Neonicotinoid insecticides differently modulate acetycholine‐induced currents on mammalian α7 nicotinic acetylcholine receptors

Neonicotinoid insecticides are nicotine-derived molecules which exert acute neurotoxic effects over the insect central nervous system by activating nicotinic acetylcholine receptors (nAChRs). However, these receptors are also present in the mammalian central and peripheral nervous system, where the effects of neonicotinoids are faintly known. In mammals, cholinergic synapses are crucial for the control of vascular tone, blood pressure and skeletal muscle contraction. We therefore hypothesized that neonicotinoids could affect cholinergic networks in mammals and sought to highlight functional consequences of acute intoxication in rats with sub-lethal concentrations of the highly used acetamiprid (ACE) and clothianidin (CLO). In this view, we characterized their electrophysiological effects on rat α3β4 nAChRs, knowing that it is predominantly expressed in ganglia of the vegetative nervous system and the adrenal medulla, which initiates catecholamine secretion. Both molecules exhibited a weak agonist effect on α3β4 receptors. Accordingly, their influence on epinephrine secretion from rat adrenal glands was also weak at 100 M, but it was stronger at 500 M. Challenging ACE or CLO together with nicotine (NIC) ended up with paradoxical effects on secretion. In addition, we measured the rat arterial blood pressure (ABP) in vivo by arterial catheterization. As expected, NIC induced a significant increase in ABP. ACE and CLO did not affect the ABP in the same conditions. However, simultaneous exposure of rats to both NIC and ACE/CLO promoted an increase of ABP and induced a biphasic response. Modeling the interaction of ACE or CLO on α3β4 nAChR is consistent with a binding site located in the agonist pocket of the receptor. We present a transversal experimental approach of mammal intoxication with neonicotinoids at different scales, including in vitro, ex vivo, in vivo and in silico. It paves the way of the acute and chronic toxicity for this class of insecticides on mammalian organisms

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“…In addition, the electrophysiological effects of neonicotinoids on mammalian nAChRs are shown in Table S3 . They act as weak agonists of human

2 receptors, and strong agonists of rat

7 receptors [ 41 , 42 ]. Different nAChR subtypes are then possibly targeted by neonicotinoids.…”

Section: Resultsmentioning

confidence: 99%

Partial Agonist Activity of Neonicotinoids on Rat Nicotinic Receptors: Consequences over Epinephrine Secretion and In Vivo Blood Pressure

Park

Taly

Bourreau

et al. 2021

IJMS

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“…However, the agonist effects of NNs depend on the type of NN and the nAChR subtype to which it binds. For example, ACE reportedly acts as a partial agonist of the α7 subtype 31 .…”

Section: Discussionmentioning

confidence: 99%

“…Clothianidin and thiamethoxam activate the α4 or α7 subtypes of nAChRs in the rat striatum and induce dopamine release 34 . Considering the variation of nAChR sensitivity among different NNs 31 , it is unclear if ACE activates α4, α7, or otherwise. Nonetheless, the above-mentioned behavioral changes were the likely result of changes in catecholamines.…”

Section: Behavioral Changes Because Of Ace Exposurementioning

confidence: 99%

Ca2+ Imaging With Two-photon Microscopy to Detect the Disruption of Brain Function in Mice Administered With Neonicotinoid Insecticides

Hirai¹,

Sugio²,

Nimako³

et al. 2021

Preprint

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Neonicotinoid pesticides are insecticides that are insecticides that reportedly have untargeted effects on bees and dragonflies causing a reduction in numbers. Neonicotinoids act as neuroreceptor modulators, and some studies have reported their association with neurodevelopmental disorders. However, the effect of neonicotinoids on the central nervous system has not yet been identified. Herein, we conducted in vivo Ca2+ imaging using a two-photon microscope to detect abnormal activity of neuronal circuits in the brain using a neonicotinoid. The oral administration of acetamiprid (ACE) (20 mg/kg body weight [bw]) in mature mice with a less than the no-observed-adverse-effect level (NOAEL) and a tenth or half of the median lethal dose (LD50) of nicotine (0.33 or 1.65 mg/kg bw, respectively), as a typical nAChRs agonist, increased anxiety-like behavior associated with altered activities of the neuronal population in the somatosensory cortex. Furthermore, we detected ACE and metabolites in the brain 1 h after ACE administration. The results suggested that in vivo Ca2+ imaging using a two-photon microscope enabled the highly sensitive detection of neurotoxicant-mediated brain disturbance of nerves.

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“…The CRB Xenope is a French national platform dedicated to X. laevis breeding for experimental research. Oocytes were defolliculated according to Cartereau et al (2018) , and were incubated in a standard oocyte saline (SOS) solution (100 mM NaCl, 2 mM KCl, 1 mM MgCl 2 , 1.8 mM CaCl 2 and 5 mM HEPES, pH 7.5) supplemented with antibiotics (50 mg/ml gentamycin, 100 U/ml penicillin, 100 mg/ml streptomycin and 2.5 mM pyruvate). Defolliculated oocytes were microinjected with 36.8 nl of the tick membrane solution using a nanoliter injector (Nanoliter, 2010; World Precision Instruments, Hertfordshire, UK) and were incubated in the SOS solution at 18 °C during 24 h before electrophysiological measurements.…”

Section: Methodsmentioning

confidence: 99%

Nicotinic acetylcholine receptors in the synganglion of the tick Ixodes ricinus: Functional characterization using membrane microtransplantation

Mauff

Chouikh²,

Cartereau³

et al. 2020

International Journal for Parasitology: Drugs and Drug Resistan

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Nicotinic acetylcholine receptors are an important class of excitatory receptors in the central nervous system of arthropods. In the ticks Ixodes ricinus , the functional and pharmacological properties of nicotinic receptors located in their neurons are still unknown. The objective of this study was to characterize the pharmacological properties of tick nicotinic receptors using membrane microtransplantation in Xenopus laevis oocytes and two-electrodes voltage clamp method. The membranes microtransplanted were extracted from the tick synganglion. We found that oocytes microtransplanted with tick synganglion membranes expressed nicotinic acetylcholine receptor subtypes which were activated by acetylcholine (1 mM) and nicotine (1 mM). Currents induced by pressure application of acetylcholine and nicotine were diminished by 10 nM α-bungarotoxin and methyllycaconitine, suggesting that they expressed two subtypes of nicotinic receptors, α-bungarotoxin-sensitive and -insensitive, respectively. In addition, we found that nicotine receptors expressed in the synganglion membranes were poorly sensitive to the neonicotinoid insecticides clothianidin (CLT), imidacloprid (IMI), acetamiprid (ACE) and thiamethoxam (TMX), in agreement with their lack of activity as acaricides. Interestingly, current amplitudes were strongly potentialized in the presence of 1 μM PNU-120596. CLT was more active as an agonist than IMI, TMX and ACE. Finally, we demonstrated that microtransplantation of purified membrane from the tick synganglion can be a valuable tool for the development and screening of compounds targeting tick nicotinic acetylcholine receptor subtypes.

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Neonicotinoid insecticides differently modulate acetycholine‐induced currents on mammalian α7 nicotinic acetylcholine receptors

Abstract: This article is part of a themed section on Nicotinic Acetylcholine Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.11/issuetoc.

Cited by 29 publications

References 63 publications

Partial Agonist Activity of Neonicotinoids on Rat Nicotinic Receptors: Consequences over Epinephrine Secretion and In Vivo Blood Pressure

Partial Agonist Activity of Neonicotinoids on Rat Nicotinic Receptors: Consequences over Epinephrine Secretion and In Vivo Blood Pressure

Ca2+ Imaging With Two-photon Microscopy to Detect the Disruption of Brain Function in Mice Administered With Neonicotinoid Insecticides

Nicotinic acetylcholine receptors in the synganglion of the tick Ixodes ricinus: Functional characterization using membrane microtransplantation

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