Fluoxetine Exposure during Adolescence Alters Responses to Aversive Stimuli in Adulthood — (The Journal of Neuroscience)

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The Journal of Neuroscience

15 January 2014, 34(3): 1007-1021; doi: 10.1523/JNEUROSCI.5725-12.2014

  1. Sergio D. Iñiguez1,
  2. Lyonna F. Alcantara2,
  3. Brandon L. Warren2,
  4. Lace M. Riggs1,
  5. Eric M. Parise2,
  6. Vincent Vialou3,
  7. Katherine N. Wright2,
  8. Genesis Dayrit1,
  9. Steven J. Nieto1,
  10. Matthew B. Wilkinson3,
  11. Mary K. Lobo4,
  12. Rachael L. Neve5,
  13. Eric J. Nestler3, and
  14. Carlos A. Bolaños-Guzmán2
  1. 1Department of Psychology, California State University, San Bernardino, California 92407,

  2. 2Department of Psychology and Program in Neuroscience, Florida State University, Tallahassee, Florida 32306,

  3. 3Fishberg Department of Neuroscience, Mount Sinai School of Medicine, New York, New York 10029,

  4. 4Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, and

  5. 5Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
  1. Author contributions: S.D.I. and C.A.B.-G. designed research; S.D.I., L.F.A., B.L.W., L.M.R., E.M.P., V.V., K.N.W., G.D., S.J.N., M.B.W., and M.K.L. performed research; R.L.N. and E.J.N. contributed unpublished reagents/analytic tools; S.D.I. and C.A.B.-G. analyzed data; S.D.I. and C.A.B.-G. wrote the paper.

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The mechanisms underlying the enduring neurobiological consequences of antidepressant exposure during adolescence are poorly understood.  Here, we assessed the long-term effects of exposure to fluoxetine (FLX), a selective serotonin reuptake inhibitor, during adolescence on behavioral reactivity to emotion-eliciting stimuli. We administered FLX (10 mg/kg, bi-daily, for 15 d) to male adolescent [postnatal day 35 (P35) to P49] C57BL/6 mice. Three weeks after treatment (P70), reactivity to aversive stimuli (i.e., social defeat stress, forced swimming, and elevated plus maze) was assessed. We also examined the effects of FLX on the expression of extra-cellular signal-regulated kinase (ERK) 1/2-related signaling within the ventral tegmental area (VTA) of adolescent mice and Sprague Dawley rats.  Adolescent FLX exposure suppressed depression-like behavior, as measured by the social interaction and forced swim tests, while enhancing anxiety-like responses in the elevated plus maze in adulthood. This complex behavioral profile was accompanied by decreases in ERK2 mRNA and protein phosphorylation within the VTA, while stress alone resulted in opposite neurobiological effects. Pharmacological (U0126) inhibition, as well as virus-mediated downregulation of ERK within the VTA mimicked the antidepressant-like profile observed after juvenile FLX treatment. Conversely, overexpression of ERK2 induced a depressive-like response, regardless of FLX pre-exposure. These findings demonstrate that exposure to FLX during adolescence modulates responsiveness to emotion-eliciting stimuli in adulthood, at least partially, via long-lasting adaptations in ERK-related signaling within the VTA. Our results further delineate the role ERK plays in regulating mood-related behaviors across the lifespan.