Desformylflustrabromine, a positive allosteric modulator of alpha4beta2-containing nicotinic acetylcholine receptors, enhances cognition in rats.

RATIONALE: The alpha4beta2 nicotinic acetylcholine receptors (alpha4beta2-nAChRs) may represent useful targets for cognitive improvement. It has been recently proposed that a strategy based on positive allosteric modulation of alpha4beta2-nAChRs reveals several advantages over the direct agonist approach. Nevertheless, the procognitive effects of alpha4beta2-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 alpha4beta2-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-beta-erythroidine, a relatively selective alpha4beta2-nAChR antagonist, indicating the involvement of alpha4beta2-nAChRs in cognitive processes. The tested alpha4beta2-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 alpha4beta2-nAChR agonist. CONCLUSIONS: These findings indicate that dFBr presents procognitive activity, supporting the strategy based on alpha4beta2-nAChR potentiation as a plausible therapy for cognitive impairment.