Sci. Signal., 16 August 2011
Behavior Stress Relief
Science Signaling, AAAS, Washington, DC 20005, USA
Stress can stimulate adaptive behaviors, but it can also trigger nonproductive or destructive behaviors, such as withdrawal or relapse into drug use (see the Commentary by Muschamp et al.). Stress activates signaling through the kappa opioid receptor (KOR), which stimulates phosphorylation and activation of the mitogen-activated protein kinase (MAPK) p38. Bruchas et al. investigated the role of this pathway in controlling the output of the mood-regulating serotonergic system. In mice, stress induced by losing a confrontation with another member of the same species [social defeat stress (SDS)] elicited KOR-dependent phosphorylation of the α isoform of p38 in the dorsal raphe nucleus (DRN), the main neuronal source of serotonin. In a model of stress-induced drug relapse in which mice were conditioned to favorably associate a location with cocaine availability [cocaine conditioned place preference (CPP)], SDS was induced after natural extinction of cocaine CPP, and then cocaine CPP was reassessed. Mice in which the gene encoding p38α was inactivated in the DRN showed reduced reinstatement of cocaine CPP compared with control mice, a phenotype that was blocked by the KOR antagonist norbinaltorphimine. Because the DRN contains a heterogeneous population of cells, the authors removed p38α in serotonergic neurons by driving deletion of the gene encoding p38α with either the promoter of a gene encoding a serotonin transporter (CKOSERT mice) or that of a transcription factor specific to serotonergic neurons (CKOePet mice). Social defeat normally elicits social avoidance in mice; however, this response was reduced in CKOePet mice. In addition, both CKOSERT and CKOePet mice failed to negatively associate a location with a pharmacological stressor (a KOR agonist) [conditioned place aversion (CPA)]. In the forced swim test, a model for stress-induced depression, immobility is thought to reflect behavioral despair, and CKOSERT mice spent less time immobile than control mice. In response to SDS, CKOSERT and CKOePet mice did not show increased phosphorylation of p38α in serotonergic neurons and showed reduced reinstatement of cocaine CPP. CPA induced by a KOR agonist was reduced by citalopram, an inhibitor of serotonin reuptake, and synaptosomes from stressed CKOSERT mice showed reduced serotonin uptake compared with those from stressed control mice, suggesting that p38α regulates the uptake of extracellular serotonin. The cell surface abundance of SERT increased in synaptosomes from control mice subjected to SDS or CPA, an effect that was reduced in synaptosomes from CKOePet mice and in those from control mice by administration of norbinaltorphimine (a KOR antagonist). Thus, stress-induced behaviors involve activation of p38α downstream of the KOR, which leads to enhanced surface abundance of SERT and increased serotonin uptake.
M. R. Bruchas, A. G. Schindler, H. Shankar, D. I. Messinger, M. Miyatake, B. B. Land, J. C. Lemos, C. E. Hagan, J. F. Neumaier, A. Quintana, R. D. Palmiter, C. Chavkin, Selective p38α MAPK deletion in serotonergic neurons produces stress resilience in models of depression and addiction. Neuron 71, 498–511 (2011). [Online Journal]
J. W. Muschamp, A. Vant Veer, W. A. Carlezon Jr., Tracking down the molecular substrates of stress: New roles for p38α MAPK and kappa-opioid receptors. Neuron 71, 383–385 (2011). [Online Journal]
Citation: W. Wong, Stress Relief. Sci. Signal. 4, ec227 (2011).
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