Differential modulation of methamphetamine-mediated behavioral sensitization by overexpression of Mu opioid receptors in nucleus accumbens and ventral tegmental area

Chi Chung Kuo, Hui Shen, Brandon K. Harvey, Seong Jin Yu, Theresa Kopajtic, Josh J. Hinkle, Stephanos Kyrkanides, Jonathan L. Katz, Yun Wang

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Rationale: Repeated administration of methamphetamine (Meth) induces behavioral sensitization which is characterized by a progressive increase in locomotor response after each injection. Previous studies have shown that Mu opioid receptors (MORs) can regulate Meth-mediated behavioral sensitization. However, the reported interactions are controversial; systemic activation of MORs either enhanced or suppressed Meth sensitization. It is possible that alteration of Meth sensitization after systemic administration of MOR ligands reflects the sum of distinct MOR reactions in multiple brain regions. Objectives: The purpose of the present study was to examine the actions of MORs on Meth sensitization after regionally selective overexpression of human MOR through an AAV6-based gene delivery system. Method: We demonstrated that adeno-associated virus (AAV)-MOR increased MOR immunoreactivity and binding in vitro. AAV-MOR or AAV-green fluorescent protein (GFP) was injected into the nucleus accumbens (NAc) or ventral tegmental area (VTA) of adult mice. Two weeks after viral infection, animals received Meth or saline for five consecutive days. Locomotor behavior and striatal dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) level were determined. Results: Repeated administration of Meth progressively increased locomotor activity; this sensitization reaction was attenuated by intra-NAc AAV-MOR microinjections. Infusion of AAV-MOR to VTA enhanced Meth sensitization. AAV-MOR significantly enhanced DA levels in VTA after VTA infection but reduced DOPAC/DA turnover in the NAc after NAc injection. Conclusion: Our data suggest a differential modulation of Meth sensitization by overexpression of MOR in NAc and VTA. Regional manipulation of MOR expression through AAV may be a novel approach to control Meth abuse and psychomimetic activity.

Original languageEnglish
Pages (from-to)661-672
Number of pages12
JournalPsychopharmacology
Volume233
Issue number4
DOIs
StatePublished - Feb 1 2016

Bibliographical note

Funding Information:
Funding for this study was provided by the NIDA Intramural Research Program, USA, and the NHRI, Taiwan.

Publisher Copyright:
© 2015 Springer-Verlag Berlin Heidelberg (outside the USA).

Keywords

  • AAV
  • Methamphetamine
  • Mu opioid receptor
  • Sensitization

ASJC Scopus subject areas

  • Pharmacology

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