Mode of action and physiological significance of endogenous cannabinoids as a retrograde messenger at central synapses

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The active component of marijuana (Δ^9-tetrahydrocannabinol) exerts various psychomotor actions through binding to the CB1 cannabinoid receptor that is distributed widely in the central nervous system. Two candidates for endogenous cannabinoid (eCB) (i.e.,endogenous ligands for the CB1 receptor) are anandamide and 2-arachidonoylglycerol. The CB1 receptor is present at presynaptic sites of central neurons and the binding of cannabinoids to this receptor results in reduction of neurotransmitter release from presynaptic terminals. However, at the beginning of the present research project, it was largely unknown what stimuli to neurons could produce eCBs and what roles eCBs played in brain functions. We have examined roles of eCBs in modulation of synaptic transmission by using electrophysiological methods and have obtained the following results.In hippocampal neurons and cerebellar Purkinje cells, depolarization and resultant elevation of intracellular Ca^<2+> concentration causes production of eCBs that retrogradely activates presynapric CB1 receptors and induces transient suppression of neurotransmitter release. Activation of Gq-coupled receptors including group I metabotropic glutamate receptors and M_1/M_3 muscarinic acetylcholine receptors also induces eCB-mediated rretrograde suppression of neurotransmitter release. Furthermore, we have found that, in cutured hippocampal neurons, weak depolarization and mild activation of M_1/M_3 muscarinic acetylcholine receptors effectively induce eCB-mediated retrograde suppression, whereas either stimulus alone causes no detectable suppression. We have disclosed that this synergism is attributable to the property of phospholipase Css1 (PLCss1) that is activated by a subunit of Gq/11 and also sensitive to physiological range of intracellular Ca^<2+>. Therefore, PLCss1 can function as a coincidence detector of cholinergic afferent activity (i.e.,presynaptic activity) and postsynaptic depolarization.