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Neuropharmacology. 2007 Jun;52(7):1496-508. Epub 2007 Feb 24.

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

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1
Inserm U513, Créteil F-94000, France.

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.

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