title: Enhanced synthesis and release of dopamine in transgenic mice with gain-of-function α6* nAChRs.
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.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA.
authors.forename: Yuexiang
authors.initials: Y
authors.lastname: Wang
authors.forename: Jang-Won
authors.initials: JW
authors.lastname: Lee
authors.forename: Gyeon
authors.initials: G
authors.lastname: Oh
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Grady
authors.forename: J Michael
authors.initials: JM
authors.lastname: McIntosh
authors.forename: Darlene H
authors.initials: DH
authors.lastname: Brunzell
authors.forename: Jason R
authors.initials: JR
authors.lastname: Cannon
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Drenan
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D004298:Dopamine / Q000096:biosynthesis / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D055724:Electrophysiological Phenomena; D005110:Extracellular Space / Q000378:metabolism; D008464:Mecamylamine / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017072:Neostriatum / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism; D018733:Nicotinic Antagonists / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D012201:Reward
chemical_list: D018765:Dopamine Uptake Inhibitors; D018377:Neurotransmitter Agents; D018733:Nicotinic Antagonists; D010879:Piperazines; D011978:Receptors, Nicotinic; C559463:alpha6beta2 nicotinic acetylcholine receptor; D015102:3,4-Dihydroxyphenylacetic Acid; D008464:Mecamylamine; C043425:vanoxerine; D004298:Dopamine
keywords: Parkinson's disease; addiction; cholinergic; dopamine; nicotinic; nucleus accumbens