title: Fluoxetine potentiation of methylphenidate-induced gene regulation in striatal output pathways: potential role for 5-HT1B receptor.
abstract: Drug combinations that include the psychostimulant methylphenidate plus a selective serotonin reuptake inhibitor (SSRI) such as fluoxetine are increasingly used in children and adolescents. For example, this combination is indicated in the treatment of attention-deficit/hyperactivity disorder and depression comorbidity and other mental disorders. Such co-exposure also occurs in patients on SSRIs who use methylphenidate as a cognitive enhancer. The neurobiological consequences of these drug combinations are poorly understood. Methylphenidate alone can produce gene regulation effects that mimic addiction-related gene regulation by cocaine, consistent with its moderate addiction liability. We have previously shown that combining SSRIs with methylphenidate potentiates methylphenidate-induced gene regulation in the striatum. The present study investigated which striatal output pathways are affected by the methylphenidate + fluoxetine combination, by assessing effects on pathway-specific neuropeptide markers, and which serotonin receptor subtypes may mediate these effects. Our results demonstrate that a 5-day repeated treatment with fluoxetine (5 mg/kg) potentiates methylphenidate (5 mg/kg)-induced expression of both dynorphin (direct pathway marker) and enkephalin (indirect pathway). These changes were accompanied by correlated increases in the expression of the 5-HT1B, but not 5-HT2C, serotonin receptor in the same striatal regions. A further study showed that the 5-HT1B receptor agonist CP94253 (3-10 mg/kg) mimics the fluoxetine potentiation of methylphenidate-induced gene regulation. These findings suggest a role for the 5-HT1B receptor in the fluoxetine effects on striatal gene regulation. Given that 5-HT1B receptors are known to facilitate addiction-related gene regulation and behavior, our results suggest that SSRIs may enhance the addiction liability of methylphenidate by increasing 5-HT1B receptor signaling.
authors.affiliation: Department of Cellular and Molecular Pharmacology, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Van Waes
authors.affiliation: Department of Cellular and Molecular Pharmacology, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ehrlich
authors.affiliation: Department of Cellular and Molecular Pharmacology, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA.
authors.forename: Joel A
authors.initials: JA
authors.lastname: Beverley
authors.affiliation: Department of Cellular and Molecular Pharmacology, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA. Electronic address: Heinz.Steiner@rosalindfranklin.edu.
authors.forename: Heinz
authors.initials: H
authors.lastname: Steiner
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology*; D004357:Drug Synergism; D005473:Fluoxetine / Q000008:administration & dosage*; D005786:Gene Expression Regulation; D008297:Male; D008774:Methylphenidate / Q000008:administration & dosage*; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044302:Receptor, Serotonin, 5-HT1B / Q000502:physiology*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology
chemical_list: D044302:Receptor, Serotonin, 5-HT1B; D058825:Serotonin 5-HT1 Receptor Agonists; D005473:Fluoxetine; D008774:Methylphenidate
keywords: Dynorphin; Enkephalin; Methylphenidate; Psychostimulant; SSRI; Striatum