Positive allosteric modulation of alpha 4 beta 2 nAChR agonist induced behaviour

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...

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Bibliographic Details
Published in:Brain research 2012-06, Vol.1458, p.67-75
Main Authors: Rode, F, Munro, G, Holst, D, Nielsen, EOe, Troelsen, K B, Timmermann, D B, Roenn, LCB, Grunnet, M
Format: Article
Language:English
Subjects:
Acetylcholine receptors (nicotinic)
Allosteric properties
Alzheimer's disease
Analgesics
Animal models
Central nervous system
Cholinergic transmission
Dopamine
Drug discovery
Formaldehyde
Ion channels
mecamylamine
Mental disorders
Movement disorders
Neostriatum
Neurodegenerative diseases
Neuromodulation
Nomifensine
Pain
Parkinson's disease
Rotational behavior
Schizophrenia
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Summary: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 alpha 4 beta 2 receptors being the most abundant heteromer. The stoichiometry of alpha 4 beta 2 receptors can be either ( alpha 4)3( beta 2)2 or ( alpha 4)2( beta 2)3 representing channels with low (LS) or high (HS) sensitivity, respectively, to endogenous ligands. In the present study we applied the partial nAChR alpha 4 beta 2 LS and HS agonist NS3956 and the LS selective positive allosteric modulator NS9283 to investigate the role of alpha 4 beta 2 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 alpha 4 beta 2 nAChR in rotational and analgesic responses and confirm striatal alpha 4 beta 2 receptors to be of the HS form.
ISSN:0006-8993
DOI:10.1016/j.brainres.2012.03.064