title: Selective serotonin re-uptake inhibitors potentiate gene blunting induced by repeated methylphenidate treatment: Zif268 versus Homer1a.
abstract: There is a growing use of psychostimulants, such as methylphenidate (Ritalin; dopamine re-uptake inhibitor), for medical treatments and as cognitive enhancers in the healthy. Methylphenidate is known to produce some addiction-related gene regulation. Recent findings in animal models show that selective serotonin re-uptake inhibitors (SSRIs), including fluoxetine, can potentiate acute induction of gene expression by methylphenidate, thus indicating an acute facilitatory role for serotonin in dopamine-induced gene regulation. We investigated whether repeated exposure to fluoxetine, in conjunction with methylphenidate, in adolescent rats facilitated a gene regulation effect well established for repeated exposure to illicit psychostimulants such as cocaine-blunting (repression) of gene inducibility. We measured, by in situ hybridization histochemistry, the effects of a 5-day repeated treatment with methylphenidate (5 mg/kg), fluoxetine (5 mg/kg) or a combination on the inducibility (by cocaine) of neuroplasticity-related genes (Zif268, Homer1a) in the striatum. Repeated methylphenidate treatment alone produced minimal gene blunting, while fluoxetine alone had no effect. In contrast, fluoxetine added to methylphenidate robustly potentiated methylphenidate-induced blunting for both genes. This potentiation was widespread throughout the striatum, but was most robust in the lateral, sensorimotor striatum, thus mimicking cocaine effects. For illicit psychostimulants, blunting of gene expression is considered part of the molecular basis of addiction. Our results thus suggest that SSRIs, such as fluoxetine, may increase the addiction liability of methylphenidate.
authors.affiliation: Department of Cellular and Molecular Pharmacology, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Van Waes
authors.forename: Malcolm
authors.initials: M
authors.lastname: Vandrevala
authors.forename: Joel
authors.initials: J
authors.lastname: Beverley
authors.forename: Heinz
authors.initials: H
authors.lastname: Steiner
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004338:Drug Combinations; D004357:Drug Synergism; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D005473:Fluoxetine / Q000494:pharmacology*; D000072233:Homer Scaffolding Proteins; D008297:Male; D008774:Methylphenidate / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
chemical_list: D002352:Carrier Proteins; D003042:Cocaine; D018765:Dopamine Uptake Inhibitors; D004338:Drug Combinations; D051766:Early Growth Response Protein 1; D005473:Fluoxetine; D000072233:Homer Scaffolding Proteins; D008774:Methylphenidate; D017367:Selective Serotonin Reuptake Inhibitors; C486110:Egr1 protein, rat
keywords: Cocaine; SSRI antidepressant; cognitive enhancer; dopamine; gene expression; psychostimulant