Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors

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Abstract
The bad news, nicotine addiction has caused the deaths of millions from smoking-related diseases. The good news, nicotine can enhance cognitive performance. In an attempt to disentangle the brain networks that mediate nicotine reward and relevant cognitive functions, Maskos et al. have developed an injectable lentiviral vector that delivers functional nicotinic acetylcholine receptors to defined regions of the mouse brain. The technique was used to generate mice that express nicotinic receptors exclusively in the midbrain ventral tegmental area, the VTA, which contains dopamine reward neurons and is associated with the response to drugs of abuse. The experiment showed that these receptors in the VTA are sufficient for all behavioural and physiological phenomena associated with nicotine dependence. And they are also involved in the higher brain or ‘cognitive’ functions in the mouse. Nicotine's ‘good’ and ‘bad’ sides are, it seems, intimately entangled and originate from a phylogenetically ancient part of the brain. Worldwide, 100 million people are expected to die this century from the consequences of nicotine addiction1, but nicotine is also known to enhance cognitive performance2. 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 deletions3,4. 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.