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Keywords:

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

Abstract

Thumbnail image of graphical 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.

Using a transgenic mouse model, we studied nicotinic acetylcholine receptors (nAChRs) containing the α6 subunit and their role regulating dopamine (DA) synthesis and release in nucleus accumbens shell. Using a combination of biochemistry and electrophysiology techniques, we show that increased activity of α6-containing nAChRs results in enhanced DA synthesis as well as increased extracellular DA levels following evoked release. These findings highlight the importance of α6 nAChRs in DA transmission, and indicate that compounds with pharmacological activity at these receptors may be useful smoking cessation therapeutics.