Two models of inescapable stress increase tph2 mRNA expression in the anxiety-related dorsomedial part of the dorsal raphe nucleus

Abstract

Expression of TPH2, the rate-limiting enzyme for brain serotonin synthesis, is elevated in the dorsal raphe nucleus (DR) of depressed suicide victims. One hypothesis is that this increase in TPH2 expression is stress-induced. Here, we used an established animal model to address whether exposure to an acute stressor, inescapable tail shock (IS), increases <i>tph2</i> mRNA and Tph2 protein expression, and if IS sensitizes the DR to a subsequent, heterotypic stressor. In <i>Experiment 1</i>, we measured <i>tph2</i> mRNA expression 4 h after IS or home cage (HC) control conditions in male rats, using <i>in situ</i> hybridization histochemistry. In <i>Experiment 2</i>, we measured Tph2 protein expression 12 h or 24 h after IS using western blot. In <i>Experiment 3</i>, we measured <i>tph2</i> mRNA expression following IS on Day 1, and cold swim stress (10 min, 15 °C) on Day 2. Inescapable tail shock was sufficient to increase <i>tph2</i> mRNA expression 4 h and 28 h later, selectively in the dorsomedial DR (caudal aspect of the dorsal DR, cDRD; an area just rostral to the caudal DR, DRC) and increased Tph2 protein expression in the DRD (rostral and caudal aspects of the dorsal DR combined) 24 h later. Cold swim increased <i>tph2</i> mRNA expression in the dorsomedial DR (cDRD) 4 h later. These effects were associated with increased immobility during cold swim, elevated plasma corticosterone, and a proinflammatory plasma cytokine milieu (increased interleukin (IL)-6, decreased IL-10). Our data demonstrate that two models of inescapable stress, IS and cold swim, increase <i>tph2</i> mRNA expression selectively in the anxiety-related dorsomedial DR (cDRD).