Tracking down the molecular substrates of stress: new roles for p38α MAPK and kappa-opioid receptors

Abstract

In this issue, Bruchas et al. (2011) uncover a novel stress-induced p38α MAPK signaling cascade within serotonergic neurons of the dorsal raphe nucleus that mediates depressive and drug-seeking behaviors. Their findings have potentially important implications for medication development.

Highly simplified schematic depicting a molecular cascade by which stress produces depressive effects via processes occurring within the dorsal raphe nucleus (DRN). Stressors such as social defeat stress (SDS) cause release of corticotropin-releasing factor (CRF), which in turn activates dynorphin-containing inputs to the DRN. Dynorphin stimulation of kappa-opioid receptors (KORs) activates (phosphorylates [P]) p38α MAPK, a crucial mediator of dysphoric (aversive) states. One down-stream consequence of p38α MAPK is translocation of SERT to neuronal membranes, which decreases extracellular concentrations of serotonin (5-HT) and alters stimulation of serotonin receptors (5HTRs). This hyposerotonergic state likely affects output to the prefrontal cortex (PFC), an element of mesocorticolimbic circuits implicated in motivation and emotion. Based on Bruchas et al., 2011 and Meloni et al., 2008, and Carlezon and Thomas, 2009.