In agreement with its role in stress responses, the SP/NK1R system also contributes to the regulation of the HPA axis. SP administration can enhance stress-induced corticosterone release (Mello et al., 2007) and expression of CRF1R (Hamke et al., 2006). Furthermore, anxiety-like responses and mild stress-induced elevations in corticosterone are blunted in mice with genetic deletion of the NK1R (Santarelli et al., 2001). The paraventricular nucleus of the hypothalamus, a region that drives HPA axis activity and stress-induced autonomic activation, receives input from SP-positive fibers (Kawano and Masuko, 1992; Womack and Barrett-Jolley, 2007; Womack et al., 2007), and NK1R antagonists can suppress stress-induced c-fos activation in this region (Ebner et al., 2008a). However, it has also been demonstrated that NK1R antagonist administration can increase adrenocorticotropic hormone (ACTH) and CRF expression and release (Jessop et al., 2000), while SP can suppress ACTH release (Jones et al., 1978). Some of these effects occur following the injection of NK1R antagonists in unstressed animals, suggesting a tonic suppression of HPA axis activity by SP/NK1R. Therefore, NK1R activation may regulate the HPA axis in a manner
