Chronic Pretreatment with Nicotine is Sufficient to Upregulate α4* nAChRs and Increase Self-Administration of Nicotine in a Two Bottle-Choice Paradigm in Mice




Renda, Anthony

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Nicotine addiction is a complex behavior linked to the alteration of nicotinic receptor (nAChR) expression within the brain caused by chronic nicotine. A crucial factor when elucidating an accurate picture of the underlying causes of addiction is the route of administration. Oral self-administration of nicotine is a non-invasive method of drug administration, able to mimic the episodic nature of nicotine consumption seen in human smokers and also provide a choice – the key feature of an accurate addiction model. Mice with YFP-tagged α4 nicotinic receptors (α4YFP) were pretreated with chronic nicotine via osmotic pumps in order to maximally upregulate their nAChRs before being subjected to a two bottle-choice assay of nicotine self-administration. The paradigm consists of periods of choice interspersed with periods of nicotine abstinence to affect withdrawal and perpetuate nicotine self-selection. Spectral confocal microscopy of the endogenous α4YFP was used to investigate the expression levels of nAChRs following chronic nicotine priming with osmotic pumps. Imaging confirms that mice exposed to chronic nicotine prior to entering the self-administration paradigm have upregulated α4-containing (α4*) nAChRs in the medial perforant path of the hippocampus, on GABAergic somata of the ventral tegmental area and on GABAergic and glutamatergic somata of the medial prefrontal cortex, areas implicated in mediating addictive behavior. Compared to control mice with basal levels of nicotinic receptors, nicotine-primed mice ingest a larger daily dose of nicotine and allocate a greater percentage of their daily fluid intake to their nicotine-containing bottle. They also show signs of withdrawal, observed as post-abstinence binging. The control mice show no withdrawal, but progress towards dependence by adjusting the percentage drank from their nicotine bottle in order to maintain a constant daily dose. Conversely, nicotine primed mice decrease their daily dose of nicotine, suggesting that maximal receptor upregulation caused by osmotic pumps is outside the physiologically relevant level that can be obtained by nicotine self-administration in mice. Taken together, these results show that our model is sufficient to yield addictive behavior in mice and also implicates nAChR upregulation as a key factor influencing nicotine self-administration.



Nicotine, Addiction, Neuroscience, Biology, Mice, Genetics, Microscopy, Behavior, Confocal, Ion Channel