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Antipsychotic drugs activate similar signaling proteins in the striatum by blocking dopamine D<jats:sub>2<\/jats:sub>receptors (D2Rs). However, the neurons in which these pathways are activated by psychotropic drugs are not precisely identified. We used transgenic mice, in which enhanced green fluorescent protein (EGFP) expression was driven by D1R promoter (<jats:italic>drd1a<\/jats:italic>-EGFP) or D2R promoter (<jats:italic>drd2<\/jats:italic>-EGFP). We confirmed the expression of<jats:italic>drd1a<\/jats:italic>-EGFP in striatonigral and<jats:italic>drd2<\/jats:italic>-EGFP in striatopallidal neurons.<jats:italic>Drd2<\/jats:italic>-EGFP was also expressed in cholinergic interneurons, whereas no expression of either promoter was detected in GABAergic interneurons. Acute cocaine treatment increased phosphorylation of ERK and its direct or indirect nuclear targets, mitogen- and stress-activated kinase-1 (MSK1) and histone H3, exclusively in D1R-expressing output neurons in the dorsal striatum and nucleus accumbens. Cocaine-induced expression of c-Fos and Zif268 predominated in D1R-expressing neurons but was also observed in D2R-expressing neurons. One week after repeated cocaine administration, cocaine-induced signaling responses were decreased, with the exception of enhanced ERK phosphorylation in dorsal striatum. The responses remained confined to D1R neurons. In contrast, acute haloperidol injection activated phosphorylation of ERK, MSK1, and H3 only in D2R neurons and induced<jats:italic>c-fos<\/jats:italic>and<jats:italic>zif268<\/jats:italic>predominantly in these neurons. Our results demonstrate that cocaine and haloperidol specifically activate signaling pathways in two completely segregated populations of striatal output neurons, providing direct evidence for the selective mechanisms by which these drugs exert their long-term effects.<\/jats:p>","DOI":"10.1523\/jneurosci.1039-08.2008","type":"journal-article","created":{"date-parts":[[2008,5,28]],"date-time":"2008-05-28T18:08:09Z","timestamp":1211998089000},"page":"5671-5685","source":"Crossref","is-referenced-by-count":599,"title":["Opposing Patterns of Signaling Activation in Dopamine D<sub>1<\/sub>and D<sub>2<\/sub>Receptor-Expressing Striatal Neurons in Response to Cocaine and 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