Repeated administration of 7 nicotinic acetylcholine receptor (nAChR) agonists, but not positive allosteric modulators, increases 7 nAChR levels in the brain

Abstract

The 7 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 7 nAChR receptor levels and responsiveness in vivo in rats. Using [125I]-bungarotoxin (BTX) autoradiography we show that acute or repeated administration with the selective 7 nAChR agonist A-582941 increases the number of 7 nAChR binding sites in several brain regions, particularly in the prefrontal cortex. The 7 nAChR agonists SSR180711 and PNU-282987 also increase [125I]-BTX binding, suggesting that this is a general consequence of 7 nAChR agonism. Interestingly, the 7 nAChR positive allosteric modulators PNU-120596 and NS1738 do not increase [125I]-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 7 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 7 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 7 nAChR. © 2010 The Authors. Journal Compilation © 2010 International Society for Neurochemistry.