CAFFEINE REGULATES NEUROTENSIN AND CHOLECYSTOKININ MESSENGER-RNA EXPRESSION IN THE RAT STRIATUM

Interactions between dopamine and neurotensin or dopamine and cholecystokinin have been demonstrated in the basal ganglia. Disruption of nigrostriatal dopaminergic transmission results in a dramatic increase in neurotensin messenger RNA and in an induction of cholecystokinin messenger RNA in the striatum. Interaction between striatal dopaminergic and adenosinergic systems have also been reported. Adenosine and the adenosine receptor antagonist, caffeine, regulate gene expression in the striatum. In the present study, in situ hybridization histochemistry was used to investigate the putative regulation of neurotensin and cholecystokinin messenger RNA expression by caffeine in the rat striatum. Using this method, cholecystokinin messenger RNA was undetectable and neurotensin messenger RNA very sparse in the normal striatum. Chronic caffeine administration induced a dramatic increase in neurotensin messenger RNA in the subcallosal region of the caudate-putamen and a moderate increase in the shell sector of the accumbens nucleus. Similarly, caffeine induced a significant striatal expression of cholecystokinin messenger RNA in the dorsolateral and ventrolateral quadrants but was not restricted to the subcallosal area. At the cellular level, this coresponded to a significant labeling of a moderate to high density of medium-sized striatal neurons. These distributions were identical to those of neurotensin and cholecystokinin messenger RNAs observed in the case of disruption of dopaminergic transmission. We therefore concluded that in the intact striatum normally innervated by dopaminergic fibers, caffeine, probably acting through a presynaptic A2 receptor, induced a relative dopamine depletion which in turn led to the induction of neurotensin and cholecystokinin expression in subsets of striatal neurons.