Fig. 2.
Neuronal vs. glial CB1 receptor signaling that regulates synaptic transmission. Presynaptic or postsynaptic neuronal depolarization may increase eCB (2-AG) release from postsynaptic neurons by glutamate-mGluR1/5 and Ca2+-dependent mechanisms. eCBs released by the postsynaptic neurons directly activate CB1Rs in the presynaptic terminals, which leads to synaptic depression at eCB-releasing synapses (homoneuronal synapses). In addition, eCBs activate CB1Rs in astrocytes, elevate their intracellular Ca2+ level, and stimulate the release of gliotransmitters (such as glutamate, ATP, D-serine) that potentiates synaptic transmission in adjacent neurons (heteroneuronal synapses). The biological effects of cannabinoids (such as Δ9-THC) may be mediated by stimulation of CB1Rs in both neurons and/or astrocytes cells, depending upon the cellular distributions of CB1Rs in different brain regions. AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, ATP adenosine triphosphate, CB1R CB1 receptor, eCB endocannabinoid, Glut glutamate, IP3R inositol trisphosphate receptor, mGluR1 type 1 metabotropic glutamate receptor, NMDA N-methyl-D-aspartate receptor, VGCC voltage-dependence calcium channel, 2-AG 2-arachidonoylglycerol, Δ9-THC Δ9-tetrahydrocannabinol