The antidepressant-like activity of nicotine, but not of 3-furan-2-yl- N - p -tolyl-acrylamide, is regulated by the nicotinic receptor β4 subunit

Arias, Hugo R.; Targowska-Duda, Katarzyna M.; Feuerbach, Dominik; Jóźwiak, Krzysztof

doi:10.1016/j.neuint.2015.06.006

Cited by 13 publications

(8 citation statements)

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“…Recently, a series of PAMs with selectivity for the α7 nAChR has been synthesised and pharmacologically characterized (Arias et al , ). Among them, 3‐furan‐2‐yl‐N‐p‐tolyl‐acrylamide (PAM‐2) presents antidepressant (Targowska‐Duda et al , ; Arias et al , ), pro‐mnesic and anxiolytic (Targowska‐Duda et al , ), and antinociceptive and anti‐inflammatory activity (Bagdas et al , ) in mice. To complete these preclinical studies, and to determine the pro‐cognitive activity of PAM‐ 2, two animal tests, namely the attentional set‐shifting task (ASST) (Nikiforuk et al , ) and the novel object recognition task (NORT) (Nikiforuk et al , ), were used with male rats.…”

Section: Introductionmentioning

confidence: 99%

Pro‐cognitive activity in rats of 3‐furan‐2‐yl‐N‐p‐tolyl‐acrylamide, a positive allosteric modulator of the α7 nicotinic acetylcholine receptor

Potasiewicz

Kos

Ravazzini

et al. 2015

British J Pharmacology

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BACKGROUND AND PURPOSEα7 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 APPROACHThe attentional set-shifting task (ASST) and the novel object recognition task (NORT) in rats, were used to evaluate the procognitive activity of each ligand [i.e., PAM-2 (0.5, 1.0, and 2.0 mg·kg À1 ), DMXBA and A-582941 (0.3 and 1.0 mg·kg À1 )], 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 À1 ) was co-injected with inactive doses of either agonist -DMXBA: 0.1 (NORT); 0.3 mg·kg À1(ASST) or A-582941: 0.1 mg·kg À1 . KEY RESULTSPAM-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 EC 50 = 34 ± 3 μM and E max = 225 ± 5 %. CONCLUSIONS AND IMPLICATIONSOur 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.Abbreviations α7 nAChR, nicotinic acetylcholine receptor with α7

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Section: Introductionmentioning

confidence: 99%

Pro‐cognitive activity in rats of 3‐furan‐2‐yl‐N‐p‐tolyl‐acrylamide, a positive allosteric modulator of the α7 nicotinic acetylcholine receptor

Potasiewicz

Kos

Ravazzini

et al. 2015

British J Pharmacology

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“…PAM-2 may constitute a promising therapeutic agent for the treatment of memory impairment in neurological conditions such as AD and schizophrenia where the cholinergic tone is altered. The combination of beneficial activities elicited by PAM-2, including promnesic (this work), procognitive [12], and antidepressant-like [9,10] activity, could be clinically relevant for the treatment of AD patients where cognitive impairment is often linked with depression, which correspond to ∼40% of the AD population [41].…”

Section: Discussionmentioning

confidence: 96%

“…3-Furan-2-yl-N-p-tolylacrylamide (PAM-2), an α7-selective PAM [8], reactivates desensitized α7 nAChRs, resembling the properties of type II PAMs [9]. Interestingly, this novel PAM produces antidepressant-like activity [9,10] as well as antinociceptive and anti-inflammatory activity in mice [11]. PAM-2, as well as other α7-PAMs (reviewed in Refs.…”

Section: Introductionmentioning

confidence: 99%

The positive allosteric modulator of α7 nicotinic acetylcholine receptors, 3-furan-2-yl-N-p-tolyl-acrylamide, enhances memory processes and stimulates ERK1/2 phosphorylation in mice

Targowska-Duda

Wnorowski

Budzyńska

et al. 2016

Behavioural Brain Research

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To determine whether 3-furan-2-yl-N-p-tolyl-acrylamide (PAM-2), a positive allosteric modulator of α7 nicotinic acetylcholine receptors (nAChRs), improves memory processes, passive avoidance tests were conducted in male mice after acute and chronic treatments. To determine the neuronal mechanisms underlying the promnesic activity elicited by PAM-2, the effect of this ligand on α7 nAChR up-regulation and ERK1/2 phosphorylation was assessed in the hippocampus and prefrontal cortex. The results indicate that: (1) PAM-2 improves memory acquisition/consolidation after acute treatment (Day 2) and memory consolidation after chronic treatment (Day 22). Although no effect was observed on α7 nAChR up-regulation, the chronic, but not acute, PAM-2 treatment increases ERK1/2 kinase phosphorylation, (2) the promnesic activity of PAM-2 was inhibited by methyllycaconitine, a selective α7-antagonist, confirming the role of α7 nAChRs, (3) a synergistic (acute) effect was observed between inactive doses of PAM-2 (0.1 mg/kg) and DMXBA (0.3 mg/kg), a selective α7-agonist, and (4) PAM-2 reversed the memory impairment elicited by scopolamine, a muscarinic antagonist. The results demonstrate that PAM-2 presents promnesic activity mediated by α7 nAChRs, and is able to trigger ERK1/2 phosphorylation only after chronic treatment.

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“…Although different types of stress trigger anxiety- and depression-like behaviours (Oliveira et al, 2015), the NSF method is designed to induce animal anxiety. Since the NSF test was conducted after an acute treatment, no depression should be developed in the animals (Harmer et al, 2017), ruling out the possibility that the observed different efficacy of PAM-2 is due to its antidepressant-like activity (Arias et al, 2015; Targowska-Duda et al, 2014). In fact, PAM-2’s different efficacy might be basically due to the need of a higher α7 nAChR activity, reflected in the higher active dose for PAM-2, to alleviate anxiety in food-deprived animals compared to fully-fed animals (i.e.…”

Section: Discussionmentioning

confidence: 99%

“…on Day 1). The doses used of PAM-2 (Arias et al, 2015; Potasiewicz et al, 2015; Targowska-Duda et al, 2014, 2016), MLA and DMXBA (Pandya and Yakel, 2013; Targowska-Duda et al, 2016), as well as the anxiogenic doses of nicotine (Anderson and Brunzell, 2015; Biala and Budzynska, 2006) and PNU-282987 (Pandya and Yakel, 2013), are based on previous works. To determine receptor selectivity, mice ( n =10) were co-injected with MLA (3.0 mg/kg) and PAM-2 (1.0 mg/kg), and after an additional 30-minute period, the EPM test was performed.…”

Section: Methodsmentioning

confidence: 99%

3-Furan-2-yl-N-p-tolyl-acrylamide, a highly selective positive allosteric modulator of α7 nicotinic receptors, produces anxiolytic-like activity in mice

et al. 2019

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Background: Several lines of investigations support the idea that nicotinic acetylcholine receptors modulate neuronal pathways involved in anxiety and depression. Aims: The purpose of this study was to determine whether 3-furan-2-yl-N-p-tolyl-acrylamide, a highly selective positive allosteric modulator of α7 nicotinic acetylcholine receptors, influences anxiety-like behaviour in mice, and to determine the modulatory activity of 3-furan-2-yl-N-p-tolyl-acrylamide on mice pretreated with either nicotine or selective α7-agonists (i.e. PNU-282987 or (2.4)-dimethoxybenzylidene anabaseine dihydrochloride). Methods: The elevated plus maze and novelty suppressed feeding tests were selected to evaluate 3-furan-2-yl-N-p-tolyl-acrylamide and other nicotinic ligands on anxiety-like behaviour in mice. Results: The results indicated that: (a) 3-furan-2-yl-N-p-tolyl-acrylamide induces anxiolytic-like activity at 0.5 (elevated plus maze) and 1.0 (novelty suppressed feeding) mg/kg, respectively, after acute treatment, whereas its efficacy is increased after chronic treatments (i.e. active at 0.1 mg/kg; elevated plus maze). This is the first time showing anxiolytic-like activity elicited by 3-furan-2-yl-N-p-tolyl-acrylamide, contrary to the lack of activity for PNU-120596 (0.1 mg/kg); (b) the anxiolytic-like activity of 0.5 mg/kg 3-furan-2-yl-N-p-tolyl-acrylamide is inhibited by methyllycaconitine, a selective α7-antagonist, suggesting that α7 nicotinic acetylcholine receptors are involved in this process; (c) 0.5 mg/kg 3-furan-2-yl-N-p-tolyl-acrylamide reverses the anxiogenic effects induced by 0.1 mg/kg nicotine but not by 10.0 mg/kg PNU-282987; and (d) inactive doses of both 3-furan-2-yl-N-p-tolyl-acrylamide (0.1 mg/kg) and (2.4)-dimethoxybenzylidene anabaseine dihydrochloride (1.0 mg/kg) produce anxiolytic-like effects, suggesting drug interactions, probably synergistic. Conclusions: Our findings indicated that anxiolytic-like activity is mediated by α7 nicotinic acetylcholine receptors, supporting the concept that these receptors modulate anxiety processes. The results indicating that the chronic treatment with 3-furan-2-yl-N-p-tolyl-acrylamide is more efficient than the acute treatment in eliciting anxiolytic-like activity, and that 3-furan-2-yl-N-p-tolyl-acrylamide reverses the anxiogenic effects induced by nicotine, might be of therapeutic importance during smoking cessation.

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The antidepressant-like activity of nicotine, but not of 3-furan-2-yl- N - p -tolyl-acrylamide, is regulated by the nicotinic receptor β4 subunit

Cited by 13 publications

References 34 publications

Pro‐cognitive activity in rats of 3‐furan‐2‐yl‐N‐p‐tolyl‐acrylamide, a positive allosteric modulator of the α7 nicotinic acetylcholine receptor

Pro‐cognitive activity in rats of 3‐furan‐2‐yl‐N‐p‐tolyl‐acrylamide, a positive allosteric modulator of the α7 nicotinic acetylcholine receptor

The positive allosteric modulator of α7 nicotinic acetylcholine receptors, 3-furan-2-yl-N-p-tolyl-acrylamide, enhances memory processes and stimulates ERK1/2 phosphorylation in mice

3-Furan-2-yl-N-p-tolyl-acrylamide, a highly selective positive allosteric modulator of α7 nicotinic receptors, produces anxiolytic-like activity in mice

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