Functional alterations of nicotinic neurotransmission in dopamine transporter knock-out mice

Neuropharmacology. 2007 Jun;52(7):1496-508. doi: 10.1016/j.neuropharm.2007.02.002. Epub 2007 Feb 24.


Mice lacking the dopamine (DA) transporter (DAT) gene exhibit a phenotype reminiscent of schizophrenia and attention deficit hyperactivity disorder (ADHD), including hyperDAergia, hyperactivity and deficits in cognitive performance, which are alleviated by antipsychotic agents. Numerous studies suggest a dysfunction of nicotinic neurotransmission in schizophrenia and show increased tobacco intake in schizophrenic and ADHD patients, possibly as a self-medication. Thus, we examined the potential alteration of nicotinic neurotransmission in DAT knock-out (KO) mice. We showed that constitutively hyperDAergic DAT KO mice exhibited modifications in nicotinic receptor density in an area- and subtype-dependent manner. In some DAergic areas, the small decrease in the beta2* nicotinic subunit (nAChR) density contrasted with the higher decrease and increase in the alpha6* and alpha7 nAChR densities, respectively. Mutant mice were hypersensitive to the stimulant locomotor effects of nicotine at low doses, probably due to enhanced nicotine-induced extracellular DA level. They also showed hypersensitivity to the hypolocomotion induced by nicotine. In contrast, no hypersensitivity was observed for other nicotine-induced behavioral effects, such as anxiety or motor activity in the elevated plus maze. Co-administration of nicotinic agonists at sub-active doses elicited opposite locomotor effects in wild-type and DAT KO mice, as reported previously for methylphenidate. Interestingly, such a co-administration of nicotinic agonists induced synergistic hypolocomotion in DAT KO mice. These findings show that a targeted increase of DA tone can be responsible for significant adaptations of the cholinergic/nicotinic neurotransmission. This study may provide potential leads for the use of nicotine or combined nicotinic agonists for the therapy of psychiatric disorders.

Publication types

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

MeSH terms

  • Analysis of Variance
  • Animals
  • Autoradiography / methods
  • Behavior, Animal
  • Binding, Competitive / drug effects
  • Cholinergic Agents / pharmacology*
  • Dopamine / metabolism
  • Dopamine Agents / pharmacology
  • Dopamine Plasma Membrane Transport Proteins / deficiency
  • Dopamine Plasma Membrane Transport Proteins / metabolism*
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Maze Learning / drug effects
  • Maze Learning / physiology
  • Methylphenidate / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Motor Activity / drug effects
  • Motor Activity / genetics
  • Nicotine / pharmacology*
  • Protein Binding / drug effects
  • Receptors, Dopamine / metabolism
  • Receptors, Nicotinic / metabolism*
  • Signal Transduction / drug effects*


  • Cholinergic Agents
  • Dopamine Agents
  • Dopamine Plasma Membrane Transport Proteins
  • Receptors, Dopamine
  • Receptors, Nicotinic
  • Methylphenidate
  • Nicotine
  • Dopamine