Serotonergic involvement in the amelioration of behavioral abnormalities in dopamine transporter knockout mice by nicotine.
Dopamine transporter knockout (DAT KO) mice exhibit elevated extracellular dopamine levels in brain regions that include the striatum and the nucleus accumbens, but not the prefrontal cortex. DAT KO mice model some aspects of psychiatric disorders, including schizophrenia. Smoking is more common in patients with schizophrenia, suggesting that nicotine might ameliorate aspects of the behavioral abnormalities and/or treatment side effects seen in these individuals. We report nicotine-induced normalization of effects on locomotion and prepulse inhibition of acoustic startle (PPI) in DAT KO mice that require intact serotonin 5-HT1A systems. First, we observed that the marked hyperactivity displayed by DAT KO mice was reduced by administration of nicotine. This nicotine effect was blocked by pretreatment with the non-specific nicotinic acetylcholine (nACh) receptor antagonist mecamylamine, or the 5-HT1A antagonist WAY100635. Secondly, we examined the effects of nicotine on PPI in DAT KO mice. Treatment with nicotine significantly ameliorated the PPI deficits observed in DAT KO mice. The ameliorating action of nicotine on PPI deficits in DAT KO mice was blocked by mecamylamine, the α₇ nACh receptor antagonist methyllycaconitine or WAY100635, while the α₄β₂ nACh receptor antagonist dihydro-β-erythroidinehydrobromide (DHβE) produced only a non-significant trend toward attenuation of nicotine effects. Finally, we observed that administration of the 5-HT1A receptor agonist 8-OH-DPAT also ameliorated the deficit in PPI observed in DAT KO mice. This amelioration was antagonized by pretreatment with WAY100635. These data support the idea that nicotine might ameliorate some of the cognitive dysfunctions found in schizophrenia in a 5-HT1A-dependent fashion. This article is part of a Special Issue entitled 'Cognitive Enhancers'.
Department of Biological Psychiatry, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Sendai 980-8574, Japan.
Osamu
O
Uchiumi
Yoshiyuki
Y
Kasahara
Asami
A
Fukui
F Scott
FS
Hall
George R
GR
Uhl
Ichiro
I
Sora
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003072:Cognition Disorders / Q000209:etiology / Q000517:prevention & control*; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D004347:Drug Interactions; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009433:Neural Inhibition / Q000187:drug effects; D009538:Nicotine / Q000627:therapeutic use; D018722:Nicotinic Agonists / Q000627:therapeutic use*; D018733:Nicotinic Antagonists / Q000009:adverse effects; D018697:Nootropic Agents / Q000627:therapeutic use*; D011596:Psychomotor Disorders / Q000209:etiology / Q000517:prevention & control; D044282:Receptor, Serotonin, 5-HT1A / Q000737:chemistry / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D058825:Serotonin 5-HT1 Receptor Agonists / Q000627:therapeutic use; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000009:adverse effects
D050483:Dopamine Plasma Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D018697:Nootropic Agents; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; C493215:Slc6a3 protein, mouse; D044282:Receptor, Serotonin, 5-HT1A; D009538:Nicotine