Nicotine improves cognitive deficits of dopamine transporter knockout mice without long-term tolerance.
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.
Full-textDOI: · Available from: Bruno Giros, Jun 27, 2015
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ABSTRACT: 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 · 4.24 Impact Factor
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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 · 5.93 Impact Factor
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ABSTRACT: Dopamine (DA) plays crucial roles in the cognitive functioning of the prefrontal cortex (PFC), which, to a large degree, depends on lasting neural traces formed in prefrontal networks. The establishment of these permanent traces requires changes in cortical synaptic efficacy. DA, via the D(1)-class receptors, is thought to gate or facilitate synaptic plasticity in the PFC, with little role recognized for the D(2)-class receptors. Here we show that, when significantly elevated, DA erodes, rather than facilitates, the induction of long-term potentiation (LTP) in the PFC by acting at the far less abundant cortical D(2)-class receptors through a dominant coupling to the protein phosphatase 1 (PP1) activity in postsynaptic neurons. In mice with persistently elevated extracellular DA, resulting from inactivation of the DA transporter (DAT) gene, LTP in layer V PFC pyramidal neurons cannot be established, regardless of induction protocols. Acute increase of dopaminergic transmission by DAT blockers or overstimulation of D(2) receptors in normal mice have similar LTP shutoff effects. LTP in mutant mice can be rescued by a single in vivo administration of D(2)-class antagonists. Suppression of postsynaptic PP1 mimics and occludes the D(2)-mediated rescue of LTP in mutant mice and prevents the acute erosion of LTP by D(2) agonists in normal mice. Our studies reveal a mechanistically unique heterosynaptic PP1 gate that is constitutively driven by background DA to influence LTP induction. By blocking prefrontal synaptic plasticity, excessive DA may prevent storage of lasting memory traces in PFC networks and impair executive functions.The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 11/2009; 29(45):14086-99. DOI:10.1523/JNEUROSCI.0974-09.2009 · 6.75 Impact Factor