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Brain Res. 2012 Jun 6;1458:67-75. doi: 10.1016/j.brainres.2012.03.064. Epub 2012 Apr 4.

Positive allosteric modulation of α4β2 nAChR agonist induced behaviour.

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NeuroSearch A/S, Pederstrupvej 93, DK-2750 Ballerup, Denmark.


Neuronal cholinergic transmission is a prerequisite for proper CNS function. Consequently, disturbance of this system is associated with a number of pathophysiological conditions such as Parkinson's disease, Alzheimer's disease, schizophrenia and ADHD. Consequently, drug discovery efforts have spurred considerable research endeavours into identifying specific compounds for this system. Nicotinic acetylcholine receptors (nAChR) are ligand gated ion channels involved in cholinergic transmission. nAChRs are homo- or heteromeric pentamers with α4β2 receptors being the most abundant heteromer. The stoichiometry of α4β2 receptors can be either (α4)(3)(β2)(2) or (α4)(2)(β2)(3) representing channels with low (LS) or high (HS) sensitivity, respectively, to endogenous ligands. In the present study we applied the partial nAChR α4β2 LS and HS agonist NS3956 and the LS selective positive allosteric modulator NS9283 to investigate the role of α4β2 in Parkinson and pain models. In 6-OHDA lesioned rats, NS3956 increased rotational behaviour when rats were co-treated with nomifensine. This effect was absent in the presence of mecamylamine. In contrast, co-treatment with NS3956 and NS9283 reduced rotational behaviour in the animals. In a rat formalin pain model NS3956 induced an analgesic response that was strongly potentiated by NS9283. Finally in vitro experiments were applied to determine dopamine release from striatal minces. NS3956 induced a concentration dependent release while NS9283 was unable to potentiate agonist induced release. Together these results emphasize involvement of α4β2 nAChR in rotational and analgesic responses and confirm striatal α4β2 receptors to be of the HS form.

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