NEURONAL LOCALIZATION AND MODULATION OF THE D2 DOPAMINE RECEPTOR MESSENGER-RNA IN BRAIN OF NORMAL MICE AND MICE LESIONED WITH 6-HYDROXYDOPAMINE

A novel oligonucleotide probe was designed, characterized and utilized to study the distribution and modulation of the mRNA encoding the D2 dopamine receptor in the brain of the mouse. Using in situ hybridization histochemistry, the highest levels of the D2 receptor mRNA were found in regions of the brain containing the cell bodies and the terminal projection fields of the nigrostriatal, mesolimbic and mesocortical dopaminergic systems. Particularly high levels of the D2 receptor mRNA were found in substantia nigra pars compacta, ventral tegmental area, caudate-putamen and olfactory tubercle. This distribution generally paralleled that of the D2 dopamine receptor. Some areas, not usually associated with dopaminergic systems, also contained significant levels of the D2 receptor mRNA signal. These areas included the hippocampus, certain thalamic nuclei, the inferior colliculus and the spinal trigeminal nucleus of the medulla and spinal cord. Lesioning the corpus striatum with 6-hydroxydopamine had little effect on the level of the D2 receptor mRNA in the striatum but greatly reduced the hybridization signal in the substantia nigra pars compacta and ventral tegmental area. Similarly, lesioning the substantia nigra, nearly abolished the signal in the pars compacta but failed to substantially alter the D2 receptor mRNA signal in the striatum. These results suggest that the D2 receptor mRNA in the substantia nigra pars compacta was localized largely to dopaminergic cell bodies, the terminal projections of which lie in the striatum and codes for D2 autoreceptors and that the D2 receptor mRNA of the striatum is in non-dopaminergic cell bodies that are intrinsic to the striatum and probably codes for post-synaptic D2 receptors. Further, the evidence that lesions of striatum and substantia nigra induced with 6-hydroxydopamine greatly reduced the D2 receptor mRNA signal in the substantia nigra, without concomitantly increasing the D2 receptor mRNA in the striatum, suggests that the increase in dopamine receptor binding in the striatum that is ipsilateral to the lesion with 6-hydroxydopamine and the enhanced behavioral sensitivity to dopaminergic agonists, cannot be accounted for solely by an increase in D2 receptor mRNA.