κ Opioid receptors in the nucleus accumbens shell mediate escalation of methamphetamine intake

• Published in: The Journal of neuroscience 2015-03, Vol.35 (10), p.4296-4305
• Main Authors: Whitfield, Jr, Timothy W, Schlosburg, Joel E, Wee, Sunmee, Gould, Adam, George, Olivier, Grant, Yanabel, Zamora-Martinez, Eva R, Edwards, Scott, Crawford, Elena, Vendruscolo, Leandro F, Koob, George F
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Animals; Central Nervous System Stimulants - administration & dosage; Conditioning, Operant - drug effects; Enkephalins - metabolism; Male; Methamphetamine - administration & dosage; Naltrexone - analogs & derivatives; Naltrexone - pharmacology; Narcotic Antagonists - pharmacology; Nucleus Accumbens - drug effects; Nucleus Accumbens - metabolism; Protein Precursors - metabolism; Rats; Rats, Wistar; Receptors, Opioid, kappa - metabolism; Reinforcement (Psychology); Self Administration
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.1978-13.2015

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.