Enhanced synthesis and release of dopamine in transgenic mice with gain-of-function α6* nAChRs

Yuexiang Wang, Jang Won Lee, Gyeon Oh, Sharon R. Grady, J. Michael McIntosh, Darlene H. Brunzell, Jason R. Cannon, Ryan M. Drenan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

α6β2* nicotinic acetylcholine receptors (nAChRs)s in the ventral tegmental area to nucleus accumbens (NAc) pathway are implicated in the response to nicotine, and recent work suggests these receptors play a role in the rewarding action of ethanol. Here, we studied mice expressing gain-of-function α6β2* nAChRs (α6L9′S mice) that are hypersensitive to nicotine and endogenous acetylcholine. Evoked extracellular dopamine (DA) levels were enhanced in α6L9′S NAc slices compared to control, non-transgenic (non-Tg) slices. Extracellular DA levels in both non-Tg and α6L9′S slices were further enhanced in the presence of GBR12909, suggesting intact DA transporter function in both mouse strains. Ongoing α6β2* nAChR activation by acetylcholine plays a role in enhancing DA levels, as α-conotoxin MII completely abolished evoked DA release in α6L9′S slices and decreased spontaneous DA release from striatal synaptosomes. In HPLC experiments, α6L9′S NAc tissue contained significantly more DA, 3,4-dihydroxyphenylacetic acid, and homovanillic acid compared to non-Tg NAc tissue. Serotonin (5-HT), 5-hydroxyindoleacetic acid, and norepinephrine (NE) were unchanged in α6L9′S compared to non-Tg tissue. Western blot analysis revealed increased tyrosine hydroxylase expression in α6L9′S NAc. Overall, these results show that enhanced α6β2* nAChR activity in NAc can stimulate DA production and lead to increased extracellular DA levels.

Original languageEnglish (US)
Pages (from-to)315-327
Number of pages13
JournalJournal of neurochemistry
Volume129
Issue number2
DOIs
StatePublished - Apr 2014

Keywords

  • Parkinson's disease
  • addiction
  • cholinergic
  • dopamine
  • nicotinic
  • nucleus accumbens

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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