The antihelminthic moxidectin enhances tonic GABA currents in rodent hippocampal pyramidal neurons

Abstract

Macrocyclic lactones (MLs) are commonly used treatments for parasitic worm and insect infections in humans, livestock, and companion animals. MLs target the invertebrate glutamate-activated chloride channel that is not present in vertebrates. MLs are not entirely inert in vertebrates, though; they have been reported to have activity in heterologous expression systems consisting of ligand-gated ion channels that are present in the mammalian central nervous system (CNS). However, these compounds are typically not able to reach significant concentrations in the CNS because of the activity of the blood-brain barrier P-glycoprotein extrusion system. Despite this, these compounds are able to reach low levels in the CNS that may be useful in the design of novel "designer" ligand-receptor systems that can be used to directly investigate neuronal control of behavior in mammals and have potential for use in treating human neurological diseases. To determine whether MLs might affect neurons in intact brains, we investigated the activity of the ML moxidectin (MOX) at native GABA receptors. Specifically, we recorded tonic and phasic miniature inhibitory postsynaptic currents (mIPSCs) in ex vivo brain slices. Our data show that MOX potentiated tonic GABA currents in a dose-dependent manner but had no concomitant effects on phasic GABA currents (i.e., MOX had no effect on the amplitude, frequency, or decay kinetics of mIPSCs). These studies indicate that behavioral experiments that implement a ML-based novel ligand-receptor system should take care to control for potential effects of the ML on native tonic GABA receptors. NEW & NOTEWORTHY We have identified a novel mechanism of action in the mammalian central nervous system for the antihelminthic moxidectin, commonly prescribed to animals worldwide and currently being evaluated for use in humans. Specifically, moxidectin applied to rodent brain slices selectively enhanced the tonic GABA conductance of hippocampal pyramidal neurons.

The effects of moxidectin nicotine-conditioned cue on nicotine-seeking behavior in mice

“…Previous investigations have explained that GABA agonists decrease nicotine addiction (Fattore et al, 2009;Varani et al, 2014;Hillmer et al, 2016). Moxidectin has GABA confirm the action and played a character in the decrease of nicotine-induced CPP during this mechanism and it brings about a decrease of nicotine-induced CPP through this mechanism (Spampanato et al, 2018;Menez et al, 2012;Rodrigues-Alves et al, 2008;Huynh et al, 2017). Moxidectin has GABA receptors activity which can contribute to the modulation of nicotine-induced CPP during this mechanism.…”

Investigation of the impact of antiparasitic drug moxidectin on the rewarding effects of alcohol

“…A series of recent studies indicated that GABA agonists reduce alcohol dependence (Bechtholt and Cunningham 2005;Banerjee 2014;Martinez et al 2018). It was demonstrated in previous investigations that moxidectin activates GABA receptors (Ménez et al 2012;Huynh et al 2017;Spampanato et al 2018). Moxidectin can contribute to the decrease in ethanol-induced CPP through this mechanism.…”

“…The more advantageous central nervous system safety profile of moxidectin is thought to be due to: 1) moxidectin having lower activity on GABA receptors compared to ivermectin which should be an advantage with respect to decreasing contraindications, and 2) differential transport across the blood-brain barrier, with moxidectin being a more limited substrate for P-glycoprotein transporter and lesser dependence on P-glycoprotein for removal from the central nervous system (Huynh et al 2017). Prior research suggests that moxidectin activates P2X4 and GABA receptors (Ménez et al 2012;Franklin et al 2014;Huynh et al 2017;Spampanato et al 2018). P2X4 and GABA receptor systems are observed to be crucial in alcohol addiction (Franklin et al 2014;Huynh et al 2017).…”