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 selfmedication. 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 a7 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.

Chronic Nicotine Exposure has Dissociable Behavioural Effects on Control and Beta2−/− Mice

“…However, in humans, it has been suggested that neuropsychiatric deficits, but not normal cognitive functioning, could be improved by nicotinic treatment (Newhouse et al 2004a, b). Moreover, similarly to our results, chronic nicotine treatment was shown to affect motor functions in wild-type mice but not in mice knockout for the dopamine transporter (DAT) gene that exhibit ADHD and schizophrenia-like phenotypes, whereas such a treatment had pro-cognitive effects in DAT mutant but not in wild-type mice (Weiss et al 2007). Very interestingly, the pro-cognitive effects of chronic nicotine in both b2-/-and DAT mutant mice have been suggested to rely on a7-subunit-containing nAChRs (Besson et al 2007;Weiss et al 2007).…”

“…Moreover, similarly to our results, chronic nicotine treatment was shown to affect motor functions in wild-type mice but not in mice knockout for the dopamine transporter (DAT) gene that exhibit ADHD and schizophrenia-like phenotypes, whereas such a treatment had pro-cognitive effects in DAT mutant but not in wild-type mice (Weiss et al 2007). Very interestingly, the pro-cognitive effects of chronic nicotine in both b2-/-and DAT mutant mice have been suggested to rely on a7-subunit-containing nAChRs (Besson et al 2007;Weiss et al 2007). A great variability in nicotine-elicited effects on behaviour is recognized and has been reported to result from the activation by nicotine of different nAChRs and neuronal pathways (Stolerman 1991;Auta et al 2000;Picciotto 2003).…”

Candidate gene studies of ADHD: a meta-analytic review

“…For example, nicotine administration has been shown to improve attention and working memory deWcits in adults diagnosed with ADHD (Levin 2002) and nicotine agonists have been shown to reduce ADHD symptom severity (Wilens et al 2006). In addition, nicotine administration has been shown to signiWcantly alter dopamine activity and produce increased locomotor activity in genetically intact mice (Fung and Lau 1988;Grady et al 1992) and DAT1 knockout-mice (Weiss et al 2007a;Weiss et al 2007b). Given such evidence, researchers have begun to examine diVerent aspects of the nicotinergic system and nicotine receptors speciWcally, with the nicotinic acetylcholine receptor 4 subunit gene (CHRNA4) receiving the most attention thus far.…”

Psychiatric Disorders as Vulnerability Factors for Nicotine Addiction: What Have We Learned from Animal Models?

“…These mice exhibit behaviors such as perseverative locomotor activity, stereotypy, and cognitive and behavioral inflexibility. DAT knockout mice were shown to have deficits in cognitive tasks (the cued and spatial versions of the Morris water maze) and administration of nicotine improved performance such that latencies, distance travelled, and successful trials needed to reach the platform approached levels seen in the wild type (Weiss et al 2007). …”