Activation of Muscarinic Acetylcholine Receptors Enhances the Release of Endogenous Cannabinoids in the Hippocampus

Abstract

Endogenous cannabinoids (endocannabinoids) are endogenous compounds that resemble the active ingredient of marijuana and activate the cannabinoid receptor in the brain. They mediate retrograde signaling from principal cells to both inhibitory ["depolarization-induced suppression of inhibition" (DSI)] and excitatory ("depolarization-induced suppression of excitation") afferent fibers. Transient endocannabinoid release is triggered by voltage-dependent Ca(2+) influx and is upregulated by group I metabotropic glutamate receptor activation. Here we show that muscarinic acetylcholine receptor (mAChR) activation also enhances transient endocannabinoid release (DSI) and induces persistent release. Inhibitory synapses in the rat hippocampal CA1 region of acute slices were studied using whole-cell patch-clamp techniques. We found that low concentrations (0.2-0.5 microm) of carbachol (CCh) enhanced DSI without affecting basal evoked IPSCs (eIPSCs) by activating mAChRs on postsynaptic cells. Higher concentrations of CCh (> or =1 microm) enhanced DSI and also persistently depressed basal eIPSCs, mainly by releasing endocannabinoids. Persistent CCh-induced endocannabinoid release did not require an increase in [Ca2+]i but was dependent on G-proteins. Although they were independent at the receptor level, muscarinic and glutamatergic mechanisms of endocannabinoid release shared intracellular machinery. Replication of the effects of CCh by blocking acetylcholinesterase with eserine suggests that mAChR-mediated endocannabinoid release is physiologically relevant. This study reveals a new role of the muscarinic cholinergic system in mammalian brain.

Exogenous and Endogenous Cannabinoids Suppress Inhibitory Neurotransmission in the Human Neocortex

“…First, it is likely that inhibition of the GABAergic input to pyramidal cells by exogenous and endogenous cannabinoids was enhanced, because carbachol increased the contribution of CB 1 receptor-bearing GABAergic axons to the GABAergic input to pyramidal cells. Second, it is possible that carbachol, by acting on Ga q/11 protein-coupled M 1 and M 3 muscarinic receptors of postsynaptic pyramidal neurons potentiated DSI, as it was shown previously in the hippocampus and the striatum of rodents (Kim et al, 2002;Ohno-Shosaku et al, 2003;Narushima et al, 2007).…”

Endocannabinoid‐mediated short‐term synaptic plasticity: depolarization‐induced suppression of inhibition (DSI) and depolarization‐induced suppression of excitation (DSE)

“…In agreement with this idea, DSI is strictly dependent on M.A. Diana & A. Marty DSI/DSE: two forms of CB1R-mediated plasticity 15 intracellular calcium increase, while the production of endocannabinoids via muscarinic and group 1 mGluR receptors is not Kim et al, 2002;Chevaleyre & Castillo, 2003). Two possibilities can be proposed at this stage.…”

“…Indeed, Varma et al (2001) (and later Ohno-Shosaku et al, 2002a) confirmed that group I mGluR activation also led to the production of endocannabinoids in hippocampal CA1 cells, and showed that this pathway, although not mediating DSI, had a powerful modulatory effect on the phenomenon. Further work extended these findings by showing that the activation of muscarinic receptors of the m1 and m3 subtypes had effects similar to those of group I mGluR activation (Martin & Alger, 1999;Kim et al, 2002;Ohno-Shosaku et al, 2003).…”

“…Strictly speaking, these forms of retrograde inhibition, which will be further described later, should not be called DSI/DSE, since they are not triggered by depolarization and since, in contrast to DSI/DSE, they do not seem to depend on postsynaptic calcium elevation Kim et al, 2002). They will therefore be considered separate from DSI/DSE throughout this review.…”

“…These CCKexpressing interneurons have been proposed to participate in the transmission to the hippocampal region of serotonergically-and cholinergically controlled emotional and motivational physiological states (Freund, 2003). Importantly in this context, DSI is greatly enhanced by the activation of muscarinic receptors (Martin & Alger, 1999;Kim et al, 2002;Ohno-Shosaku et al, 2003). We invite interested readers to look at the extensive review by Freund et al (2003), for a discussion of the possible importance of DSI in relation to this fact and to the network rhythms of the hippocampal formation.…”