In vivo activation of midbrain dopamine neurons via sensitized, high-affinity alpha 6 nicotinic acetylcholine receptors

Neuron. 2008 Oct 9;60(1):123-36. doi: 10.1016/j.neuron.2008.09.009.


Alpha6-containing (alpha6*) 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 alpha6* 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 alpha6* nAChRs and DA neurons is sufficient to cause locomotor hyperactivity. alpha6(L9'S) mice are hyperactive in their home cage and fail to habituate to a novel environment. Selective activation of alpha6* 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 alpha6* provides fine tuning of DA release and locomotor responses. alpha6*-specific agonists or antagonists may, by targeting endogenous cholinergic mechanisms in midbrain or striatum, provide a method for manipulating DA transmission in neural disorders.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chromosomes, Artificial, Bacterial / genetics
  • Dopamine / genetics
  • Dopamine / metabolism
  • Dopamine / physiology*
  • Mesencephalon / chemistry
  • Mesencephalon / metabolism*
  • Mice
  • Mice, Transgenic
  • Neurons / metabolism
  • Neurons / physiology*
  • Receptors, Nicotinic / biosynthesis
  • Receptors, Nicotinic / genetics
  • Receptors, Nicotinic / metabolism
  • Receptors, Nicotinic / physiology*
  • Recombination, Genetic
  • Synaptic Transmission / genetics


  • Receptors, Nicotinic
  • nicotinic receptor alpha6
  • Dopamine