Selective p38α MAPK deletion in serotonergic neurons produces stress resilience in models of depression and addiction

Neuron. 2011 Aug 11;71(3):498-511. doi: 10.1016/j.neuron.2011.06.011.

Abstract

Maladaptive responses to stress adversely affect human behavior, yet the signaling mechanisms underlying stress-responsive behaviors remain poorly understood. Using a conditional gene knockout approach, the α isoform of p38 mitogen-activated protein kinase (MAPK) was selectively inactivated by AAV1-Cre-recombinase infection in specific brain regions or by promoter-driven excision of p38α MAPK in serotonergic neurons (by Slc6a4-Cre or ePet1-Cre) or astrocytes (by Gfap-CreERT2). Social defeat stress produced social avoidance (a model of depression-like behaviors) and reinstatement of cocaine preference (a measure of addiction risk) in wild-type mice, but not in mice having p38α MAPK selectively deleted in serotonin-producing neurons of the dorsal raphe nucleus. Stress-induced activation of p38α MAPK translocated the serotonin transporter to the plasma membrane and increased the rate of transmitter uptake at serotonergic nerve terminals. These findings suggest that stress initiates a cascade of molecular and cellular events in which p38α MAPK induces a hyposerotonergic state underlying depression-like and drug-seeking behaviors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Avoidance Learning / physiology
  • Choice Behavior / physiology
  • Cocaine-Related Disorders / genetics*
  • Cocaine-Related Disorders / psychology
  • Conditioning, Psychological / physiology
  • Depression / genetics*
  • Depression / psychology
  • Disease Models, Animal
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 14 / genetics
  • Mitogen-Activated Protein Kinase 14 / metabolism
  • Mitogen-Activated Protein Kinase 14 / physiology*
  • Neurons / physiology*
  • Raphe Nuclei / metabolism
  • Raphe Nuclei / physiology
  • Raphe Nuclei / physiopathology
  • Receptors, Opioid / physiology
  • Serotonin / metabolism
  • Serotonin / physiology*
  • Serotonin Plasma Membrane Transport Proteins / metabolism
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Stress, Psychological / physiopathology
  • Stress, Psychological / psychology*

Substances

  • Receptors, Opioid
  • Serotonin Plasma Membrane Transport Proteins
  • Slc6a4 protein, mouse
  • Serotonin
  • nociceptin receptor
  • Mitogen-Activated Protein Kinase 14