PMID- 35460713 OWN - NLM STAT- MEDLINE DCOM- 20220519 LR - 20230715 IS - 1873-7064 (Electronic) IS - 0028-3908 (Print) IS - 0028-3908 (Linking) VI - 212 DP - 2022 Jul 1 TI - Pituitary adenylate cyclase-activating polypeptide type 1 receptor within the nucleus accumbens core mediates excessive alcohol drinking in alcohol-preferring rats. PG - 109063 LID - S0028-3908(22)00122-8 [pii] LID - 10.1016/j.neuropharm.2022.109063 [doi] AB - Alcohol use disorders (AUD) have a strong component of heritability; however, the neurobiological mechanisms mediating the propensity to consume excessive amounts of alcohol are still not well understood. Pituitary adenylate cyclase-activating polypeptide (PACAP), a highly conserved neuropeptide which exerts its effects mainly through the PAC1 receptor (PAC1R), has been suggested to be one of the mediators of the effects of drugs of abuse and alcohol. Here, we investigated the role of the PACAP/PAC1R system in excessive alcohol drinking in alcohol-preferring rats, an established animal model of AUD. Intracerebroventricular (i.c.v.) administration of the PAC1R antagonist PACAP(6-38) blocked excessive alcohol drinking and motivation to drink in Sardinian alcohol-preferring (Scr:sP) rats, without affecting water, saccharin, or sucrose intake. Notably, PACAP(6-38) did not affect ethanol responding in outbred Wistar rats. PACAP(6-38) also significantly reduced alcohol-seeking behavior under a second-order schedule of reinforcement. Using immunohistochemistry, a significant increase in the number of PAC1R positive cells was observed selectively in the nucleus accumbens (NAcc) Core of Scr:sP rats, compared to Wistar rats, following alcohol drinking. Finally, excessive drinking in Scr:sP rats was suppressed by intra-NAcc Core, but not intra-NAcc Shell, PACAP(6-38), as well as by virally-mediated PAC1R knockdown in the NAcc Core. The present study shows that hyperactivity of the PACAP/PAC1R system specifically in the NAcc Core mediates excessive drinking of alcohol-preferring rats, and indicates that this system may represent a novel target for the treatment of AUD. CI - Copyright (c) 2022 Elsevier Ltd. All rights reserved. FAU - Minnig, Margaret A AU - Minnig MA AD - Laboratory of Addictive Disorders, Departments of Pharmacology and Experimental Therapeutics and Psychiatry, Boston University School of Medicine, Boston, MA, USA. FAU - Blasio, Angelo AU - Blasio A AD - Laboratory of Addictive Disorders, Departments of Pharmacology and Experimental Therapeutics and Psychiatry, Boston University School of Medicine, Boston, MA, USA. FAU - Ferragud, Antonio AU - Ferragud A AD - Laboratory of Addictive Disorders, Departments of Pharmacology and Experimental Therapeutics and Psychiatry, Boston University School of Medicine, Boston, MA, USA. FAU - Sami, Yasmine N AU - Sami YN AD - Laboratory of Addictive Disorders, Departments of Pharmacology and Experimental Therapeutics and Psychiatry, Boston University School of Medicine, Boston, MA, USA. FAU - Erhard, Emily E AU - Erhard EE AD - Laboratory of Addictive Disorders, Departments of Pharmacology and Experimental Therapeutics and Psychiatry, Boston University School of Medicine, Boston, MA, USA. FAU - Clark, Rose H AU - Clark RH AD - Laboratory of Addictive Disorders, Departments of Pharmacology and Experimental Therapeutics and Psychiatry, Boston University School of Medicine, Boston, MA, USA. FAU - DiLeo, Alyssa AU - DiLeo A AD - Laboratory of Addictive Disorders, Departments of Pharmacology and Experimental Therapeutics and Psychiatry, Boston University School of Medicine, Boston, MA, USA. FAU - Giuliano, Chiara AU - Giuliano C AD - Behavioral and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Cambridge, UK. FAU - Everitt, Barry J AU - Everitt BJ AD - Behavioral and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Cambridge, UK. FAU - Cottone, Pietro AU - Cottone P AD - Laboratory of Addictive Disorders, Departments of Pharmacology and Experimental Therapeutics and Psychiatry, Boston University School of Medicine, Boston, MA, USA. FAU - Sabino, Valentina AU - Sabino V AD - Laboratory of Addictive Disorders, Departments of Pharmacology and Experimental Therapeutics and Psychiatry, Boston University School of Medicine, Boston, MA, USA. Electronic address: vsabino@bu.edu. LA - eng GR - R21 AA026051/AA/NIAAA NIH HHS/United States GR - R21 AA029495/AA/NIAAA NIH HHS/United States GR - R00 AA016731/AA/NIAAA NIH HHS/United States GR - F30 AA028184/AA/NIAAA NIH HHS/United States GR - R01 AA025038/AA/NIAAA NIH HHS/United States GR - R01 AA024439/AA/NIAAA NIH HHS/United States GR - R21 MH113128/MH/NIMH NIH HHS/United States GR - R01 MH093650/MH/NIMH NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20220420 PL - England TA - Neuropharmacology JT - Neuropharmacology JID - 0236217 RN - 0 (Pituitary Adenylate Cyclase-Activating Polypeptide) RN - 0 (Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I) SB - IM MH - *Alcohol Drinking/drug therapy/metabolism MH - *Alcoholism/drug therapy/metabolism MH - Animals MH - Nucleus Accumbens/metabolism MH - *Pituitary Adenylate Cyclase-Activating Polypeptide/pharmacology MH - Rats MH - Rats, Wistar MH - *Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I/antagonists & inhibitors/metabolism PMC - PMC10342914 MID - NIHMS1911292 EDAT- 2022/04/24 06:00 MHDA- 2022/05/20 06:00 PMCR- 2023/07/13 CRDT- 2022/04/23 20:09 PHST- 2022/02/04 00:00 [received] PHST- 2022/03/19 00:00 [revised] PHST- 2022/04/12 00:00 [accepted] PHST- 2022/04/24 06:00 [pubmed] PHST- 2022/05/20 06:00 [medline] PHST- 2022/04/23 20:09 [entrez] PHST- 2023/07/13 00:00 [pmc-release] AID - S0028-3908(22)00122-8 [pii] AID - 10.1016/j.neuropharm.2022.109063 [doi] PST - ppublish SO - Neuropharmacology. 2022 Jul 1;212:109063. doi: 10.1016/j.neuropharm.2022.109063. Epub 2022 Apr 20.