CRF Mediates the Anxiogenic and Anti-Rewarding, But Not the Anorectic Effects of PACAP

• Published in: Neuropsychopharmacology (New York, N.Y.) Vol. 38; no. 11; pp. 2160 - 2169
• Main Authors: DORE, Riccardo, LEMOLO, Attilio, SMITH, Karen L, XIAOFAN WANG, COTTONE, Pietro, SABINO, Valentina
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.10.2013
• Subjects: Adult and adolescent clinical studies; Amygdala - drug effects; Amygdala - metabolism; Animals; Anorexia; Anorexia nervosa; Anxiety - blood; Anxiety - chemically induced; Anxiety - physiopathology; Anxiety disorders; Behavior; Biological and medical sciences; Body Weight - drug effects; Corticosterone - blood; Corticotropin-Releasing Hormone - analogs & derivatives; Corticotropin-Releasing Hormone - metabolism; Corticotropin-Releasing Hormone - physiology; Eating - drug effects; Eating behavior disorders; Food; Hypothalamus; Infusions, Intraventricular; Male; Maze Learning - drug effects; Medical sciences; Neuropeptides; Neuropharmacology; Original; Paraventricular Hypothalamic Nucleus - drug effects; Paraventricular Hypothalamic Nucleus - metabolism; Peptides - pharmacology; Pharmacology. Drug treatments; Pituitary Adenylate Cyclase-Activating Polypeptide - administration & dosage; Pituitary Adenylate Cyclase-Activating Polypeptide - pharmacology; Polypeptides; Post traumatic stress disorder; Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychopharmacology; Rats; Receptors, Corticotropin-Releasing Hormone - antagonists & inhibitors; Reward; Self Stimulation - drug effects; United States > US; Amygdala; Peptides; Psychotropic; Central nervous system; Corticotropin releasing factor; Phosphorus-oxygen lyases; corticotropin-releasing factor OR CRH; Lyases; Eating disorder; Encephalon; anxiety OR anxiolytic; Adenylate cyclase; anorexia OR anorexic; Pituitary gland; Anxiety; Hormone releasing factor; Amygdaloid nucleus; Intracranial; Enzyme; pituitary adenylate cyclase-activating peptide; Basal ganglion; Anorexia nervosa; Hypothalamic hormone; intracranial self-stimulation OR ICSS; Tranquillizer; Self stimulation; Anorectic; Reward
• ISSN: 0893-133X; 1740-634X
• DOI: 10.1038/npp.2013.113

Anxiety disorders represent the most common mental disturbances in the world, and they are characterized by an abnormal response to stress. Pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptor PAC1 have been proposed to have a key role in mediating the responses to stress as well as the regulation of food intake and body weight. Corticotropin-releasing factor (CRF), the major stress peptide in the brain, has been hypothesized to be involved in PACAP effects, but the reports are conflicting so far. The present study was aimed at further characterizing the behavioral effects of PACAP in rats and at determining the role of central CRF receptors. We found that intracerebroventricular PACAP treatment induced anxiety-like behavior in the elevated plus maze test and elevated intracranial self-stimulation thresholds; both of these effects were fully blocked by concurrent treatment with the CRF receptor antagonist D-Phe-CRF(12-41). Interestingly, the CRF antagonist had no effect on PACAP-induced increased plasma corticosterone, reduction of food intake, and body weight loss. Finally, we found that PACAP increased CRF levels in the paraventricular nucleus of the hypothalamus and, importantly, in the central nucleus of the amygdala, as measured by solid phase radioimmunoassay and quantitative real-time PCR. Our results strengthen the notion that PACAP is a strong mediator of the behavioral response to stress and prove for the first time that this neuropeptide has anti-rewarding (ie, pro-depressant) effects. In addition, we identified the mechanism by which PACAP exerts its anxiogenic and pro-depressant effects, via the recruitment of the central CRF system and independently from HPA axis activation.