Pharmacological intervention remains largely powerless to treat stress-related illnesses, and far too often this lack of treatment efficacy results in attempts to self-medicate with alcohol or drugs of abuse. Without breakthroughs, the consequences of stressors that occur today will affect us long into the future. For these reasons, research that advances our understanding of the neurobiology of stress is of broad interest. In this issue of Neuron, Bruchas and colleagues describe an elegant series of studies that provides novel insight on the molecular pathways by which stress affects mood and motivation. The work is particularly

important because it identifies both familiar and novel targets for medications that may enable improved treatment—and perhaps even prevention—of 3-Methyladenine chemical structure stress-related illness. Corticotropin-releasing factor (CRF) is a peptide that is released in the brain in response to stress (Koob, 1999). Administration of CRF produces many of the same physiological and behavioral effects Pictilisib datasheet as stress in people and laboratory animals (Hauger et al., 2009). Recent evidence suggests that key stress-related effects of CRF are mediated by kappa-opioid receptors (KORs) (Land et al., 2009). The new work of Bruchas and colleagues provides exquisite detail on the nature of

this interaction, using an ethologically relevant form of stress (social defeat stress [SDS]) that recapitulates some of the physical and psychological consequences that are elements of many modern-day stressors and is known to cause persistent behavioral and molecular adaptations in mice (Krishnan et al., 2007). Focusing on the dorsal raphe Thymidine kinase nucleus (DRN), a brain region in which CRF, KOR, and serotonin (5-HT) systems converge, the authors show that SDS causes an increase in the activity (phosphorylation) of the intracellular signaling molecule p38α MAPK. This effect is mimicked by administration of a highly selective

KOR agonist (U50,488) and blocked by a highly selective KOR antagonist (norBNI), demonstrating dependence on KOR function. Using viral-mediated gene transfer and genetic engineering, they demonstrate that p38α MAPK activation within the DRN is responsible for the ability of stress to trigger depressive- and anxiety-like states, including dysphoria (aversion) and drug-seeking behavior. Since p38α MAPK is expressed ubiquitously, they used selective promoters to further isolate these effects to 5-HT-containing neurons. Importantly, they then used neurochemistry and immunoblotting techniques to demonstrate that p38α MAPK activation causes translocation of the serotonin transporter (SERT) from intracellular stores to neuronal membranes, thereby increasing clearance of extracellular 5-HT (Figure 1). These data raise the possibility that the therapeutic effects of selective serotonin reuptake inhibitors (SSRIs) could be related, at least in part, to an ability to offset stress-induced enhancements of SERT function within the DRN.