title: Pituitary adenylate cyclase-activating polypeptide (PACAP) in the central nucleus of the amygdala induces anxiety via melanocortin receptors.
abstract: Anxiety disorders are the most common mental disorders in the USA. 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  These data prove an anxiogenic role for the PACAP system of the CeA and reveal that the melanocortin receptor 4 (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.
authors.affiliation: Laboratory of Addictive Disorders, Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry, Boston University School of Medicine, 72 E Concord St, R-612, Boston, MA, 02118, USA.
authors.forename: Attilio
authors.initials: A
authors.lastname: Iemolo
authors.affiliation: Laboratory of Addictive Disorders, Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry, Boston University School of Medicine, 72 E Concord St, R-612, Boston, MA, 02118, USA.|Graduate Program in Neuroscience, Boston University, Boston, MA, USA.
authors.forename: Mariel
authors.initials: M
authors.lastname: Seiglie
authors.affiliation: Laboratory of Addictive Disorders, Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry, Boston University School of Medicine, 72 E Concord St, R-612, Boston, MA, 02118, USA.
authors.forename: Angelo
authors.initials: A
authors.lastname: Blasio
authors.affiliation: Laboratory of Addictive Disorders, Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry, Boston University School of Medicine, 72 E Concord St, R-612, Boston, MA, 02118, USA.
authors.forename: Pietro
authors.initials: P
authors.lastname: Cottone
authors.affiliation: Laboratory of Addictive Disorders, Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry, Boston University School of Medicine, 72 E Concord St, R-612, Boston, MA, 02118, USA. vsabino@bu.edu.
authors.forename: Valentina
authors.initials: V
authors.lastname: Sabino
mesh_terms: D000818:Animals; D001007:Anxiety; D001008:Anxiety Disorders; D066272:Basolateral Nuclear Complex / Q000187:drug effects / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects*; D066274:Central Amygdaloid Nucleus / Q000187:drug effects* / Q000378:metabolism; D003345:Corticosterone / Q000097:blood; D004644:Emotions / Q000187:drug effects; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000494:pharmacology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000494:pharmacology*; D010913:Pituitary-Adrenal System / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D044105:Receptor, Melanocortin, Type 4 / Q000187:drug effects* / Q000378:metabolism; D044101:Receptors, Melanocortin / Q000037:antagonists & inhibitors; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / Q000378:metabolism
chemical_list: D018377:Neurotransmitter Agents; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D044105:Receptor, Melanocortin, Type 4; D044101:Receptors, Melanocortin; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; C000613745:melanocortin receptor type 4, rat; C103272:SHU 9119; D009074:Melanocyte-Stimulating Hormones; D003345:Corticosterone
keywords: Animal model; Anxiety; Depression; HPA axis; MC4; Neuropeptide; Stress