Nicotine persistently activates ventral tegmental area dopaminergic neurons via nicotinic acetylcholine receptors containing alpha4 and alpha6 subunits
UMass Chan Affiliations
Tapper LabGardner Lab
Brudnick Neuropsychiatric Research Institute
Department of Psychiatry
Document Type
Journal ArticlePublication Date
2012-04-01
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Show full item recordAbstract
Nicotine is reinforcing because it activates dopaminergic (DAergic) neurons within the ventral tegmental area (VTA) of the brain's mesocorticolimbic reward circuitry. This increase in activity can occur for a period of several minutes up to an hour and is thought to be a critical component of nicotine dependence. However, nicotine concentrations that are routinely self-administered by smokers are predicted to desensitize high-affinity alpha4beta2 neuronal nicotinic acetylcholine receptors (nAChRs) in seconds. Thus, how physiologically relevant nicotine concentrations persistently activate VTA DAergic neurons is unknown. Here we show that nicotine can directly and robustly increase the firing frequency of VTA DAergic neurons for several minutes. In mouse midbrain slices, 300 nM nicotine elicited a persistent inward current in VTA DAergic neurons that was blocked by alpha-conotoxin MII[H9A;L15A], a selective antagonist of nAChRs containing the alpha6 subunit. alpha-conotoxin MII[H9A;L15A] also significantly reduced the long-lasting increase in DAergic neuronal activity produced by low concentrations of nicotine. In addition, nicotine failed to significantly activate VTA DAergic neurons in mice that did not express either alpha4 or alpha6 nAChR subunits. Conversely, selective activation of nAChRs containing the alpha4 subunit in knock-in mice expressing a hypersensitive version of these receptors yielded a biphasic response to nicotine consisting of an acute desensitizing increase in firing frequency followed by a sustained increase that lasted several minutes and was sensitive to alpha-conotoxin MII[H9A;L15A]. These data indicate that nicotine persistently activates VTA DAergic neurons via nAChRs containing alpha4 and alpha6 subunits.Source
Mol Pharmacol. 2012 Apr;81(4):541-8. doi: 10.1124/mol.111.076661. Epub 2012 Jan 5. Link to article on publisher's site
DOI
10.1124/mol.111.076661Permanent Link to this Item
http://hdl.handle.net/20.500.14038/29230PubMed ID
22222765Related Resources
ae974a485f413a2113503eed53cd6c53
10.1124/mol.111.076661