title: Hypocretin receptor 2 antagonism dose-dependently reduces escalated heroin self-administration in rats.
abstract: The hypocretin/orexin (HCRT) system has been associated with both positive and negative drug reinforcement, implicating HCRT receptor 1 (HCRT-R1) signaling in drug-related behaviors for all major drug classes, including opioids. However, to date there are limited studies investigating the role of HCRT receptor 2 (HCRT-R2) signaling in compulsive-like drug seeking. Escalation of drug intake with extended access has been suggested to model the transition from controlled drug use to compulsive-like drug seeking/taking. The current study examined the effects of a HCRT-R2 antagonist, NBI-80713, on heroin self-administration in rats allowed short- (1 h; ShA) or long- (12 h; LgA) access to intravenous heroin self-administration. Results indicate that systemically administered NBI-80713 dose-dependently decreased heroin self-administration in LgA, but not in ShA, animals. Quantitative PCR analyses showed an increase in Hcrtr2 mRNA levels in the central amygdala, a stress-related brain region, of LgA rats. These observations suggest a functional role for HCRT-R2 signaling in compulsive-like heroin self-administration associated with extended access and indicate HCRT-R2 antagonism as a potential pharmacological target for the treatment of heroin dependence.
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Brooke E
authors.initials: BE
authors.lastname: Schmeichel
authors.affiliation: Laboratories of Neurogenetics and Clinical and Translational Studies, Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA.
authors.forename: Estelle
authors.initials: E
authors.lastname: Barbier
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Kaushik K
authors.initials: KK
authors.lastname: Misra
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Candice
authors.initials: C
authors.lastname: Contet
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Joel E
authors.initials: JE
authors.lastname: Schlosburg
authors.affiliation: Neurocrine Biosciences, San Diego, CA, USA.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Grigoriadis
authors.affiliation: Neurocrine Biosciences, San Diego, CA, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Williams
authors.affiliation: Laboratories of Neurogenetics and Clinical and Translational Studies, Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA.
authors.forename: Camilla
authors.initials: C
authors.lastname: Karlsson
authors.affiliation: Laboratories of Neurogenetics and Clinical and Translational Studies, Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA.
authors.forename: Caleb
authors.initials: C
authors.lastname: Pitcairn
authors.affiliation: Laboratories of Neurogenetics and Clinical and Translational Studies, Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Heilig
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: George F
authors.initials: GF
authors.lastname: Koob
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Leandro F
authors.initials: LF
authors.lastname: Vendruscolo
mesh_terms: D000818:Animals; D066274:Central Amygdaloid Nucleus / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004327:Drinking Behavior / Q000187:drug effects / Q000502:physiology; D058999:Drug-Seeking Behavior / Q000187:drug effects / Q000502:physiology; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology; D003932:Heroin / Q000008:administration & dosage*; D006556:Heroin Dependence / Q000188:drug therapy* / Q000378:metabolism; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D008297:Male; D009294:Narcotics / Q000008:administration & dosage*; D000068796:Orexin Receptor Antagonists / Q000494:pharmacology*; D064446:Orexin Receptors / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017208:Rats, Wistar; D012646:Self Administration; D013375:Substance Withdrawal Syndrome / Q000378:metabolism; D013997:Time Factors
chemical_list: D009294:Narcotics; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D012333:RNA, Messenger; D003932:Heroin