Chemical signalling in the basal ganglia : manipulation of dopamine neurotransmission
The role of endogenous dopamine in mediating striatal preproenkephalin A, proneurotensin and preprosomatostatin gene expression in vivo was studied in monkeys treated with the catecholamine neurotoxin MPTP, and in rats treated acutely with selective dopamine D1 and D2 receptor antagonists. The effect on striatal neuropeptide gene expression were assessed by in situ hybridisation. The effect of MPTP treatment on the striatal content of substance P-like immunoreactivity was also studied by quantitative immunocytochemistry. Chronic MPTP treatment resulted in a significant loss (> 90&37) of tyrosine hydroxylase mRNA-containing cells in the ipsilateral substantia nigra pars compacta and ventral tegmental area; an increase in preproenkephalin A gene expression; and a decrease in the tissue content of substance P-like immunoreactivity in the ipsilateral striatum. Selective blockade of D2 receptors in rats also resulted in an increase in preproenkephalin A gene expression, whereas blockade of D1 receptors reduced expression of this gene, hence it appears that the dominant action of endogenous dopamine on preproenkephalin gene expression is via D2 receptors. Acute dopamine receptor blockade has different effects on other peptide genes in the striatum: proneurotensin gene expression was activated following D2 but not D1 receptor blockade, while preprosomatostatin gene expression was attenuated following blockade of either receptor subtype. The coupling of receptor activation to gene expression was studied by treatment of rats with pertussis toxin, which irreversibly ribosylates membrane Gi/o proteins. Microinjection of pertussis toxin into the striatum led to an increase in expression of both proneurotensin and preproenkephalin A genes, consistent with the hypothesis that Gi/o proteins mediate the effects of D2 receptor activation on striatal enkephalin and neurotensin cells.