[Show abstract][Hide abstract] 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 α(7) nACh receptor antagonist methyllycaconitine or WAY100635, while the α(4)β(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'.
No preview · Article · Jul 2012 · Neuropharmacology
[Show abstract][Hide abstract] ABSTRACT: Dopamine transporter knockout (DAT KO) mice exhibited hyperdopaminergic tone in the nucleus accumbens and striatum, whereas they showed normal levels of extracellular dopamine in the prefrontal cortex. DAT KO mice showed numerous behavioral alterations that can be linked to abnormal dopaminergic function, including hyperlocomotion, deficits of prepulse inhibition (1PI) and impairment of working memory. PPI deficits were also shown in schizophrenic patients and hyperlocomotion was observed in AD/HD patients; therefore DAT KO mice had face validity for these psychiatric disorders. Impairment of neuronal development such as brain volume loss and decrease in spine density was reported especially in the prefrontal cortex of schizophrenia and AD/HD patients. We therefore investigated the neuronal development of DAT KO mice. Our results indicated that DAT KO mice had deficits of neuronal development in the prefrontal cortex similar to schizophrenia and AD/HD patients at least in part. These findings suggest that DAT KO mice are one of the useful models to investigate the impairment of neuronal development observed in psychiatric disorders including schizophrenia and AD/HD.
No preview · Article · Nov 2011 · Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology
[Show abstract][Hide abstract] ABSTRACT: Psychostimulant drugs including cocaine increase extracellular levels of monoamines by blocking the neuronal plasma membrane transporters. Increased extracellular dopamine levels in mesocorticolimbic dopamine systems have been postulated to mediate the rewarding effects of cocaine. Studies in genetically modified mice models, particularly knockout mice have contributed a great deal to our understanding of the mechanisms underlying psychostimulant actions. Phenotypic analysis of genetically modified mice models has been instrumental in identifying the role of specific molecular targets of cocaine. In this article, we summarize studies that have reported the effects of cocaine using genetically modified mice especially gene knockouts of the monoamine transporters and receptors.
No preview · Article · Aug 2010 · Nippon rinsho. Japanese journal of clinical medicine
[Show abstract][Hide abstract] ABSTRACT: Methamphetamine (MAP), a drug of abuse known worldwide for its addictive effects and neurotoxicity, causes somatic and psychiatric disorders. MAP enters terminals/neurons via monoamine transporters, displaces both vesicular and intracellular monoamines, and facilitates the release of monoamines into the extraneuronal space through synaptic transport via the monoamine transporters. Chronic psychostimulant abusers exhibit psychotic features, including delusions and auditory hallucinations. The dopamine transporter (DAT) and the vesicular monoamine transporter 2 (VMAT2) play pivotal roles in the action of MAP, including locomotor effects. The deletion of DAT attenuates the locomotor effects of MAP and may play larger role in behavioral responses to MAP compared to the deletion of VMAT2. MAP produces hyperthermia and/or neuronal toxicity in most species. The effects of MAP in DAT or serotonin transporter (SERT) single knockout (KO) mice and DAT/SERT double KO mice suggested that DAT and SERT are key molecules for hyperthermia and neuronal toxicity of MAP.
No preview · Article · Feb 2009 · International Review of Neurobiology