TY - JOUR
T1 - Desformylflustrabromine, a positive allosteric modulator of α4β2-containing nicotinic acetylcholine receptors, enhances cognition in rats
AU - Nikiforuk, Agnieszka
AU - Litwa, Ewa
AU - Krawczyk, Martyna
AU - Popik, Piotr
AU - Arias, Hugo
N1 - Funding Information:
This study was supported by the Statutory Activity of the Maj Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland and by the Polish National Science Centre (NCN) Grant No. 2016/23/B/NZ7/01131. Open access publishing of this article was funded by the Ministry of Science and Higher Education under the agreement No. 879/P-DUN/2019.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/6/1
Y1 - 2020/6/1
N2 - Rationale: The α4β2 nicotinic acetylcholine receptors (α4β2-nAChRs) may represent useful targets for cognitive improvement. It has been recently proposed that a strategy based on positive allosteric modulation of α4β2-nAChRs reveals several advantages over the direct agonist approach. Nevertheless, the procognitive effects of α4β2-nAChR positive allosteric modulators (PAMs) have not been extensively characterized. Objectives: The aim of the present study was to evaluate the procognitive efficacy of desformylflustrabromine (dFBr), a selective α4β2-nAChR PAM. Methods: Cognitive effects were investigated in the novel object recognition task (NORT) and the attentional set-shifting task (ASST) in rats. Results: The results demonstrate that dFBr attenuated the delay-induced impairment in NORT performance and facilitated cognitive flexibility in the ASST. The beneficial effects of dFBr were inhibited by dihydro-β-erythroidine, a relatively selective α4β2-nAChR antagonist, indicating the involvement of α4β2-nAChRs in cognitive processes. The tested α4β2-PAM was also effective against ketamine- and scopolamine-induced deficits of object recognition memory. Moreover, procognitive effects were also observed after combined treatment with inactive doses of dFBr and TC-2403, a selective α4β2-nAChR agonist. Conclusions: These findings indicate that dFBr presents procognitive activity, supporting the strategy based on α4β2-nAChR potentiation as a plausible therapy for cognitive impairment.
AB - Rationale: The α4β2 nicotinic acetylcholine receptors (α4β2-nAChRs) may represent useful targets for cognitive improvement. It has been recently proposed that a strategy based on positive allosteric modulation of α4β2-nAChRs reveals several advantages over the direct agonist approach. Nevertheless, the procognitive effects of α4β2-nAChR positive allosteric modulators (PAMs) have not been extensively characterized. Objectives: The aim of the present study was to evaluate the procognitive efficacy of desformylflustrabromine (dFBr), a selective α4β2-nAChR PAM. Methods: Cognitive effects were investigated in the novel object recognition task (NORT) and the attentional set-shifting task (ASST) in rats. Results: The results demonstrate that dFBr attenuated the delay-induced impairment in NORT performance and facilitated cognitive flexibility in the ASST. The beneficial effects of dFBr were inhibited by dihydro-β-erythroidine, a relatively selective α4β2-nAChR antagonist, indicating the involvement of α4β2-nAChRs in cognitive processes. The tested α4β2-PAM was also effective against ketamine- and scopolamine-induced deficits of object recognition memory. Moreover, procognitive effects were also observed after combined treatment with inactive doses of dFBr and TC-2403, a selective α4β2-nAChR agonist. Conclusions: These findings indicate that dFBr presents procognitive activity, supporting the strategy based on α4β2-nAChR potentiation as a plausible therapy for cognitive impairment.
KW - Cognition
KW - Desformylflustrabromine
KW - Positive allosteric modulators
KW - Rat
KW - Α4β2-nAChRs
UR - http://www.scopus.com/inward/record.url?scp=85082196559&partnerID=8YFLogxK
U2 - 10.1007/s43440-020-00092-4
DO - 10.1007/s43440-020-00092-4
M3 - Article
C2 - 32207091
AN - SCOPUS:85082196559
SN - 1734-1140
VL - 72
SP - 589
EP - 599
JO - Pharmacological Reports
JF - Pharmacological Reports
IS - 3
ER -