Retrograde activation of CB1R by muscarinic receptors protects against central organophosphorus toxicity

Katie M. Hoffman, Margaret R. Eisen, Jessica K. Chandler, Marian R. Nelson, Erik A. Johnson, Patrick M. McNutt

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

The acute toxicity of organophosphorus-based compounds is primarily a result of acetylcholinesterase inhibition in the central and peripheral nervous systems. The resulting cholinergic crisis manifests as seizure, paralysis, respiratory failure and neurotoxicity. Though overstimulation of muscarinic receptors is the mechanistic basis of central organophosphorus (OP) toxicities, short-term changes in synapse physiology that precede OP-induced seizures have not been investigated in detail. To study acute effects of OP exposure on synaptic function, field excitatory postsynaptic potentials (fEPSPs) were recorded from Schaffer collateral synapses in the mouse hippocampus CA1 stratum radiatum during perfusion with various OP compounds. Administration of the OPs paraoxon, soman or VX rapidly and stably depressed fEPSPs via a presynaptic mechanism, while the non-OP proconvulsant tetramethylenedisulfotetramine had no effect on fEPSP amplitudes. OP-induced presynaptic long-term depression manifested prior to interictal spiking, occurred independent of recurrent firing, and did not require NMDA receptor currents, suggesting that it was not mediated by activity-dependent calcium uptake. Pharmacological dissection revealed that the presynaptic endocannabinoid type 1 receptor (CB1R) as well as postsynaptic M1 and M3 muscarinic acetylcholine receptors were necessary for OP-LTD. Administration of CB1R antagonists significantly reduced survival in mice after a soman challenge, revealing an acute protective role for endogenous CB1R signaling during OP exposure. Collectively these data demonstrate that the endocannabinoid system alters glutamatergic synaptic function during the acute response to OP acetylcholinesterase inhibitors.

Original languageEnglish
Pages (from-to)113-120
Number of pages8
JournalNeuropharmacology
Volume155
DOIs
StatePublished - Sep 1 2019

Keywords

  • Cannabinoid type 1 receptor
  • Cholinergic receptors
  • Cholinesterase inhibitors
  • Endocannabinoid system
  • Muscarinic receptors
  • Organophosphorus nerve agents

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