title: κ Opioid receptors in the nucleus accumbens shell mediate escalation of methamphetamine intake.
abstract: Given that the κ opioid receptor (KOR) system has been implicated in psychostimulant abuse, we evaluated whether the selective KOR antagonist norbinaltorphimine dihydrochloride (nor-BNI) would attenuate the escalation of methamphetamine (METH) intake in an extended-access self-administration model. Systemic nor-BNI decreased the escalation of intake of long-access (LgA) but not short-access (ShA) self-administration. nor-BNI also decreased elevated progressive-ratio (PR) breakpoints in rats in the LgA condition and continued to decrease intake after 17 d of abstinence, demonstrating that the effects of a nor-BNI injection are long lasting. Rats with an ShA history showed an increase in prodynorphin immunoreactivity in both the nucleus accumbens (NAc) core and shell, but LgA animals showed a selective increase in the NAc shell. Other cohorts of rats received nor-BNI directly into the NAc shell or core and entered into ShA or LgA. nor-BNI infusion in the NAc shell, but not NAc core, attenuated escalation of intake and PR responding for METH in LgA rats. These data indicate that the development and/or expression of compulsive-like responding for METH under LgA conditions depends on activation of the KOR system in the NAc shell and suggest that the dynorphin-KOR system is a central component of the neuroplasticity associated with negative reinforcement systems that drive the dark side of addiction.
authors.affiliation: The Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037, whitfiet@scripps.edu.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Whitfield
authors.affiliation: The Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037.
authors.forename: Joel E
authors.initials: JE
authors.lastname: Schlosburg
authors.affiliation: Department of Molecular Therapeutics, Scripps Research Institute, Jupiter, Florida 33458.
authors.forename: Sunmee
authors.initials: S
authors.lastname: Wee
authors.affiliation: The Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037.
authors.forename: Adam
authors.initials: A
authors.lastname: Gould
authors.affiliation: The Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037.
authors.forename: Olivier
authors.identifier: http://orcid.org/0000-0002-3700-5003
authors.initials: O
authors.lastname: George
authors.affiliation: The Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037.
authors.forename: Yanabel
authors.initials: Y
authors.lastname: Grant
authors.affiliation: The Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037.
authors.forename: Eva R
authors.initials: ER
authors.lastname: Zamora-Martinez
authors.affiliation: Department of Physiology, Alcohol and Drug Abuse Center of Excellence, Louisiana State University Health Science Center, New Orleans, Louisiana 70112.
authors.forename: Scott
authors.initials: S
authors.lastname: Edwards
authors.affiliation: The Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037.
authors.forename: Elena
authors.initials: E
authors.lastname: Crawford
authors.affiliation: The Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037.
authors.forename: Leandro F
authors.initials: LF
authors.lastname: Vendruscolo
authors.affiliation: The Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037.
authors.forename: George F
authors.initials: GF
authors.lastname: Koob
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000697:Central Nervous System Stimulants / Q000008:administration & dosage*; D003216:Conditioning, Operant / Q000187:drug effects; D004745:Enkephalins / Q000378:metabolism; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage*; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism*; D011498:Protein Precursors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017473:Receptors, Opioid, kappa / Q000378:metabolism*; D012054:Reinforcement, Psychology; D012646:Self Administration
chemical_list: D000697:Central Nervous System Stimulants; D004745:Enkephalins; D009292:Narcotic Antagonists; D011498:Protein Precursors; D017473:Receptors, Opioid, kappa; C051844:norbinaltorphimine; D008694:Methamphetamine; D009271:Naltrexone; C033660:preproenkephalin
keywords: dynorphin; escalation; kappa opioid receptors; methamphetamine; nucleus accumbens; substances of abuse