Functional alterations of nicotinic neurotransmission in dopamine transporter knock-out mice.
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.
Weiss
Stéphanie
S
Inserm U513, Créteil F-94000, France.
Tzavara
Eleni T
ET
Davis
Richard J
RJ
Nomikos
George G
GG
Michael McIntosh
J
J
Giros
Bruno
B
Martres
Marie-Pascale
MP
D000704:Analysis of Variance; D000818:Animals; D001345:Autoradiography / Q000379:methods; D001522:Behavior, Animal; D001667:Binding, Competitive / Q000187:drug effects; D018678:Cholinergic Agents / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000172:deficiency / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008774:Methylphenidate / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009538:Nicotine / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011954:Receptors, Dopamine / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
D018678:Cholinergic Agents; D015259:Dopamine Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D011954:Receptors, Dopamine; D011978:Receptors, Nicotinic; D008774:Methylphenidate; D009538:Nicotine; D004298:Dopamine