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

Osamu Uchiumi, Yoshiyuki Kasahara, Asami Fukui, F. Scott Hall, George R. Uhl, Ichiro Sora

Research output: Contribution to journalArticle

Abstract

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 α4β 2 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'.

Original languageEnglish (US)
Pages (from-to)348-356
Number of pages9
JournalNeuropharmacology
Volume64
DOIs
StatePublished - Jan 2013
Externally publishedYes

Fingerprint

Dopamine Plasma Membrane Transport Proteins
Nicotine
Knockout Mice
Nicotinic Receptors
Cholinergic Antagonists
Mecamylamine
Schizophrenia
Serotonin 5-HT1 Receptor Antagonists
Nootropic Agents
Serotonin 5-HT1 Receptor Agonists
8-Hydroxy-2-(di-n-propylamino)tetralin
Receptor, Serotonin, 5-HT1A
Nucleus Accumbens
Locomotion
Prefrontal Cortex
Acoustics
Psychiatry
Dopamine
Serotonin
Smoking

Keywords

  • αβ nACh receptor
  • α nACh receptor
  • 5-HT1A receptor
  • Locomotor activity
  • Prepulse inhibition
  • Schizophrenia

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

Cite this

Serotonergic involvement in the amelioration of behavioral abnormalities in dopamine transporter knockout mice by nicotine. / Uchiumi, Osamu; Kasahara, Yoshiyuki; Fukui, Asami; Hall, F. Scott; Uhl, George R.; Sora, Ichiro.

In: Neuropharmacology, Vol. 64, 01.2013, p. 348-356.

Research output: Contribution to journalArticle

Uchiumi, Osamu ; Kasahara, Yoshiyuki ; Fukui, Asami ; Hall, F. Scott ; Uhl, George R. ; Sora, Ichiro. / Serotonergic involvement in the amelioration of behavioral abnormalities in dopamine transporter knockout mice by nicotine. In: Neuropharmacology. 2013 ; Vol. 64. pp. 348-356.
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abstract = "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 α4β 2 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'.",
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