Abstract
RationaleThe 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.ObjectivesThe aim of the present study was to evaluate the procognitive efficacy of desformylflustrabromine (dFBr), a selective α4β2-nAChR PAM.MethodsCognitive effects were investigated in the novel object recognition task (NORT) and the attentional set-shifting task (ASST) in rats.ResultsThe 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.ConclusionsThese findings indicate that dFBr presents procognitive activity, supporting the strategy based on α4β2-nAChR potentiation as a plausible therapy for cognitive impairment.
Highlights
Converging lines of evidence indicate that nicotinic acetylcholine receptors are involved in the regulation of cognitive processes as well as in the pathophysiology of disorders that affect cognitive abilities, such as schizophrenia and Alzheimer’s disease (AD) [1,2,3]
The cognitive enhancement elicited by 1.0 mg/kg dFBr was blocked by 3.0 mg/kg DHβE, demonstrating that the observed effect was α4β2dependent (Fig. 2, a three-way ANOVA interaction: F[6, 120] = 21.27, p < 0.001)
The present study demonstrated for the first time that dFBr facilitates cognitive flexibility and recognition memory in rats
Summary
Converging lines of evidence indicate that nicotinic acetylcholine receptors (nAChRs) are involved in the regulation of cognitive processes as well as in the pathophysiology of disorders that affect cognitive abilities, such as schizophrenia and Alzheimer’s disease (AD) [1,2,3]. The two most predominant nAChRs in the brain are heteropentameric α4β2-nAChRs and homopentameric α7-nAChRs. Recently, studies on possible therapies for cognitive decline in schizophrenia and AD have focused primarily on α7-nAChRs (e.g., [3]). Experimental evidence supports the involvement of α4β2-nAChRs in the pathogenesis of schizophrenia and AD [4,5,6,7,8,9]. Post-mortem studies showed that the density of α4β2-nAChRs was decreased in the hippocampus [4] and striatum [5] of schizophrenia patients.
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