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Selective p38α MAPK Deletion in Serotonergic Neurons Produces Stress Resilience in Models of Depression and Addiction

2011; Cell Press; Volume: 71; Issue: 3 Linguagem: Inglês

10.1016/j.neuron.2011.06.011

1097-4199

Michael R. Bruchas, Abigail G. Schindler, Haripriya Shankar, Daniel I. Messinger, Mayumi Miyatake, Benjamin B. Land, Julia C. Lemos, Catherine E. Hagan, John F. Neumaier, Albert Quintana, R D Palmiter, Charles Chavkin,

Receptor Mechanisms and Signaling

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.