Forskning
Udskriv Udskriv
Switch language
Region Hovedstaden - en del af Københavns Universitetshospital
Udgivet

Repeated administration of alpha7 nicotinic acetylcholine receptor (nAChR) agonists, but not positive allosteric modulators, increases alpha7 nAChR levels in the brain

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  1. Functional interaction between Lypd6 and nicotinic acetylcholine receptors

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. Altered Alpha-Synuclein, Parkin, and Synphilin Isoform Levels in Multiple System Atrophy Brains

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Vis graf over relationer
The alpha7 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 alpha7 nAChR receptor levels and responsiveness in vivo in rats. Using [(125)I]-alpha-bungarotoxin (BTX) autoradiography we show that acute or repeated administration with the selective alpha7 nAChR agonist A-582941 increases the number of alpha7 nAChR binding sites in several brain regions, particularly in the prefrontal cortex. The alpha7 nAChR agonists SSR180711 and PNU-282987 also increase [(125)I]-BTX binding, suggesting that this is a general consequence of alpha7 nAChR agonism. Interestingly, the alpha7 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 alpha7 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 alpha7 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 alpha7 nAChR.
OriginalsprogEngelsk
TidsskriftJournal of Neurochemistry
Vol/bind114
Udgave nummer4
Sider (fra-til)1205-16
Antal sider12
ISSN0022-3042
DOI
StatusUdgivet - 1 aug. 2010

ID: 32198190