PMID- 21753012
OWN - NLM
STAT- MEDLINE
DCOM- 20110912
LR  - 20211203
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 31
IP  - 28
DP  - 2011 Jul 13
TI  - 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.
PG  - 10347-58
LID - 10.1523/JNEUROSCI.1470-11.2011 [doi]
AB  - 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.
FAU - Warren, Brandon L
AU  - Warren BL
AD  - Department of Psychology and Program in Neuroscience, Florida State University, 
      Tallahassee, Florida 32306, USA.
FAU - Iniguez, Sergio D
AU  - Iniguez SD
FAU - Alcantara, Lyonna F
AU  - Alcantara LF
FAU - Wright, Katherine N
AU  - Wright KN
FAU - Parise, Eric M
AU  - Parise EM
FAU - Weakley, Sarah K
AU  - Weakley SK
FAU - Bolanos-Guzman, Carlos A
AU  - Bolanos-Guzman CA
LA  - eng
GR  - F31 DA027300/DA/NIDA NIH HHS/United States
GR  - F31DA027300/DA/NIDA NIH HHS/United States
GR  - R21DA022351-01/DA/NIDA NIH HHS/United States
GR  - R011DA026854-01/DA/NIDA NIH HHS/United States
GR  - R01 DA026854/DA/NIDA NIH HHS/United States
GR  - R21 DA022351/DA/NIDA NIH HHS/United States
GR  - R01 DA026854-02/DA/NIDA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Cyclic AMP Response Element-Binding Protein)
RN  - 01K63SUP8D (Fluoxetine)
RN  - 207ZZ9QZ49 (Methylphenidate)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
SB  - IM
MH  - Animals
MH  - Anxiety
MH  - Cyclic AMP Response Element-Binding Protein/genetics/metabolism
MH  - Extracellular Signal-Regulated MAP Kinases/*genetics/metabolism
MH  - Fluoxetine/*administration & dosage
MH  - Gene Expression/*drug effects
MH  - Male
MH  - Methylphenidate/*administration & dosage
MH  - Phosphorylation/drug effects
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Reward
MH  - Signal Transduction/drug effects/genetics
MH  - TOR Serine-Threonine Kinases/genetics/metabolism
MH  - Ventral Tegmental Area/*drug effects/metabolism
PMC - PMC3139175
MID - NIHMS310355
EDAT- 2011/07/15 06:00
MHDA- 2011/09/13 06:00
PMCR- 2012/01/13
CRDT- 2011/07/15 06:00
PHST- 2011/07/15 06:00 [entrez]
PHST- 2011/07/15 06:00 [pubmed]
PHST- 2011/09/13 06:00 [medline]
PHST- 2012/01/13 00:00 [pmc-release]
AID - 31/28/10347 [pii]
AID - 3707214 [pii]
AID - 10.1523/JNEUROSCI.1470-11.2011 [doi]
PST - ppublish
SO  - J Neurosci. 2011 Jul 13;31(28):10347-58. doi: 10.1523/JNEUROSCI.1470-11.2011.