title: Juvenile administration of concomitant methylphenidate and fluoxetine alters behavioral reactivity to reward- and mood-related stimuli and disrupts ventral tegmental area gene expression in adulthood.
abstract: There is a rise in the concurrent use of methylphenidate (MPH) and fluoxetine (FLX) in pediatric populations. However, the long-term neurobiological consequences of combined MPH and FLX treatment (MPH + FLX) during juvenile periods are unknown. We administered saline (VEH), MPH, FLX, or MPH + FLX to juvenile Sprague Dawley male rats from postnatal day 20 to 34, and assessed their reactivity to reward- and mood-related stimuli 24 h or 2 months after drug exposure. We also assessed mRNA and protein levels within the ventral tegmental area (VTA) to determine the effect of MPH, FLX, or MPH + FLX on the extracellular signal-regulated protein kinase-1/2 (ERK) pathway--a signaling cascade implicated in motivation and mood regulation. MPH + FLX enhanced sensitivity to drug (i.e., cocaine) and sucrose rewards, as well as anxiety (i.e., elevated plus maze)- and stress (i.e., forced swimming)-eliciting situations when compared with VEH-treated rats. MPH + FLX exposure also increased mRNA of ERK2 and its downstream targets cAMP response element-binding protein (CREB), BDNF, c-Fos, early growth response protein-1 (Zif268), and mammalian target of rapamycin (mTOR), and also increased protein phosphorylation of ERK2, CREB, and mTOR 2 months after drug exposure when compared with VEH-treated rats. Using herpes simplex virus-mediated gene transfer to block ERK2 activity within the VTA, we rescued the MPH and FLX-induced behavioral deficits seen in the forced-swimming task 2 months after drug treatment. These results indicate that concurrent MPH + FLX exposure during preadolescence increases sensitivity to reward-related stimuli while simultaneously enhancing susceptibility to stressful situations, at least in part, due to long-lasting disruptions in ERK signaling within the VTA.
authors.affiliation: Department of Psychology and Program in Neuroscience, Florida State University, Tallahassee, Florida 32306, USA.
authors.forename: Brandon L
authors.initials: BL
authors.lastname: Warren
authors.forename: Sergio D
authors.initials: SD
authors.lastname: Iñiguez
authors.forename: Lyonna F
authors.initials: LF
authors.lastname: Alcantara
authors.forename: Katherine N
authors.initials: KN
authors.lastname: Wright
authors.forename: Eric M
authors.initials: EM
authors.lastname: Parise
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Weakley
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Bolaños-Guzmán
mesh_terms: D000818:Animals; D001007:Anxiety; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics* / Q000378:metabolism; D005473:Fluoxetine / Q000008:administration & dosage*; D015870:Gene Expression / Q000187:drug effects*; D008297:Male; D008774:Methylphenidate / Q000008:administration & dosage*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012201:Reward; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000378:metabolism
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D005473:Fluoxetine; D008774:Methylphenidate; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases