Lydia O Ayanwuyi1, Serena Stopponi1, Massimo Ubaldi1, Andrea Cippitelli1, Cinzia Nasuti1, Ruslan Damadzic2, Markus Heilig2, Jesse Schank3, Kejun Cheng4, Kenner C Rice4, Roberto Ciccocioppo1. 1. School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino, 62032, Italy. 2. Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD, 20892-1108, USA. 3. Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA, 30602, USA. 4. Drug Design and Synthesis Section, Chemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
Abstract
BACKGROUND AND PURPOSE: Substance P and its preferred neurokinin receptor NK1 have been implicated in stress and anxiety and have been proposed as possible therapeutic targets for the treatment of anxiety/depression. Attention is also being focused on the role this neuropeptide system may play in drug addiction, because stress-related mechanisms promote drug abuse. EXPERIMENTAL APPROACH: The effects of the rat-specific NK1 receptor antagonist, L822429, on alcohol intake and seeking behaviour was investigated in genetically selected Marchigian Sardinian alcohol preferring rats. These rats demonstrate an anxious phenotype and are highly sensitive to stress and stress-induced drinking. KEY RESULTS: Systemic administration of L822429 significantly reduced operant alcohol self-administration in Marchigian Sardinian alcohol preferring rats, but did not reduce alcohol self-administration in stock Wistar rats. NK1 receptor antagonism also attenuated yohimbine-induced reinstatement of alcohol seeking at all doses tested but had no effect on cue-induced reinstatement of alcohol seeking. L822429 reduced operant alcohol self-administration when injected into the lateral cerebroventricles or the medial amygdala. L822429 injected into the medial amygdala also significantly reduced anxiety-like behaviour in the elevated plus maze test. No effects on alcohol intake were observed following injection of L822429 into the dorsal or the ventral hippocampus. Conclusions and Implications Our results suggest that NK1 receptor antagonists may be useful for the treatment of alcohol addiction associated with stress or comorbid anxiety disorders. The medial amygdala appears to be an important brain site of action of NK1 receptor antagonism.
BACKGROUND AND PURPOSE: Substance P and its preferred neurokinin receptor NK1 have been implicated in stress and anxiety and have been proposed as possible therapeutic targets for the treatment of anxiety/depression. Attention is also being focused on the role this neuropeptide system may play in drug addiction, because stress-related mechanisms promote drug abuse. EXPERIMENTAL APPROACH: The effects of the rat-specific NK1 receptor antagonist, L822429, on alcohol intake and seeking behaviour was investigated in genetically selected Marchigian Sardinian alcohol preferring rats. These rats demonstrate an anxious phenotype and are highly sensitive to stress and stress-induced drinking. KEY RESULTS: Systemic administration of L822429 significantly reduced operant alcohol self-administration in Marchigian Sardinian alcohol preferring rats, but did not reduce alcohol self-administration in stock Wistar rats. NK1 receptor antagonism also attenuated yohimbine-induced reinstatement of alcohol seeking at all doses tested but had no effect on cue-induced reinstatement of alcohol seeking. L822429 reduced operant alcohol self-administration when injected into the lateral cerebroventricles or the medial amygdala. L822429 injected into the medial amygdala also significantly reduced anxiety-like behaviour in the elevated plus maze test. No effects on alcohol intake were observed following injection of L822429 into the dorsal or the ventral hippocampus. Conclusions and Implications Our results suggest that NK1 receptor antagonists may be useful for the treatment of alcohol addiction associated with stress or comorbid anxiety disorders. The medial amygdala appears to be an important brain site of action of NK1 receptor antagonism.
Authors: John C Umhau; Melanie L Schwandt; Julie Usala; Christopher Geyer; Erick Singley; David T George; Markus Heilig Journal: Neuropsychopharmacology Date: 2011-02-02 Impact factor: 7.853
Authors: Andrea Cippitelli; Ruslan Damadzic; Erick Singley; Annika Thorsell; Roberto Ciccocioppo; Robert L Eskay; Markus Heilig Journal: Pharmacol Biochem Behav Date: 2011-10-20 Impact factor: 3.533
Authors: Anita C Hansson; Andrea Cippitelli; Wolfgang H Sommer; Roberto Ciccocioppo; Markus Heilig Journal: Addict Biol Date: 2007-03 Impact factor: 4.280
Authors: Britta S Nelson; Hannah D Fulenwider; Sadie E Nennig; Britessia M Smith; Michelle K Sequeira; Scott H Chimberoff; Christopher T Richie; Kejun Cheng; Kenner C Rice; Brandon K Harvey; Markus Heilig; Jesse R Schank Journal: Neuroscience Date: 2019-06-23 Impact factor: 3.590