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

Abstract

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

Neurotoxic Effects of Neonicotinoids on Mammals: What Is There beyond the Activation of Nicotinic Acetylcholine Receptors?—A Systematic Review

“…Consequently, the accumulated neurotransmitter can stimulate the nAChRs to a greater extent, causing their opening and the influx of Na + , K + and Ca +2 ions across the membrane. Furthermore, as has been extensively demonstrated, the NNs can act as partial agonists of mammalian nAChRs, and thus may even compete with acetylcholine for binding to these receptors [118,119].…”

Mono and biallelic variants inHCN2cause severe neurodevelopmental disorders

“…Adult Xenopus laevis females were used for oocytes collection as previously described. 33,34 For HCN2 expression, 21 ng of mRNA (wt-HCN2 or its variants) were injected into individual defolliculated oocytes, using an automatic nanoinjector (Nanoject II Drummond Scientific) or the Roboinject (Multi Channel Systems, Reutlingen, Germany). To mimic heterozygosity, heterotetrameric channels (e.g.…”

Thiacloprid Induced Developmental Neurotoxicity via ROS-Oxidative Injury and Inflammation in Chicken Embryo: The Possible Attenuating Role of Chicoric and Rosmarinic Acids

“…Neonics mainly act against chewing and sucking parasites, predatory insects, zoophages, and phytophages as well as parasitic infection of pet animals as cats and dogs [ 7 ]. However, as neonics act on the nicotinic acetylcholine receptors of the targeted insect, they showed potential risks to mammalians including humans [ 8 , 9 , 10 ].…”