title: alpha(7) Nicotinic acetylcholine receptor activation prevents behavioral and molecular changes induced by repeated phencyclidine treatment.
abstract: The core features of schizophrenia include deficits in cognitive processes, such as attention and working memory, subserved by the prefrontal cortex (PFC). These deficits are believed to involve deficient neurotransmission through NMDA receptors, particularly on parvalbumin-containing interneurons, and administration of the NMDA-antagonist phencyclidine (PCP) in rodents is a well validated model of such cognitive deficits. Here we show that repeated PCP treatment (10 mg/kg/day for 10 days) decreased the expression of parvalbumin and synaptophysin mRNA in the mouse PFC, which corresponds to changes seen in patients with schizophrenia. In addition, PCP increased the basal mRNA expression in the PFC of the activity-regulated cytoskeleton-associated protein (Arc), a molecule involved in synaptic plasticity. These molecular changes produced by PCP were accompanied by a behavioral impairment as determined in a modified Y-maze test. Polymorphisms in the alpha(7) nicotinic acetylcholine receptor (nAChR) gene have been linked to schizophrenia. Here we demonstrate that acute administration of the selective alpha(7) nAChR partial agonist SSR180711 dose-dependently reversed the behavioral impairment induced by PCP. Importantly, repeated co-administration of SSR180711 (3 mg/kg) with PCP prevented both the changes in parvalbumin, synaptophysin, and Arc mRNA expression in the PFC, and the behavioral impairment induced by PCP. These results are the first to demonstrate prevention of the deleterious effects induced by repeated PCP treatment. The behavioral and molecular effects of alpha(7) nAChR agonism in this model, particularly the prevention of a decline in parvalbumin mRNA expression, suggest an involvement of the alpha(7) nAChR not only in the symptomatic relief, but also the pathophysiology, of schizophrenia.
authors.affiliation: Department of Translational Neurobiology, NeuroSearch A/S, Ballerup, Denmark. mst@neurosearch.dk
authors.forename: Morten S
authors.initials: MS
authors.lastname: Thomsen
authors.forename: Ditte Z
authors.initials: DZ
authors.lastname: Christensen
authors.forename: Henrik H
authors.initials: HH
authors.lastname: Hansen
authors.forename: John P
authors.initials: JP
authors.lastname: Redrobe
authors.forename: Jens D
authors.initials: JD
authors.lastname: Mikkelsen
mesh_terms: D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D003072:Cognition Disorders / Q000139:chemically induced / Q000378:metabolism / Q000523:psychology; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000235:genetics; D054333:Drug Partial Agonism; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D018722:Nicotinic Agonists / Q000494:pharmacology*; D010320:Parvalbumins / Q000096:biosynthesis / Q000235:genetics; D010622:Phencyclidine / Q000633:toxicity*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D011963:Receptors, GABA-A / Q000096:biosynthesis / Q000235:genetics; D018094:Receptors, Metabotropic Glutamate / Q000096:biosynthesis / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D011978:Receptors, Nicotinic / Q000502:physiology*; D016708:Synaptophysin / Q000096:biosynthesis / Q000235:genetics; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; C579166:Chrna7 protein, mouse; D003598:Cytoskeletal Proteins; C493920:Gabra2 protein, mouse; C409466:NR1 NMDA receptor; D009419:Nerve Tissue Proteins; D018722:Nicotinic Agonists; D010320:Parvalbumins; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D011978:Receptors, Nicotinic; C516833:SSR180711; D016708:Synaptophysin; C092069:activity regulated cytoskeletal-associated protein; D064569:alpha7 Nicotinic Acetylcholine Receptor; C108822:metabotropic glutamate receptor 2; D010622:Phencyclidine