Serotonergic involvement in the amelioration of behavioral abnormalities in dopamine transporter knockout mice by nicotine

• Published in: Neuropharmacology 2013-01, Vol.64, p.348-356
• Main Authors: Uchiumi, Osamu, Kasahara, Yoshiyuki, Fukui, Asami, Hall, F. Scott, Uhl, George R., Sora, Ichiro
• Format: Article
• Language: English
• Subjects: 5-HT1A receptor; Animals; Behavior, Animal - drug effects; Cognition Disorders - etiology; Cognition Disorders - prevention & control; Crosses, Genetic; Disease Models, Animal; Dopamine Plasma Membrane Transport Proteins - genetics; Dopamine Plasma Membrane Transport Proteins - metabolism; Drug Interactions; Female; Locomotor activity; Male; Mice; Mice, Knockout; Nerve Tissue Proteins - agonists; Nerve Tissue Proteins - antagonists & inhibitors; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neural Inhibition - drug effects; Nicotine - therapeutic use; Nicotinic Agonists - therapeutic use; Nicotinic Antagonists - adverse effects; Nootropic Agents - therapeutic use; Prepulse inhibition; Psychomotor Disorders - etiology; Psychomotor Disorders - prevention & control; Receptor, Serotonin, 5-HT1A - chemistry; Receptor, Serotonin, 5-HT1A - metabolism; Schizophrenia; Schizophrenia - drug therapy; Schizophrenia - metabolism; Schizophrenia - physiopathology; Serotonin 5-HT1 Receptor Agonists - therapeutic use; Serotonin 5-HT1 Receptor Antagonists - adverse effects; α4β2 nACh receptor; α7 nACh receptor
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2012.07.016

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’. ► Nicotine attenuated hyperlocomotion in DAT KO mice. ► Nicotinic effect on hyperlocomotion was reversed by 5-HT1A antagonism. ► PPI deficit in DAT KO mice ameliorated by nicotine treatment. ► 5-HT1A agonist ameliorated PPI deficits in DAT KO mice.