Cannabinoid pharmacology has proven nettlesome with issues of promiscuity a common theme among both agonists and antagonists. One recourse is to develop allosteric ligands to modulate cannabinoid receptor signaling. Cannabinoids have come late to the allosteric table. The ‘first-generation’ negative and positive allosteric modulators (NAMs and PAMs) represent an important first effort. However, most studies have relied on synthetic agonists, often tested in over-expression systems rather than a defined neuronal model system that utilizes endogenously synthesized and released cannabinoids. We have systematically examined first-generation NAMs and a PAM on endocannabinoid modulation of synaptic transmission in cultured autaptic hippocampal neurons. These neurons exhibit CB1 and 2-arachidonoyl glycerol (2-AG)-mediated depolarization induced suppression of excitation (DSE) and therefore serve as a model to test CB1 modulators in a neuronal model of endogenous cannabinoid signaling.
We find ORG27569, PSNCBAM-1, and PEPCAN12 attenuate DSE and do not directly inhibit CB1 receptors. Of these PSNCBAM-1 is the most efficacious while PEPCAN12 has the distinction of being an endogenous NAM. The reported NAMs pregnenolone and hemopressin as well as the reported PAM lipoxin A4 are without effect in this model of endocannabinoid signaling.
In summary, three of the allosteric modulators evaluated function in a manner consistent with allosterism in a neuronal 2-AG-based model of endogenous cannabinoid signaling.
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.
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