Enhanced systhesis and release of dopamine in transgenic mice with gain-of-function α6*nACHRs

alpha 6 beta 2* 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 alpha 6 beta 2* nAChRs (alpha 6L9'S mice) that are hypersensitive to nicotine and endogenous acetylcholine. Evoked extracellular dopamine (DA) levels were enhanced in alpha 6L9'S NAc slices compared to control, non-transgenic (non-Tg) slices. Extracellular DA levels in both non-Tg and alpha 6L9'S slices were further enhanced in the presence of GBR12909, suggesting intact DA transporter function in both mouse strains. Ongoing alpha 6 beta 2* nAChR activation by acetylcholine plays a role in enhancing DA levels, as alpha-conotoxin MII completely abolished evoked DA release in alpha 6L9'S slices and decreased spontaneous DA release from striatal synaptosomes. In HPLC experiments, alpha 6L9'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 alpha 6L9'S compared to non-Tg tissue. Western blot analysis revealed increased tyrosine hydroxylase expression in alpha 6L9'S NAc. Overall, these results show that enhanced alpha 6 beta 2* nAChR activity in NAc can stimulate DA production and lead to increased extracellular DA levels.