 partially counteracted by a pre-treatment with the D1 antagonist SCH 23390, 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 lesion. The transplant reversed the effect of the lesion and, moreover, led to a c-fos over-expression in the dorsolateral neostriatum and the globus pallidus. These overcompensations positively correlated with the 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 adult-stage lesion, modifies the reactivity of c-fos in the neostriatum to stress, presumably in relation with compensatory reorganizations occurring following the neonatal lesion. Grafts made into neonates, when challenged with amphetamine, induce an abnormal c-fos expression which can predict the degree of overshoot observed for rotation activity. This over-expression, which depends upon the stimulation of D1 receptors, indicate an abnormal activation of postsynaptic target cells by the grafts.
Abrous
D N
DN
INSERM U.259, Bordeaux, France.
Desjardins
S
S
Sorin
B
B
Hancock
D
D
Le Moal
M
M
Herman
J P
JP
D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D016380:Brain Tissue Transplantation / Q000502:physiology*; D017690:Cell Transplantation / Q000502:physiology; D003913:Dextroamphetamine / Q000494:pharmacology; D004298:Dopamine / Q000502:physiology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D016332:Fetal Tissue Transplantation / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D017781:Genes, Immediate-Early / Q000502:physiology*; D007150:Immunohistochemistry; D008297:Male; D008969:Molecular Sequence Data; D017072:Neostriatum / Q000378:metabolism* / Q000637:transplantation*; D051381:Rats; D017208:Rats, Wistar; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D012399:Rotation; D013239:Stereotyped Behavior / Q000187:drug effects
D018765:Dopamine Uptake Inhibitors; D017447:Receptors, Dopamine D1; D003913:Dextroamphetamine; D004298:Dopamine