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Decreased α4β2 nicotinic receptor number in the absence of mRNA changes suggests post‐transcriptional regulation in the spontaneously hypertensive rat model of ADHD
Author(s) -
Wigestrand Mattis B.,
Mineur Yann S.,
Heath Christopher J.,
Fonnum Frode,
Picciotto Marina R.,
Walaas Sven Ivar
Publication year - 2011
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2011.07415.x
Subject(s) - methyllycaconitine , epibatidine , endocrinology , medicine , messenger rna , cerebellum , nicotinic agonist , striatum , chemistry , receptor , biology , neuroscience , nicotinic acetylcholine receptor , biochemistry , dopamine , gene
J. Neurochem. (2011) 119 , 240–250. Abstract The spontaneously hypertensive rat (SHR) is widely used as a model of attention‐deficit/hyperactivity disorder (ADHD). Deficits in central nicotinic receptors (nAChRs) have been previously observed in SHRs, which is interesting since epidemiological studies have identified an association between smoking and ADHD symptoms in humans. Here, we examine whether nAChR deficits in SHRs compared with Wistar Kyoto rat (WKY) controls are nAChR subtype‐specific and whether these deficits correlate with changes at the level of mRNA transcription in specific brain regions. Levels of binding sites (B max ) and dissociation constants (K d ) for nAChRs were determined from saturation curves of high‐affinity [ 3 H]epibatidine‐ and [ 3 H] Methyllycaconitine (MLA) binding to membranes from cortex, striatum, hippocampus and cerebellum. In additional brain regions, nAChRs were examined by autoradiography with [ 125 I]A‐85380 and [ 125 I]α‐bungarotoxin. Levels of mRNA encoding nAChR subunits were measured using quantitative real‐time PCR (qPCR). We showed that the number of α4β2 nAChR binding sites is lower globally in the SHR brain compared with WKY in the absence of significant differences in mRNA levels, with the exception of lower α4 mRNA in cerebellum of SHR compared with WKY. Furthermore, nAChR deficits were subtype‐ specific because no strain difference was found in α7 nAChR binding or α7 mRNA levels. Our results suggest that the lower α4β2 nAChR number in SHR compared with WKY may be a consequence of dysfunctional post‐transcriptional regulation of nAChRs.