Stimulation of nicotinic acetylcholine alpha7 receptors rescue schizophrenia-like cognitive impairments in rats.
Alpha7 nicotinic acetylcholine receptor (α7 nAChR) dysfunction plays an important role in schizophrenia. Positive allosteric modulators of α7 nAChR have emerged as a promising therapeutic approach to manage cognitive deficits that are inadequately treated in schizophrenic patients. The aim of the present study was to evaluate the ability of type I (CCMI) and type II (PNU120596) α7 nAChR positive allosteric modulators to counteract MK-801-induced cognitive and sensorimotor gating deficits. The activity of these compounds was compared with the action of the α7 nAChR agonist A582941. CCMI, PNU120596 and A582941 reversed the sensorimotor gating impairment evoked by MK-801 based on the prepulse inhibition of the startle response. Additionally, no MK-801-evoked working memory deficits were observed with α7 nAChR ligand pretreatment as assessed in a discrete paired-trial delayed alternation task. However, these compounds did not affect the rats' attentional performances in the five-choice serial reaction time test. The α7 nAChR agents demonstrated a beneficial effect on sensorimotor gating and some aspects of cognition tested in a rat model of schizophrenia. Therefore, these results support the use of α7 nAChR positive allosteric modulators as a potential treatment strategy in schizophrenia.
1 Department of Behavioural Neuroscience and Drug Development, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.
Agnieszka
A
Potasiewicz
1 Department of Behavioural Neuroscience and Drug Development, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.
Agnieszka
A
Nikiforuk
1 Department of Behavioural Neuroscience and Drug Development, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.
Małgorzata
M
Hołuj
1 Department of Behavioural Neuroscience and Drug Development, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.|2 Faculty of Health Sciences, Jagiellonian University Medical College, Krakow, Poland.
Piotr
P
Popik
D000109:Acetylcholine / Q000494:pharmacology; D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D001288:Attention / Q000187:drug effects; D003071:Cognition / Q000187:drug effects; D060825:Cognitive Dysfunction / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D008570:Memory, Short-Term / Q000187:drug effects; D018722:Nicotinic Agonists / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle / Q000187:drug effects; D012559:Schizophrenia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism*; D055139:Sensory Gating / Q000187:drug effects; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism*
C547642:(N-(4-chlorophenyl))-alpha-((4-chlorophenyl)-aminomethylene)-3-methyl-5-isoxazoleacet-amide; C508388:1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea; D007555:Isoxazoles; D018722:Nicotinic Agonists; D010671:Phenylurea Compounds; D064569:alpha7 Nicotinic Acetylcholine Receptor; D016291:Dizocilpine Maleate; D000109:Acetylcholine
N-methyl-d-aspartate antagonist model; Schizophrenia; alpha7 nicotinic acetylcholine receptor; cognition; rats