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. Author manuscript; available in PMC: 2011 Sep 1.
Published in final edited form as: Neurotoxicology. 2009 Dec 5;31(5):562–571. doi: 10.1016/j.neuro.2009.12.002

Figure 7.

Figure 7

Possible interactions between cholinergic and eCB signaling in the toxicity of organophosphorus anticholinesterases. OPs may enhance eCB signaling either indirectly through acetylcholinesterase inhibition or directly by binding to components of the eCB pathway. Extensive acetylcholinesterase inhibition will increase synaptic acetylcholine levels and prolong cholinergic receptor activation to elicit cholinergic signs of toxicity. Depolarization of postsynaptic neurons can lead to release of eCBs and modulation of neurotransmitter release. Prolonged cholinergic receptor activation can stimulate downstream non-cholinergic neurons. Glutamatergic neuron activation through NMDA receptors can increase intracellular Ca++ levels and cellular toxicity, or through metabotropic MGluR receptors can lead to eCB release that may attenuate further recruitment of downstream signaling and toxicity. Postsynaptic muscarinic M1/M3 receptor activation leads to receptor-mediated eCB release to activate CB1 receptors and inhibit ACh release at the presynaptic cholinergic terminal. Upon release, AEA can activate CB1 receptors (extracellularly) to inhibit neurotransmitter release and TRPV1 receptors (intracellularly) to increase Ca++ influx, while 2-AG acts at the CB1 receptor but not at the TRPV1 site. In the direct pathway, some OPs may bind to molecular components of eCB signaling to alter CB1 receptor activation, eCB synthesis, eCB degradation or eCB uptake and modulate cholinergic and/or non-cholinergic neurotransmitter release. Direct FAAH inhibition by some OPs can increase intracellular AEA, and in some neurons, this may lead to increased TRPV1 activation, elevated intracellular Ca++ and decreased 2-AG signaling. Reduced 2-AG signaling could in turn reduce eCB mediated inhibition of neurotransmitter release, enhancing cholinergic and non-cholinergic signaling. Direct inhibition of MAGL by some OPs may in turn selectively increase 2-AG signaling.