期刊
JOURNAL OF NEUROSCIENCE
卷 35, 期 10, 页码 4296-4305出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1978-13.2015
关键词
dynorphin; escalation; kappa opioid receptors; methamphetamine; nucleus accumbens; substances of abuse
资金
- National Institutes of Health Grant from the National Institute on Drug Abuse [R01 DA010072]
- Pearson Center for Alcoholism and Addiction Research at The Scripps Research Institute
- National Institute on Alcohol Abuse and Alcoholism Grant [T32 AA007456]
- National Institute on Drug Abuse Grant [F32DA033726]
Given that the kappa 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 shortaccess (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 NAcshell. Other cohorts of rats received nor-BNI directly into theNAcshell 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.
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