Pro-cognitive activity in rats of 3-furan-2-yl-N-p-tolyl-acrylamide, a positive allosteric modulator of the α7 nicotinic acetylcholine receptor.
OBJECTIVE
α7 nicotinic acetylcholine receptors (α7 nAChRs) may represent useful targets for cognitive improvement. The aim of this study is to compare the pro-cognitive activity of selective α7-nAChR ligands, including the partial agonists, DMXBA and A-582941, as well as the positive allosteric modulator, 3-furan-2-yl-N-p-tolyl-acrylamide (PAM-2).


METHODS
The attentional set-shifting task (ASST) and the novel object recognition task (NORT) in rats, were used to evaluate the pro-cognitive activity of each ligand [i.e., PAM-2 (0.5, 1.0, and 2.0 mg·kg(-1) ), DMXBA and A-582941 (0.3 and 1.0 mg·kg(-1) )], in the absence and presence of methyllycaconitine (MLA), a selective competitive antagonist. To determine potential drug interactions, an inactive dose of PAM-2 (0.5 mg·kg(-1) ) was co-injected with inactive doses of either agonist - DMXBA: 0.1 (NORT); 0.3 mg·kg(-1) (ASST) or A-582941: 0.1 mg·kg(-1) .


RESULTS
PAM-2, DMXBA, and A-582941 improved cognition in a MLA-dependent manner, indicating that the observed activities are mediated by α7 nAChRs. Interestingly, the co-injection of inactive doses of PAM-2 and DMXBA or A-582941 also improved cognition, suggesting drug interactions. Moreover, PAM-2 reversed the scopolamine-induced NORT deficit. The electrophysiological results also support the view that PAM-2 potentiates the α7 nAChR currents elicited by a fixed concentration (3 μM) of DMXBA with apparent EC50 = 34 ± 3 μM and Emax = 225 ± 5 %.


CONCLUSIONS
Our results support the view that α7 nAChRs are involved in cognition processes and that PAM-2 is a novel promising candidate for the treatment of cognitive disorders.
Behavioral Neuroscience and Drug Development, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343, Kraków, Poland.
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Potasiewicz
Behavioral Neuroscience and Drug Development, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343, Kraków, Poland.
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Kos
Department of Life Science, University of Modena and Reggio Emilia, Modena, Italy.
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Ravazzini
Department of Life Science, University of Modena and Reggio Emilia, Modena, Italy.
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Puia
Department of Medical Education, California Northstate University College of Medicine, CA, 95757, USA.
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Arias
Behavioral Neuroscience and Drug Development, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343, Kraków, Poland.
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Popik
Behavioral Neuroscience and Drug Development, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343, Kraków, Poland.
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Nikiforuk
D000178:Acrylamides / Q000494:pharmacology*; D000494:Allosteric Regulation; D000818:Animals; D001597:Benzylidene Compounds; D045744:Cell Line, Tumor; D003071:Cognition / Q000187:drug effects*; D005663:Furans / Q000494:pharmacology*; D006801:Humans; D008297:Male; D018722:Nicotinic Agonists / Q000494:pharmacology*; D011724:Pyridazines; D011725:Pyridines; D011758:Pyrroles; D051381:Rats; D017207:Rats, Sprague-Dawley; D012601:Scopolamine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000187:drug effects*
C000593312:3-furan-2-yl-N-p-tolylacrylamide; C524029:A-582941; D000178:Acrylamides; D001597:Benzylidene Compounds; D005663:Furans; D018722:Nicotinic Agonists; D011724:Pyridazines; D011725:Pyridines; D011758:Pyrroles; D064569:alpha7 Nicotinic Acetylcholine Receptor; C088936:3-(2,4-dimethoxybenzylidene)anabaseine; D012601:Scopolamine