Desformylflustrabromine, a positive allosteric modulator of ?4?2-containing nicotinic acetylcholine receptors, enhances cognition in rats.

ABSTRACT: RATIONALE:The ?4?2 nicotinic acetylcholine receptors (?4?2-nAChRs) may represent useful targets for cognitive improvement. It has been recently proposed that a strategy based on positive allosteric modulation of ?4?2-nAChRs reveals several advantages over the direct agonist approach. Nevertheless, the procognitive effects of ?4?2-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 ?4?2-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-?-erythroidine, a relatively selective ?4?2-nAChR antagonist, indicating the involvement of ?4?2-nAChRs in cognitive processes. The tested ?4?2-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 ?4?2-nAChR agonist. CONCLUSIONS:These findings indicate that dFBr presents procognitive activity, supporting the strategy based on ?4?2-nAChR potentiation as a plausible therapy for cognitive impairment.

SUBMITTER: Nikiforuk A 

PROVIDER: S-EPMC7329799 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature