Nicotine Improves Cognitive Deficits of Dopamine Transporter Knockout Mice without Long-Term Tolerance

Inserm, U513, Laboratoire de Neurobiologie et Psychiatrie, University Paris 12, Créteil, France.
Neuropsychopharmacology (Impact Factor: 7.05). 01/2008; 32(12):2465-78. DOI: 10.1038/sj.npp.1301385
Source: PubMed

ABSTRACT Various studies suggest a dysfunction of nicotinic neurotransmission in schizophrenia and establish that patients suffering from schizophrenia and attention deficit hyperactivity disorder (ADHD) have a high tobacco consumption, potentially for the purpose of self-medication. Owing to its neuroprotective and procognitive effects, transdermal nicotine was proposed to be an effective treatment of some neurodegenerative and psychiatric diseases. Mice deficient in the dopamine transporter (DAT KO) exhibit a phenotype reminiscent of schizophrenia and ADHD, including hyperdopaminergia, hyperactivity, paradoxical calming by methylphenidate and cognitive deficits, some of which being improved by antipsychotic agents. We recently demonstrated that nicotinic receptor content and function were profoundly modified in DAT KO mice. In this study, we assessed the effects of a chronic nicotine treatment in the drinking water on the nicotine-induced locomotion, anxiety status and learning performance. Chronically nicotine-treated DAT KO mice were always hypersensitive to the hypolocomotor effect of nicotine without tolerance and did not exhibit the anxiogenic effect of nicotine treatment observed in WT mice. Very interestingly, both acute and chronic nicotine treatments greatly improved their deficits in the cued and spatial learning, without eliciting tolerance. We speculate that the procognitive effects of nicotine in DAT KO mice are related to the upregulation of alpha7 nicotinic receptors in the hippocampus, amygdala, and prelimbic cortex, all areas involved in cognition. Data from our studies on DAT KO mice shed light on the nicotine self-medication in psychiatric patients and suggest that nicotinic agonists could favorably lead to additional therapy of psychiatric diseases.

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Available from: Bruno Giros, Sep 28, 2015
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    • "The spatial version of the Morris watermaze test was conducted as already reported (Weiss et al. 2007; see Appendix S1) in a pool filled with opaque water, under a 150 lux illumination. Mice learned the fixed position of the submerged platform using distal extra-maze cues. "
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    ABSTRACT: J. Neurochem. (2012) 121, 99–114. The microtubule-associated Stable Tubulie Only Polypeptide (STOP; also known as MAP6) protein plays a key role in neuron architecture and synaptic plasticity, the dysfunctions of which are thought to be implicated in the pathophysiology of psychiatric diseases. The deletion of STOP in mice leads to severe disorders reminiscent of several schizophrenia-like symptoms, which are also associated with differential alterations of the serotonergic tone in somas versus terminals. In STOP knockout (KO) compared with wild-type mice, serotonin (5-HT) markers are found to be markedly accumulated in the raphe nuclei and, in contrast, deeply depleted in all serotonergic projection areas. In the present study, we carefully examined whether the 5-HT imbalance would lead to behavioral consequences evocative of mood and/or cognitive disorders. We showed that STOP KO mice exhibited depression-like behavior, associated with a decreased anxiety-status in validated paradigms. In addition, although STOP KO mice had a preserved very short-term memory, they failed to perform well in all other learning and memory tasks. We also showed that STOP KO mice exhibited regional imbalance of the norepinephrine tone as observed for 5-HT. As a consequence, mutant mice were hypersensitive to acute antidepressants with different selectivity. Altogether, these data indicate that the deletion of STOP protein in mice caused deep alterations in mood and cognitive performances and that STOP protein might have a crucial role in the 5-HT and norepinephrine networks development.
    Journal of Neurochemistry 12/2011; 121(1):99-114. DOI:10.1111/j.1471-4159.2011.07615.x · 4.28 Impact Factor
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    • "The DATko phenotype is more severe and complicated with developmental abnormalities, including growth retardation, pituitary hypoplasia, lactation deficits, and high mortality (Bosse et al., 1997), none of which occur in the knock-down line used here (Zhuang et al., 2001). More importantly, the DATko, consistent with a loss of PFC LTP, show learning, and memory deficits (Giros et al., 1996; Gainetdinov et al., 1999; Morice et al., 2007; Weiss et al., 2007; Dzirasa et al., 2009). In contrast, learning has been shown to be normal in the DATkd (Cagniard et al., 2006a,b; Yin et al., 2006), including in the present study. "
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    ABSTRACT: The impact of dopamine on adaptive behavior in a naturalistic environment is largely unexamined. Experimental work suggests that phasic dopamine is central to reinforcement learning whereas tonic dopamine may modulate performance without altering learning per se; however, this idea has not been developed formally or integrated with computational models of dopamine function. We quantitatively evaluate the role of tonic dopamine in these functions by studying the behavior of hyperdopaminergic DAT knockdown mice in an instrumental task in a semi-naturalistic homecage environment. In this "closed economy" paradigm, subjects earn all of their food by pressing either of two levers, but the relative cost for food on each lever shifts frequently. Compared to wild-type mice, hyperdopaminergic mice allocate more lever presses on high-cost levers, thus working harder to earn a given amount of food and maintain their body weight. However, both groups show a similarly quick reaction to shifts in lever cost, suggesting that the hyperdominergic mice are not slower at detecting changes, as with a learning deficit. We fit the lever choice data using reinforcement learning models to assess the distinction between acquisition and expression the models formalize. In these analyses, hyperdopaminergic mice displayed normal learning from recent reward history but diminished capacity to exploit this learning: a reduced coupling between choice and reward history. These data suggest that dopamine modulates the degree to which prior learning biases action selection and consequently alters the expression of learned, motivated behavior.
    Frontiers in Behavioral Neuroscience 11/2010; 4:170. DOI:10.3389/fnbeh.2010.00170 · 3.27 Impact Factor
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    • "Variable depending on dose KO + low dose nicotine → ↑locomotor effects KO + high dose nicotine →↓locomotor effects Weiss et al., 2007 "
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    ABSTRACT: Cigarette smoking is the main preventable cause of death in developed countries, and the development of more effective treatments is necessary. Cumulating evidence suggests that cognitive enhancement may contribute to the addictive actions of nicotine. Several studies have demonstrated that nicotine enhances cognitive performance in both smokers and non-smokers. Genetic studies support the role of both dopamine (DA) and nicotinic acetylcholine receptors (nAChRs) associated with nicotine-induced cognitive enhancement. Based on knockout mice studies, beta2 nAChRs are thought to be essential in mediating the cognitive effects of nicotine. alpha7nAChRs are associated with attentional and sensory filtering response, especially in schizophrenic individuals. Genetic variation in D2 type DA receptors and the catechol-O-methyltransferase enzyme appears to moderate cognitive deficits induced by smoking abstinence. Serotonin transporter (5-HTT) gene variation also moderates nicotine-induced improvement in spatial working memory. Less is known about the contribution of genetic variation in DA transporter and D4 type DA receptor genetic variation on the cognitive effects of nicotine. Future research will provide a clearer understanding of the mechanism underlying the cognitive-enhancing actions of nicotine.
    Addiction Biology 04/2010; 15(3):250-65. DOI:10.1111/j.1369-1600.2010.00213.x · 5.36 Impact Factor
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