title: Selective p38α MAPK deletion in serotonergic neurons produces stress resilience in models of depression and addiction.
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.
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, WA 98195, USA. bruchasm@wustl.edu
authors.forename: Michael R
authors.initials: MR
authors.lastname: Bruchas
authors.forename: Abigail G
authors.initials: AG
authors.lastname: Schindler
authors.forename: Haripriya
authors.initials: H
authors.lastname: Shankar
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Messinger
authors.forename: Mayumi
authors.initials: M
authors.lastname: Miyatake
authors.forename: Benjamin B
authors.initials: BB
authors.lastname: Land
authors.forename: Julia C
authors.initials: JC
authors.lastname: Lemos
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Hagan
authors.forename: John F
authors.initials: JF
authors.lastname: Neumaier
authors.forename: Albert
authors.initials: A
authors.lastname: Quintana
authors.forename: Richard D
authors.initials: RD
authors.lastname: Palmiter
authors.forename: Charles
authors.initials: C
authors.lastname: Chavkin
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000502:physiology; D002755:Choice Behavior / Q000502:physiology; D019970:Cocaine-Related Disorders / Q000235:genetics* / Q000523:psychology; D003213:Conditioning, Psychological / Q000502:physiology; D003863:Depression / Q000235:genetics* / Q000523:psychology; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D011903:Raphe Nuclei / Q000378:metabolism / Q000502:physiology / Q000503:physiopathology; D011957:Receptors, Opioid / Q000502:physiology; D012701:Serotonin / Q000378:metabolism / Q000502:physiology*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013315:Stress, Psychological / Q000503:physiopathology / Q000523:psychology*; D000094942:Nociceptin Receptor
chemical_list: D011957:Receptors, Opioid; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D012701:Serotonin; D048308:Mitogen-Activated Protein Kinase 14; D000094942:Nociceptin Receptor; C000722287:Oprl1 protein, mouse