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Repeated administration of α7 nicotinic acetylcholine receptor (nAChR) agonists, but not positive allosteric modulators, increases α7 nAChR levels in the brain
Author(s) -
Christensen Ditte Z.,
Mikkelsen Jens D.,
Hansen Henrik H.,
Thomsen Morten S.
Publication year - 2010
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.1471-4159.2010.06845.x
Subject(s) - allosteric modulator , agonist , nicotinic agonist , allosteric regulation , chemistry , pharmacology , prefrontal cortex , neuroscience , nicotinic acetylcholine receptor , receptor , partial agonist , acetylcholine receptor , psychology , medicine , biochemistry , cognition
J. Neurochem. (2010) 114 , 1205–1216. Abstract The α7 nicotinic acetylcholine receptor (nAChR) is an important target for treatment of cognitive deficits in schizophrenia and Alzheimer’s disease. However, the receptor desensitizes rapidly in vitro , which has led to concern regarding its applicability as a clinically relevant drug target. Here we investigate the effects of repeated agonism on α7 nAChR receptor levels and responsiveness in vivo in rats. Using [ 125 I]‐α‐bungarotoxin (BTX) autoradiography we show that acute or repeated administration with the selective α7 nAChR agonist A‐582941 increases the number of α7 nAChR binding sites in several brain regions, particularly in the prefrontal cortex. The α7 nAChR agonists SSR180711 and PNU‐282987 also increase [ 125 I]‐BTX binding, suggesting that this is a general consequence of α7 nAChR agonism. Interestingly, the α7 nAChR positive allosteric modulators PNU‐120596 and NS1738 do not increase [ 125 I]‐BTX binding. Furthermore, A‐582941‐induced increase in Arc and c‐ fos mRNA expression in the prefrontal cortex is enhanced and unaltered, respectively, after repeated administration, demonstrating that the α7 nAChRs remain responsive. Contrarily, A‐582941‐induced phosphorylation of Erk2 in the prefrontal cortex occurs following acute, but not repeated administration. Our results demonstrate that repeated agonist administration increases the number of α7 nAChRs in the brain, and leads to coupling versus uncoupling of specific intracellular signaling pathways. Additionally, our data suggest a fundamental difference between the sequelae of repeated administration with agonists and allosteric modulators of the α7 nAChR.