Dopaminergic neurons of the substantia nigra modulate preproenkephalin A gene expression in rat striatal neurons

Abstract

The messenger RNA coding for preproenkephalin A (PPA) was detected by in situ hybridization in striatal neurons in normal rats and in rats having had the right substantia nigra destroyed by an injection of 6-hydroxydopamine or by electrolysis. Animals were killed 15, 30, 45 and 70 days following the lesion. A double-stranded PPA cDNA and a single-stranded PPA cRNA labeled with 32P or 35S were used as probes to detect the PPA mRNA in brain sections. The controls demonstrated the specificity of the labeling. The darkening of X-ray film in contact with the striatum was appraised, the optical density was measured, and the density of the cells expressing the PPA gene in sections was calculated using an image analyzer. The mean number of silver grains per labeled cell (reflecting the number of PPA mRNA copies per cell) was also calculated using an image analyzer. The 6-hydroxydopamine lesion which destroyed all dopaminergic neurons in the right substantia nigra, provoked a large increase in the number of PPA mRNA copies in enkephalin neurons of the right striatum, and decreased the number of cells expressing the PPA mRNA in the left striatum. These variations were not time dependent. PPA neurons of the septum seemed to follow the same variations while those of the olfactory tubercle did not. Electrolytic lesions that spared 20–40% of the dopamine neurons in the substantia nigra provoked similar variations, but less intense. These results show that a unilateral alteration of the dopaminergic nigrostriatal pathway modifies PPA gene expression in the ipsi- and in the contralateral striatum, to a degree dependent on the extent of the lesion. These results suggest that dopaminergic nigral neurons tonically inhibit PPA biosynthesis in the ipsilateral striatum and influence the PPA gene expression in a subpopulation of the enkephalin neurons in the contralateral striatum. These results show that a permanent alteration of an endogenous neurotransmitter system can effect gene transcription for neuropeptides in its target neurons.