Research Highlight: Role of β4* Nicotinic Acetylcholine Receptors in the Habenulo-Interpeduncular Pathway in Nicotine Reinforcement in Mice.

ENP team leaders Uwe Maskos and Philippe Faure, and ENP student Lauriane Harrington, have published a study in the journal Neuropsychopharmacology revealing a crucial neural mechanism of nicotine reward, a process that underlies nicotine addiction. In collaboration with researchers at the IMIM-Hospital del Mar Research Institute, the University Pompeu Fabra, the authors used a combination of transgenic mouse lines, lentivirus technology, behaviour, and in vivo electrochemical recordings, to stratify the region-specific role of a subset of neuronal receptors in nicotine reward.

Nicotine, the principal psychoactive compound in tobacco, exerts its psychopharmacological effects by activating the nicotinic acetylcholine receptor (nAChR). This receptor is composed of alpha and beta subunits that give rise to a diverse population of receptors with distinct pharmacology. Mice lacking the β4 subunit-encoding gene showed reduced nicotine consumption and an abnormal neural response of the mesolimbic dopamine reward system to nicotine. Selectively replacing this nicotinic receptor subunit in the medial habenula or interpeduncular nucleus of these mice using a lentivirus restored both nicotine consumption and dopamine function, therefore locating β4'saction to these brain regions. This research is consistent with human genetic data showing that variants in the β4 subunit-encoding gene alter smoking behaviour and vulnerability to nicotine addiction. These findings put forward a new neurobiological target for clarifying the basis of nicotine addiction, and therefore facilitates the future design of more rational therapeutic leads for smoking cessation.

Check out the article:

Role of β4* Nicotinic Acetylcholine Receptors in the Habenulo-Interpeduncular Pathway in Nicotine Reinforcement in Mice. Lauriane Harrington, PhD, Xavier Viñals, PhD, Andrea Herrera-Solís, Africa Flores, Carole Morel, Stefania Tolu, Philippe Faure, Rafael Maldonado, Uwe Maskos and Patricia Robledo.

DOI: 10.1038/npp.2015.346 

Keywords: nicotine, nicotinic acetylcholine receptor, interpeduncular nucleus, lentivirus..

Figure: Conditional expression of a fluorophore (green, anti-GFP) in β4-expressing neurons of the interpeduncular nucleus (IPN) using a cre-lox strategy. The expression of postsynaptic β4 subunits is usually masked by β4-rich cholinergic (red, anti-ChAT) input from the medial habenula, which we diverted using a transgenic mouse line. GFP (green) - green fluorescent protein; TH (blue) - tyrosine hydroxylase, labelling dopamine neurons; ChAT (red) - choline acetyl transferase.