A Potasiewicz1, T Kos1, F Ravazzini2, G Puia2, H R Arias3, P Popik1, A Nikiforuk1. 1. Behavioral Neuroscience and Drug Development, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343, Kraków, Poland. 2. Department of Life Science, University of Modena and Reggio Emilia, Modena, Italy. 3. Department of Medical Education, California Northstate University College of Medicine, CA, 95757, USA.
Abstract
BACKGROUND AND PURPOSE: 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). EXPERIMENTAL APPROACH: 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) . KEY 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 AND IMPLICATIONS: 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.
BACKGROUND AND PURPOSE: 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). EXPERIMENTAL APPROACH: 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) . KEY 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 AND IMPLICATIONS: 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.
Authors: Karin R Tietje; David J Anderson; R Scott Bitner; Eric A Blomme; Paul J Brackemeyer; Clark A Briggs; Kaitlin E Browman; Dagmar Bury; Peter Curzon; Karla U Drescher; Jennifer M Frost; Ryan M Fryer; Gerard B Fox; Jens Halvard Gronlien; Monika Håkerud; Earl J Gubbins; Sabine Halm; Richard Harris; Rosalind J Helfrich; Kathy L Kohlhaas; Devalina Law; John Malysz; Kennan C Marsh; Ruth L Martin; Michael D Meyer; Angela L Molesky; Arthur L Nikkel; Stephani Otte; Liping Pan; Pamela S Puttfarcken; Richard J Radek; Holly M Robb; Eva Spies; Kirsten Thorin-Hagene; Jeffrey F Waring; Hilde Ween; Hongyu Xu; Murali Gopalakrishnan; William H Bunnelle Journal: CNS Neurosci Ther Date: 2008 Impact factor: 5.243
Authors: Julie M Brooks; Michelle L Pershing; Morten S Thomsen; Jens D Mikkelsen; Martin Sarter; John P Bruno Journal: Neuropsychopharmacology Date: 2012-07-11 Impact factor: 7.853
Authors: Jørgen Eskildsen; John P Redrobe; Anette G Sams; Kim Dekermendjian; Morten Laursen; Jette B Boll; Roger L Papke; Christoffer Bundgaard; Kristen Frederiksen; Jesper F Bastlund Journal: Bioorg Med Chem Lett Date: 2013-11-20 Impact factor: 2.823
Authors: David Phenis; Sarah A Vunck; Valentina Valentini; Hugo Arias; Robert Schwarcz; John P Bruno Journal: Psychopharmacology (Berl) Date: 2020-03-11 Impact factor: 4.530