Anne Cormier

Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors

Worldwide, 100 million people are expected to die this century from the consequences of nicotine addiction, but nicotine is also known to enhance cognitive performance. Identifying the molecular mechanisms involved in nicotine reinforcement and cognition is a priority and requires the development of new in vivo experimental paradigms. The ventral tegmental area (VTA) of the midbrain is thought to mediate the reinforcement properties of many drugs of abuse. Here we specifically re-expressed the β2-subunit of the nicotinic acetylcholine receptor (nAChR) by stereotaxically injecting a lentiviral vector into the VTA of mice carrying β2-subunit deletions. We demonstrate the efficient re-expression of electrophysiologically responsive, ligand-binding nicotinic acetylcholine receptors in dopamine-containing neurons of the VTA, together with the recovery of nicotine-elicited dopamine release and nicotine self-administration. We also quantified exploratory behaviours of the mice, and showed that β2-subunit re-expression restored slow exploratory behaviour (a measure of cognitive function) to wild-type levels, but did not affect fast navigation behaviour. We thus demonstrate the sufficient role of the VTA in both nicotine reinforcement and endogenous cholinergic regulation of cognitive functions.

Long-term effects of chronic nicotine exposure on brain nicotinic receptors

Chronic nicotine exposure results in long-term homeostatic regulation of nicotinic acetylcholine receptors (nAChRs) that play a key role in the adaptative cellular processes leading to addiction. However, the relative contribution of the different nAChR subunits in this process is unclear. Using genetically modified mice and pharmacological manipulations, we provide behavioral, electrophysiological, and pharmacological evidence for a long-term mechanism by which chronic nicotine triggers opposing processes differentially mediated by β2*- vs. α7*nAChRs. These data offer previously undescribed insights into the understanding of nicotine addiction and the treatment of several human pathologies by nicotine-like agents chronically acting on β2*- or α7*nAChRs.

Genetic dissociation of two behaviors associated with nicotine addiction: Beta-2 containing nicotinic receptors are involved in nicotine reinforcement but not in withdrawal syndrome

RationaleNicotine addiction is characterized by two distinct behaviors, chronic compulsive self-administration and the induction of a withdrawal syndrome upon cessation of nicotine consumption.ObjectiveTo examine if these two processes rely on β2-containing nicotinic receptors—β2*nAChRs—we analyzed the behavior of mice lacking these receptors in the two situations.ResultsFirst, we showed that, in contrast to wild-type (WT) mice, β2-knockout (β2−/−) mice exhibit no intra-ventral tegmental area (VTA) nicotine self-administration, whereas their ability to self-administer morphine is intact. However, β2−/− mice showed some sensitivity to locomotor effects of nicotine, implying an effect of the drug on other nicotinic subtypes. Then, we observed that β2−/− mice exhibited a normal nicotine withdrawal syndrome, i.e., increased levels of rearing and jumping upon precipitated withdrawal. Thus, the β2*nAChRs are not involved in the behaviors induced by cessation of nicotine consumption.ConclusionTaken together, the present data demonstrated a genetic dissociation of two distinct behavioral patterns associated with nicotine addiction. They further suggested that independent molecular mechanisms underlie these two aspects, offering the possibility of controlling them separately.

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

Nicotine exerts beneficial effects on various neurological and psychiatric pathologies, yet its effects on cognitive performance remain unclear. Mice lacking the beta2 subunit of the nicotinic receptor (β2−/−) show characteristic deficits in executive functions and are suggested as reliable animal models for some specific endophenotypes of human pathologies, notably ADHD. We use β2−/− and their controls to investigate the consequences of chronic nicotine exposure on cognitive behaviour. We show that in control mice, this treatment elicits somewhat slight effects, particularly affecting nocturnal activity and self-grooming. By contrast, in β2−/− mice, chronic nicotine treatment had restorative effects on exploratory behaviour in the open-field and affected rearing, but did not modify motor functions. We confirmed that β2−/− mice exhibit impaired exploratory and social behaviour, and further demonstrated their nocturnal hyperactivity. These data support the proposal that β2−/− mice represent a relevant model for cognitive disorders in humans and that nicotine administered chronically at low dose may relieve some of these.

Targeted in vivo expression of nicotinic acetylcholine receptors in mouse brain using lentiviral expression vectors.

Nicotinic acetylcholine receptors (nAChRs) in the brain exhibit diverse functional properties and ubiquitous distribution. Yet, except for providing a receptor for the exogenously applied nicotine of tobacco products, their role in the normal functioning of the brain has remained elusive. We have used a lentiviral expression vector to re-express the beta2 subunit specifically in the ventral tegmental area (VTA) of beta2-/- mice. The viral vector efficiently expresses beta2- subunit protein leading to new nAChR-binding sites. VTA neurons transduced by the lentiviral vector are responsive to intravenous nicotine when analyzed using in vivo electrophysiology. Nicotine-induced dopamine release from the nucleus accumbens (NuAcc) was also restored in re-expressing beta2-/- mice. Intra-VTA injection of nicotine was found to be reinforcing in both wild-type and beta2-subunit re-expressing beta2-/- mice, but not in beta2-/- mice. Furthermore, in the absence of applied nicotine, the spontaneous slow exploratory behavior of the mice was restored, whereas fast navigation did not change. This latter behavioral analysis suggests a role for beta2* nAChR, specifically expressed in the VTA, in mammalian cognitive function.