Impact of PACAP and PAC1 receptor deficiency on the neurochemical and behavioral effects of acute and chronic restraint stress in male C57BL/6 mice

Abstract

Acute restraint stress (ARS) for 3 hours causes CORT elevation in venous blood, which is accompanied by Fos up-regulation in the paraventricular nucleus (PVN) of male C57BL/6 mice. CORT elevation by ARS is attenuated in PACAP-deficient mice, but unaffected in PAC1-deficient mice. Correspondingly, Fos up-regulation by ARS is greatly attenuated in PACAP-deficient mice, but much less so in PAC1-deficient animals. We noted that both PACAP- and PAC1-deficiency greatly attenuate CORT elevation after ARS when CORT measurements are performed on trunk blood following euthanasia by abrupt cervical separation: this latter observation is of critical importance in assessing the role of PACAP neurotransmission in ARS, based on previous reports in which serum CORT was sampled from trunk blood. Seven days of chronic restraint stress (CRS) induces non-habituating CORT elevation, and weight loss consequent to hypophagia, in wild-type male C57BL/6 mice. Both CORT elevation and weight loss following seven day CRS are severely blunted in PACAP-deficient mice, but only slightly in PAC1 deficient mice. However, longer periods of daily restraint (14–21 days) resulted in sustained weight loss and elevated CORT in wild-type mice, and these effects of long-term chronic stress were attenuated or abolished in both PACAP- and PAC1-deficient mice. We conclude that while a PACAP receptor in addition to PAC1 may mediate some of the PACAP-dependent central effects of acute restraint stress and short-term (<7 days) chronic restraint stress on the HPA axis, the PAC1 receptor plays a prominent role in mediating PACAP-dependent HPA axis activation, and hypophagia, during long-term (>7 days) chronic restraint stress.

Reduced response to chronic mild stress in PACAP mutant mice is associated with blunted FosB expression in limbic forebrain and brainstem centers

“…(Nanopoulos et al, 1982;Bagdy et al, 2000;Lin, 2015). 957 In the next step, we quantified the number of 5-HT- The CVMS model (Willner, 2005) which fits with the findings of Mustafa et al (2015). Imipra-1017 mine seems to reduce the bodyweight gain in non-1018 stressed WT mice, which phenomenon was observed 1019 by other laboratories both in rats (Lewis et al, 1983) 1020 and mice (Zhao et al, 2015).…”

C-terminal amidation of PACAP-38 and PACAP-27 is dispensable for biological activity at the PAC1 receptor

“…A translational issue that is re-cast by our data is the potential mode of gene therapeutic delivery of PACAP, or closely related peptide analogs, in vivo , in the context of neuroprotection [24], tumor suppression [30], treatment of stress-related affective disorders [29], PTSD [10], and migraine [1]. Therapeutic application of neuropeptides for these and other disorders is highly dependent on the need for amidation, since the latter can occur only in secretory granule-releasing tissues [13, 14], and cannot be programmed within DNA-based expression vectors if the latter are expressed in non-neuroendocrine tissues.…”

Activation of the HPA axis and depression of feeding behavior induced by restraint stress are separately regulated by PACAPergic neurotransmission in the mouse

“…is attenuated in PACAP-deficient mice, and that chronic restraint stress, with as little as 2 hr of restraint stress daily, triggers hypophagia, measured by weight loss consequent to decreased food consumption, throughout a three-week period (Mustafa et al, 2015). Furthermore, the chronic effects of PACAP deficiency were phenocopied in mice deficient in expression of the PAC1 PACAP receptor, indicating a potential therapeutic target for blunting the maladaptive behaviors emergent during chronic stress (Mustafa et al, 2015). Here, we have administered restraint stress for 1, 2 or 3 hours over a period of 7 days, and monitored CORT elevation as an index of HPA axis (endocrine) activation, and decreased food consumption as an index of stress-dependent behavioral alteration.…”