Bupropion-induced inhibition of α7 nicotinic acetylcholine receptors expressed in heterologous cells and neurons from dorsal raphe nucleus and hippocampus

Vázquez-Gómez, Elizabeth; Arias, Hugo R.; Feuerbach, Dominik; Miranda–Morales, Marcela; Mihailescu, Stefan; Targowska-Duda, Katarzyna M.; Jóźwiak, Krzysztof; Garcı́a-Colunga, Jesús

doi:10.1016/j.ejphar.2014.06.059

Cited by 22 publications

(34 citation statements)

References 38 publications

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“…In particular, the aromatic rings of each ligand form π-π interactions with β4-Phe255 residues at position 13′ (Arias et al, 2010b; Arias et al, 2015). Since a valine ring (position 13′) is instead found at the hα4β2 and hα7 AChRs (Arias et al, 2016; Vázquez-Gómez et al, 2014; reviewed in Arias et al, 2014), the Phe residues are not present, decreasing ligand (i.e., π-π) interaction, and thus inhibitory activity, as observed in our results.…”

Section: Discussionsupporting

confidence: 69%

Selectivity of coronaridine congeners at nicotinic acetylcholine receptors and inhibitory activity on mouse medial habenula

Arias

Jin

Feuerbach

et al. 2017

The International Journal of Biochemistry & Cell Biology

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The inhibitory activity of coronaridine congeners on human (h) α4β2 and α7 nicotinic acetylcholine receptors (AChRs) is determined by Ca2+ influx assays, whereas their effects on neurons in the ventral inferior (VI) aspect of the mouse medial habenula (MHb) are determined by patch-clamp recordings. The Ca2+ influx results clearly establish that coronaridine congeners inhibit hα3β4 AChRs with higher selectivity compared to hα4β2 and hα7 subtypes, and with the following potency sequence, for hα4β2: (±)-18-methoxycoronaridine [(±)-18-MC] > (+)-catharanthine > (±)-18-methylaminocoronaridine [(±)-18-MAC] ∼ (±)-18-hydroxycoronaridine [(±)-18-HC]; and for hα7: (+)-catharanthine > (±)-18-MC > (±)-18-HC > (±)-18-MAC. Interestingly, the inhibitory potency of (+)-catharanthine (27 ± 4 μM) and (±)-18-MC (28 ± 6 μM) on MHb (VI) neurons was lower than that observed on hα3β4 AChRs, suggesting that these compounds inhibit a variety of endogenous α3β4* AChRs. In addition, the interaction of bupropion with (−)-ibogaine sites on hα3β4 AChRs is tested by [3H]ibogaine competition binding experiments. The results indicate that bupropion binds to ibogaine sites at desensitized hα3β4 AChRs with 2-fold higher affinity than at resting receptors, suggesting that these compounds share the same binding sites. In conclusion, coronaridine congeners inhibit hα3β4 AChRs with higher selectivity compared to other AChRs, by interacting with the bupropion (luminal) site. Coronaridine congeners also inhibit α3β4*AChRs expressed in MHb (VI) neurons, supporting the notion that these receptors are important endogenous targets for their anti-addictive activities.

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Section: Discussionsupporting

confidence: 69%

Selectivity of coronaridine congeners at nicotinic acetylcholine receptors and inhibitory activity on mouse medial habenula

Arias

Jin

Feuerbach

et al. 2017

The International Journal of Biochemistry & Cell Biology

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“…Bupropion is reported to concentrate in many tissues, with a brain to plasma ratio of 25:1 (Schroeder, 1983). Therefore, in the brain, bupropion concentrations can reach up to ~ 20 μM (Vazquez-Gomez et al, 2014). Importantly, here we report that in addition to bupropion, its major metabolite, hydroxybupropion, also inhibits 5-HT 3A Rs with comparable affinity.…”

Section: Discussionmentioning

confidence: 99%

The antidepressant bupropion is a negative allosteric modulator of serotonin type 3A receptors

et al. 2017

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The FDA-approved antidepressant and smoking cessation drug bupropion is known to inhibit dopamine and norepinephrine reuptake transporters, as well as nicotinic acetylcholine receptors (nAChRs) which are cation-conducting members of the Cys-loop superfamily of ion channels, and more broadly pentameric ligand-gated ion channels (pLGICs). In the present study, we examined the ability of bupropion and its primary metabolite hydroxybupropion to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs), and further characterized bupropion’s pharmacological effects at these receptors. Mouse 5-HT3ARs were heterologously expressed in HEK-293 cells or Xenopus laevis oocytes for equilibrium binding studies. In addition, the latter expression system was utilized for functional studies by employing two-electrode voltage-clamp recordings. Both bupropion and hydroxybupropion inhibited serotonin-gated currents from 5-HT3ARs reversibly and dose-dependently with inhibitory potencies of 87 μM and 112 μM, respectively. Notably, the measured IC50 value for hydroxybupropion is within its therapeutically-relevant concentrations. The blockade by bupropion was largely non-competitive and non-use-dependent. Unlike its modulation at cation-selective pLGICs, bupropion displayed no significant inhibition of the function of anion-selective pLGICs. In summary, our results demonstrate allosteric blockade by bupropion of the 5-HT3AR. Importantly, given the possibility that bupropion’s major active metabolite may achieve clinically relevant concentrations in the brain, our novel findings delineate a not yet identified pharmacological principle underlying its antidepressant effect.

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“…For radioligand binding, S -MEPH was screened at 10 μM for binding to the following receptors: 5-HT (5-HT 1A,B,D , 5-HT 2A-C , 5-HT 3 , 5-HT 6 , 5-HT 7 ); DA (D 1 , D 2 , D 3 , D 4 , D 5 ); sigma (sigma-1); kappa opioid; adrenergic (α 1A , α 1B , α 1D , α 2A , α 2B , α 2C , β 1 , β 2 , β 3 ); muscarinic (M 1 –M 4 ); and nicotinic (α 2 β 2 ; α 2 β 4 ; α 3 β 2 ; α 3 β 4 ; α 4 β 2 ; α 4 β 4 ; α 7 ). 5-HT receptor subtypes were screened because 5-HT receptor activity influences DA transmission during cocaine addiction [Vázquez-Gómez et al, 2014]. Nicotinic receptors were screened because S -MEPH is structurally similar to the cathinone derivative bupropion (Wellbutrin), which inhibits monoamine reuptake and nicotinic receptors [Arias et al, 2009; Filip et al, 2006].…”

Section: Methodsmentioning

confidence: 99%

Synthetic cathinones and stereochemistry: S enantiomer of mephedrone reduces anxiety- and depressant-like effects in cocaine- or MDPV-abstinent rats

Philogene-Khalid

Hicks

Reitz

et al. 2017

Drug and Alcohol Dependence

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Background and Purpose The neuropharmacological profile of the synthetic cathinone mephedrone (MEPH) is influenced by stereochemistry. Both MEPH enantiomers are monoamine transporter substrates, but R-MEPH is primarily responsible for rewarding effects of MEPH as it produces greater locomotor activation and intracranial self-stimulation than S-MEPH. S-MEPH is a 50-fold more potent 5-HT releaser than R-MEPH and does not place preference in rats. MEPH is also structurally similar to the cathinone derivative bupropion, an antidepressant and smoking cessation medication, suggesting MEPH has therapeutic and addictive properties. Methods We tested the hypothesis that S-MEPH reduces anxiety- and depression-like behaviors in rats withdrawn from chronic cocaine or methylenedioxypyrovalerone (MDPV) using the elevated plus maze (EPM) and forced swim test (FST), respectively. Rats were tested 48-h after a binge-like paradigm (3x/day for 10 days in 1-h intervals) of cocaine (10 mg/kg), MDPV (1 mg/kg) or saline. In vitro studies assessed the receptor binding and activity of S-MEPH. Key Results Rats withdrawn from chronic cocaine or MDPV displayed an increase in anxiety- and depression-like behaviors that was antagonized by treatment with S-MEPH (10, 30 mg/kg). S-MEPH displayed affinity, but not agonist activity, for 5-HT2 receptors (2A, 2B, 2C) and showed negligible affinity for dopaminergic, adrenergic and nicotinic receptors. Conclusion and Implication S-MEPH attenuated withdrawal behaviors following chronic cocaine or MDPV, perhaps through 5-HT release and/or 5-HT2 receptor interactions. The present data suggest S-MEPH may be a possible structural and pharmacological template to develop maintenance therapy for acute anxiety and depression during early withdrawal from psychostimulant abuse.

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Bupropion-induced inhibition of α7 nicotinic acetylcholine receptors expressed in heterologous cells and neurons from dorsal raphe nucleus and hippocampus

Cited by 22 publications

References 38 publications

Selectivity of coronaridine congeners at nicotinic acetylcholine receptors and inhibitory activity on mouse medial habenula

Selectivity of coronaridine congeners at nicotinic acetylcholine receptors and inhibitory activity on mouse medial habenula

The antidepressant bupropion is a negative allosteric modulator of serotonin type 3A receptors

Synthetic cathinones and stereochemistry: S enantiomer of mephedrone reduces anxiety- and depressant-like effects in cocaine- or MDPV-abstinent rats

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