Role of paraventricular nucleus-projecting norepinephrine/epinephrine neurons in acute and chronic stress

Chronic variable stress (CVS) exposure modifies the paraventricular nucleus of the hypothalamus (PVN) in a manner consistent with enhanced central drive of the hypothalamo-pituitary-adrenocortical (HPA) axis. As previous reports suggest that post-stress enhancement of norepinephrine (NE) action contributes to chronic stress regulation at the level of the PVN, we hypothesised that PVN-projecting NE neurons were necessary for the stress facilitatory effects of CVS. Following intra-PVN injection of saporin toxin conjugated to a dopamine beta-hydroxylase (DBH) antibody (DSAP), in rats PVN DBH immunoreactivity was almost completely eliminated, but immunoreactive afferents to other key regions involved in stress integration were spared (e.g. DBH fiber densities were unaffected in the central nucleus of the amygdala). Reductions in DBH-positive fiber density were associated with reduced numbers of DBH-immunoreactive neurons in the nucleus of the solitary tract and locus coeruleus. Following 2weeks of CVS, DSAP injection did not alter stress-induced adrenal hypertrophy or attenuation of body weight gain, indicating that PVN-projecting NE [and epinephrine (E)] neurons are not essential for these physiological effects of chronic stress. In response to acute restraint stress, PVN-targeted DSAP injection attenuated peak adrenocorticotrophic hormone (ACTH) and corticosterone in controls, but only attenuated peak ACTH in CVS animals, suggesting that enhanced adrenal sensitivity compensated for reduced excitatory drive of the PVN. Our data suggest that PVN-projecting NE/E neurons contribute to the generation of acute stress responses, and are required for HPA axis drive (ACTH release) during chronic stress. However, loss of NE/E drive at the PVN appears to be buffered by compensation at the level of the adrenal.