Pituitary adenylate cyclase-activating polypeptide (PACAP) in the central nucleus of the amygdala induces anxiety via melanocortin receptors

Abstract

Rationale Anxiety disorders are the most common mental disorders in the United States. Characterized by feelings of uncontrollable apprehension, they are accompanied by physical, affective, and behavioral symptoms. The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptor PAC1 (PAC1R) are highly expressed in the central nucleus of the amygdala (CeA) and they have gained growing attention for their proposed role in mediating the body’s response to stress. Objectives The aim of this study was to evaluate the anxiogenic effects of PACAP in the CeA and its effects on the hypothalamic-pituitary-adrenal (HPA) axis. Furthermore, the mechanism of action of PACAP in the CeA was investigated. Methods PACAP was microinfused into the CeA of rats and its effects in the elevated plus maze (EPM), the defensive withdrawal tests, and plasma corticosterone levels were evaluated. The ability of the melanocortin receptor antagonist SHU9119 to block PACAP effect in the EPM was assessed. Results Intra-CeA PACAP exerted a dose-dependent anxiogenic effect and activated the HPA axis. In contrast, PACAP microinfused into the basolateral nucleus of the amygdala (BlA) had no effect. Finally, the anxiogenic effect of intra-CeA PACAP was prevented by SHU9119. Conclusions These data prove an anxiogenic role for the PACAP system of the CeA, and reveal that the MC4R system of CeA mediates these effects. Our data provide insights into this neuropeptide system as a mechanism for modulating the behavioral and endocrine response to stress, and suggest that dysregulations of this system may contribute to the pathophysiology of anxiety-related disorders.

The potential role of the novel hypothalamic neuropeptides nesfatin-1, phoenixin, spexin and kisspeptin in the pathogenesis of anxiety and anorexia nervosa

“…The melanocortin receptors, especially MC4R, which is highly expressed in brain, may play crucial roles in the regulation of stress and anxiety reactions (Chaki and Okubo 2007). A recent study proved that the anxiogenic action of another central neuropeptide PACAP was dependent on MC4R stimulation in the rat CeA (Iemolo et al 2016). Moreover, activating MC4R in the medial amygdala (MeA) exerted anxiogenic and anorexigenic effects with a stimulation of the HPA axis in rats.…”

PACAP deficiency as a model of aging

“…The expression of PACAP and the activation of PAC1/PACAP signaling also depend on a variety of factors, including developmental stage (Basille et al 2000), balance between signaling pathways (Fukuchi et al 2016), environmental factors (Horvath et al 2015), physiological conditions (Kiss et al 2007;Nemeth et al 2006;Rudecki and Gray 2016), daily rhythm (Jozsa et al 2001;Somogyvari-Vigh et al 2002), and the presence of harmful stimuli (Giunta et al 2012;Lam et al 2012;Pettersson et al 2014;Somogyvari-Vigh et al 2002;Szakaly et al 2010) and pathological conditions (Ergang et al 2015;Feher et al 2018;Han et al 2014aHan et al , 2014bHelyes et al 2015;Sarszegi et al 2018). PACAP's actions are very diverse, among others, it plays important roles during the development of the nervous system and several peripheral organs (Fulop et al 2018a;Watanabe et al 2016), influences anxiety, stress coping and addictionrelated behaviors (Iemolo et al 2016;King et al 2017;Kormos et al 2016;Mai et al 2018;Miles et al 2018), cognitive functions (Han et al 2014a(Han et al , 2014b, feeding (Sekar et al 2017), thermoregulation (Barrett et al 2017;Garami et al 2016), endocrine functions (Egri et al 2016;Koves 2016), gastrointestinal secretion and motility (Padua et al 2016;Reglodi et al 2018b), urinary functions…”

PACAP increases Arc/Arg 3.1 expression within the extended amygdala after fear conditioning in rats

“…One possibility is that PACAP+FC effects on Arc expression may reflect amplification of intracellular cascades activated by PACAP actions at its cognate receptor PAC1 and/or VPAC½ (G s and G q coupled receptors with high densities in the CeA and BNST; Dickson & Finlayson, 2009; Joo et al, 2004) together with putative glutamatergic drive (i.e., induced by fear conditioning) converging on populations of CeA and BNST neurons. Consistent with this possibility, we have previously shown that PACAP potentiates NMDA receptor-dependent EPSCs in a majority of CeA neurons after electrical stimulation of afferent input from the BLA (Cho et al, 2012).…”

“…The high density of PACAPergic afferents and PACAP-type-I receptors (PAC1) within the extended amygdala (e.g. central nucleus of the amygdala [CeA] and bed nucleus of the stria terminalis [BNST]; Alheid & Heimer, 1988; Hannibal 2002; Joo et al, 2004; Piggins et al, 1996) suggests a role in modulating neural activity related to stress, anxiety, and fear-related learning (Hammack & May, 2014; Iemolo et al, 2016; Lebow & Chen, 2016). Along these lines, we have demonstrated that PACAP influences NMDA and AMPA-dependent synaptic transmission in the CeA (Cho et al, 2012), which receives heavy PACAPergic innervation from the parabrachial nucleus (Missig et al, 2014) and may be endogenously released in response to pain.…”