| Abstract | 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. |
| Authors | Stéphanie Weiss, Eleni T Tzavara, Richard J Davis, George G Nomikos, J Michael McIntosh, Bruno Giros, Marie-Pascale Martres
(Affiliation: Inserm U513, Créteil F-94000, France.)
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| Journal | Neuropharmacology
(Neuropharmacology)
Vol. 52
Issue 7
Pg. 1496-508
(Jun 2007)
ISSN: 0028-3908 England |
| PMID | 17433376
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
|
| Chemical References |
- Cholinergic Agents
- Dopamine Agents
- Dopamine Plasma Membrane Transport Proteins
- Receptors, Dopamine
- Receptors, Nicotinic
- Methylphenidate
- Dopamine
- Nicotine
|
| Topics |
- 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, metabolism)
- Dose-Response Relationship, Drug
- Drug Synergism
- Maze Learning
(drug effects, physiology)
- Methylphenidate
(pharmacology)
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Motor Activity
(drug effects, genetics)
- Nicotine
(pharmacology)
- Protein Binding
(drug effects)
- Receptors, Dopamine
(metabolism)
- Receptors, Nicotinic
(metabolism)
- Signal Transduction
(drug effects)
|
