title: Perinatal nicotine treatment induces transient increases in NACHO protein levels in the rat frontal cortex.
abstract: The nicotinic acetylcholine receptor (nAChR) regulator chaperone (NACHO) was recently identified as an important regulator of nAChR maturation and surface expression. Here we show that NACHO levels decrease during early postnatal development in rats. This decrease occurs earlier and to a greater degree in the frontal cortex (FC) compared with the hippocampus (HIP). We further show that rats exposed to nicotine during pre- and postnatal development exhibit significantly higher NACHO levels in the FC at postnatal day (PND) 21, but not at PND60. Repeated exposure to nicotine selectively during early (PND8-14) or late (PND54-60) postnatal stages did not affect NACHO protein levels in the FC or HIP, neither did exposure to high doses of the selective α7 nAChR agonists SSR180711, A-582941, or PNU-282987. However, we found significantly increased NACHO protein levels in the FC of PND36 rats after a single exposure to a combination of nicotine and the type II α7 nAChR positive allosteric modulator (PAM) PNU-120596, but not the type I PAM AVL-3288. These findings suggest that exposure to nAChR agonism affects NACHO protein levels, and that this effect is more pronounced during pre- or early postnatal development. The effect of PNU-120596 further suggests that the increase in NACHO expression is caused by activation rather than desensitization of nAChRs.
authors.affiliation: Department of Drug Design & Pharmacology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Franziska
authors.initials: F
authors.lastname: Wichern
authors.affiliation: Neurobiology Research Unit, University Hospital Copenhagen, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Majbrit M
authors.initials: MM
authors.lastname: Jensen
authors.affiliation: Neurobiology Research Unit, University Hospital Copenhagen, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Ditte Z
authors.initials: DZ
authors.lastname: Christensen
authors.affiliation: Neurobiology Research Unit, University Hospital Copenhagen, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Jens D
authors.initials: JD
authors.lastname: Mikkelsen
authors.affiliation: Laboratory for Neurodevelopment, Department of Anatomy, Howard University College of Medicine, Washington D.C., USA; Neuropsychopharmacology Laboratory, Dept. of Psychiatry and Behavioral Sciences, Howard University College of Medicine, Washington D.C., USA.
authors.forename: Marjorie C
authors.initials: MC
authors.lastname: Gondré-Lewis
authors.affiliation: Department of Drug Design & Pharmacology, University of Copenhagen, Copenhagen, Denmark. Electronic address: mokt@lundbeck.com.
authors.forename: Morten S
authors.initials: MS
authors.lastname: Thomsen
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D005260:Female; D005625:Frontal Lobe / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism*; D006624:Hippocampus / Q000196:embryology / Q000378:metabolism; D008297:Male; D018832:Molecular Chaperones / Q000378:metabolism*; D009538:Nicotine / Q000008:administration & dosage*; D018722:Nicotinic Agonists / Q000008:administration & dosage; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism*
chemical_list: D018832:Molecular Chaperones; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D009538:Nicotine
keywords: TMEM35; allosteric modulator; chaperone; development; nicotinic acetylcholine receptor; nicotinic acetylcholine receptor regulator