In Vivo Activation of Midbrain Dopamine Neurons via Sensitized, High-Affinity α6* Nicotinic Acetylcholine Receptors

Ryan M. Drenan, Sharon R. Grady, Paul Whiteaker, Tristan McClure-Begley, Sheri McKinney, Julie M. Miwa, Sujata Bupp, Nathaniel Heintz, J. Michael McIntosh, Merouane Bencherif, Michael J. Marks, Henry A. Lester*

*Corresponding author for this work

Research output: Contribution to journalArticle

162 Scopus citations

Abstract

α6-containing (α6*) nicotinic ACh receptors (nAChRs) are selectively expressed in dopamine (DA) neurons and participate in cholinergic transmission. We generated and studied mice with gain-of-function α6* nAChRs, which isolate and amplify cholinergic control of DA transmission. In contrast to gene knockouts or pharmacological blockers, which show necessity, we show that activating α6* nAChRs and DA neurons is sufficient to cause locomotor hyperactivity. α6L9′S mice are hyperactive in their home cage and fail to habituate to a novel environment. Selective activation of α6* nAChRs with low doses of nicotine, by stimulating DA but not GABA neurons, exaggerates these phenotypes and produces a hyperdopaminergic state in vivo. Experiments with additional nicotinic drugs show that altering agonist efficacy at α6* provides fine tuning of DA release and locomotor responses. α6*-specific agonists or antagonists may, by targeting endogenous cholinergic mechanisms in midbrain or striatum, provide a method for manipulating DA transmission in neural disorders.

Original languageEnglish (US)
Pages (from-to)123-136
Number of pages14
JournalNeuron
Volume60
Issue number1
DOIs
StatePublished - Oct 9 2008

Keywords

  • MOLNEURO
  • SYSNEURO

ASJC Scopus subject areas

  • Neuroscience(all)

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    Drenan, R. M., Grady, S. R., Whiteaker, P., McClure-Begley, T., McKinney, S., Miwa, J. M., Bupp, S., Heintz, N., McIntosh, J. M., Bencherif, M., Marks, M. J., & Lester, H. A. (2008). In Vivo Activation of Midbrain Dopamine Neurons via Sensitized, High-Affinity α6* Nicotinic Acetylcholine Receptors. Neuron, 60(1), 123-136. https://doi.org/10.1016/j.neuron.2008.09.009