Pituitary adenylate cyclase-activating polypeptide (PACAP) in the bed nucleus of the stria terminalis (BNST) increases corticosterone in male and female rats

Abstract

Single nucleotide polymorphisms (SNP) in the genes for pituitary adenylate cyclase-activating polypeptide (PACAP) and the PAC1 receptor have been associated with several psychiatric disorders whose etiology has been associated with stressor exposure and/or dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. In rats, exposure to repeated variate stress has been shown to increase PACAP and its cognate PAC1 receptor expression in the bed nucleus of the stria terminalis (BNST), a brain region implicated in anxiety and depression-related behaviors as well as the regulation of HPA axis activity. We have argued that changes in BNST PACAP signaling may mediate the changes in emotional behavior and dysregulation of the HPA axis associated with anxiety and mood disorders. The current set of studies was designed to determine whether BNST PACAP infusion leads to activation of the HPA axis as determined by increases in plasma corticosterone. We observed an increase in plasma corticosterone levels 30min following BNST PACAP38 infusion in male and female rats, which was independent of estradiol (E2) treatment in females, and we found that plasma corticosterone levels were increased at both 30min and 60min, but returned to baseline levels 4h following the highest dose. PACAP38 infusion into the lateral ventricles immediately above the BNST did not alter plasma corticosterone level, and the increased plasma corticosterone following BNST PACAP was not blocked by BNST corticotropin releasing hormone (CRH) receptor antagonism. These results support others suggesting that BNST PACAP plays a key role in regulating stress responses.

Keywords: Anxiety; Corticotropin-releasing factor; Corticotropin-releasing hormone; Cortisol; Estradiol; Estrogen; Extended amygdala; Glucocorticoids; HPA axis; Stress.

Figure 1

A. Estimates of center of drug infusion for experiment 1. Open dots represent one or multiple site(s) of drug infusion depicted on coronal sections as a distance (mm) from bregma. B. Dose- response of plasma corticosterone 30 minutes following BNST PACAP38 infusion for male rats. PACAP dose dependently increased plasma corticosterone levels 30 minutes following infusion in comparison to vehicle (0.05% bovine serum albumin, BSA). Infusion of 1.0 µg PACAP38 into the BNST caused a significant increase in plasma corticosterone levels in comparison to vehicle 30 minutes following infusion. * p < 0.05 compared to vehicle

Figure 2

A. Estimates of center of drug infusion for experiment 2. Open dots represent one or multiple site(s) of drug infusion depicted on coronal sections as a distance (mm) from bregma. B. Infusion of PACAP38 1.0 µg into the BNST caused a significant increase in blood plasma levels at 30 minutes and 60 minutes in comparison to vehicle (0.05% BSA). * p < 0.05 compared to vehicle

Figure 3

A. Estimates of center of drug infusion for experiment 3. Open dots represent one or multiple site(s) of drug infusion depicted on coronal sections as a distance (mm) from bregma. B. Dose- response of plasma corticosterone 30 minutes following BNST PACAP38 infusion for female rats. There was a main effect of PACAP, but no main effect of E2 treatment or interaction between PACAP and E2 treatment. Infusion of 1.0 µg PACAP38 into the BNST caused a significant increase in plasma corticosterone levels in comparison to vehicle (0.05% BSA) 30 minutes following infusion. * p < 0.05 compared to vehicle

Figure 4

A. Estimates of center of drug infusion for experiment 5. Open dots represent one or multiple site(s) of drug infusion depicted on coronal sections as a distance (mm) from bregma. B. Infusion of D-Phe CRH(12–41) prior to 1.0 µg PACAP38 into the BNST did not block the PACAP38 induced corticosterone rise. There was a main effect of PACAP38 but no main effect of D-Phe CRH(12–41) or interaction between PACAP38 and D-Phe CRH(12–41).