TY - JOUR

T1 - alpha(7) Nicotinic acetylcholine receptor activation prevents behavioral and molecular changes induced by repeated phencyclidine treatment

AU - Thomsen, Morten Skøtt

AU - Christensen, Ditte Z

AU - Hansen, Henrik H

AU - Redrobe, John P

AU - Mikkelsen, Jens D

N1 - Keywords: Animals; Bicyclo Compounds, Heterocyclic; Cognition Disorders; Cytoskeletal Proteins; Drug Partial Agonism; Gene Expression; Male; Maze Learning; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Nicotinic Agonists; Parvalbumins; Phencyclidine; Prefrontal Cortex; RNA, Messenger; Receptors, GABA-A; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Receptors, Nicotinic; Synaptophysin

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

U2 - 10.1016/j.neuropharm.2009.02.003

DO - 10.1016/j.neuropharm.2009.02.003

M3 - Journal article

C2 - 19233218

VL - 56

SP - 1001

EP - 1009

JO - Neuropharmacology

JF - Neuropharmacology

SN - 0028-3908

IS - 6-7

ER -