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

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

Journal of neurochemistry (2013-11-26)
Yuexiang Wang, Jang-Won Lee, Gyeon Oh, Sharon R Grady, J Michael McIntosh, Darlene H Brunzell, Jason R Cannon, Ryan M Drenan
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
3,4-Dihydroxyphenylacetic acid, 98%
Sigma-Aldrich
Anti-Tyrosine Hydroxylase Antibody, Chemicon®, from sheep
Sigma-Aldrich
Anti-Beta III Tubulin Antibody, Chemicon®, from chicken
Sigma-Aldrich
GBR 12909 dihydrochloride, solid, ≥98% (HPLC)