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(2012)<jats:bold>122<\/jats:bold>, 1054\u20131064.<\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Concomitant therapies combining psychostimulants such as methylphenidate and selective serotonin reuptake inhibitors (SSRIs) are used to treat several mental disorders, including attention\u2010deficit hyperactivity disorder\/depression comorbidity. The neurobiological consequences of these drug combinations are poorly understood. Methylphenidate alone induces gene regulation that mimics partly effects of cocaine, consistent with some addiction liability. We previously showed that the SSRI fluoxetine potentiates methylphenidate\u2010induced gene regulation in the striatum. The present study investigated which striatal output pathways are affected by the methylphenidate\u2003+\u2003fluoxetine combination, by assessing effects on pathway\u2010specific neuropeptide markers. Results demonstrate that fluoxetine (5\u2003mg\/kg) potentiates methylphenidate (5\u2003mg\/kg)\u2010induced expression of substance P and dynorphin, markers for direct pathway neurons. In contrast, no drug effects on the indirect pathway marker enkephalin were found. Because methylphenidate alone has minimal effects on dynorphin, the potentiation of dynorphin induction represents a more cocaine\u2010like effect for the drug combination. On the other hand, the lack of an effect on enkephalin suggests a greater selectivity for the direct pathway compared with psychostimulants such as cocaine. Overall, the fluoxetine potentiation of gene regulation by methylphenidate occurs preferentially in sensorimotor striatal circuits, similar to other addictive psychostimulants. These results suggest that SSRIs may enhance the addiction liability of methylphenidate.<\/jats:p><\/jats:sec>","DOI":"10.1111\/j.1471-4159.2012.07852.x","type":"journal-article","created":{"date-parts":[[2012,6,27]],"date-time":"2012-06-27T19:41:08Z","timestamp":1340826068000},"page":"1054-1064","source":"Crossref","is-referenced-by-count":14,"title":["Fluoxetine potentiation of methylphenidate\u2010induced neuropeptide expression in the striatum occurs selectively in direct pathway (striatonigral) neurons"],"prefix":"10.1111","volume":"122","author":[{"given":"Vincent","family":"Van Waes","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Betsy","family":"Carr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel A.","family":"Beverley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heinz","family":"Steiner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2012,7,23]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2011.07215.x"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)81056-9"},{"key":"e_1_2_8_4_1","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1016\/S0022-3565(25)39533-9","article-title":"Activation of transcription factor genes in striatum by cocaine: role of both serotonin and dopamine systems","volume":"267","author":"Bhat R. 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