title: The selective alpha7 nicotinic acetylcholine receptor agonist A-582941 activates immediate early genes in limbic regions of the forebrain: Differential effects in the juvenile and adult rat.
abstract: Due to the cognitive-enhancing properties of alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) agonists, they have attracted interest for the treatment of cognitive disturbances in schizophrenia. Schizophrenia typically presents in late adolescence or early adulthood. It is therefore important to study whether alpha7 nAChR stimulation activates brain regions involved in cognition in juvenile as well as adult individuals. Here, we compared the effects of the novel and selective alpha7 nAChR agonist 2-methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole (A-582941) in the juvenile and adult rat forebrain using two markers, activity-regulated cytoskeleton-associated protein (Arc) and c-Fos, to map neuronal activity. Acute administration of A-582941 (1, 3, 10 mg/kg) induced a dose-dependent increase in Arc mRNA expression in the medial prefrontal cortex (mPFC) and the ventral/lateral orbitofrontal (VO/LO) cortex of juvenile, but not adult rats. This effect was mitigated by the alpha7 nAChR antagonist methyllycaconitine. A-582941 also increased c-Fos mRNA expression in the mPFC of juvenile, but not adult rats. Furthermore, A-582941 increased the number of Arc and c-Fos immunopositive cells in the mPFC, VO/LO, and shell of the nucleus accumbens, in both juvenile and adult rats. The A-582941-induced c-Fos protein expression was significantly greater in the mPFC and VO/LO of juvenile compared with adult rats. These data indicate that A-582941-induced alpha7 nAChR stimulation activates brain regions critically involved in working memory and attention. Furthermore, this effect is more pronounced in juvenile than adult rats, indicating that the juvenile forebrain is more responsive to alpha7 nAChR stimulation. This observation may be relevant in the treatment of juvenile-onset schizophrenia.
authors.affiliation: Department of Translational Neurobiology, NeuroSearch A/S, Pederstrupvej 93, Ballerup, Denmark.
authors.forename: M S
authors.initials: MS
authors.lastname: Thomsen
authors.forename: J D
authors.initials: JD
authors.lastname: Mikkelsen
authors.forename: D B
authors.initials: DB
authors.lastname: Timmermann
authors.forename: D
authors.initials: D
authors.lastname: Peters
authors.forename: A
authors.initials: A
authors.lastname: Hay-Schmidt
authors.forename: H
authors.initials: H
authors.lastname: Martens
authors.forename: H H
authors.initials: HH
authors.lastname: Hansen
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D003598:Cytoskeletal Proteins / Q000378:metabolism; D017781:Genes, Immediate-Early / Q000187:drug effects*; D016762:Genes, fos / Q000187:drug effects; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008032:Limbic System / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism*; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018722:Nicotinic Agonists / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D016548:Prosencephalon / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism*; D011724:Pyridazines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000187:drug effects*; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C524029:A-582941; C579165:Chrna7 protein, rat; D003598:Cytoskeletal Proteins; D009419:Nerve Tissue Proteins; D018722:Nicotinic Agonists; D011724:Pyridazines; D011758:Pyrroles; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; C092069:activity regulated cytoskeletal-associated protein; D064569:alpha7 Nicotinic Acetylcholine Receptor