Synaptic effects of cannabinoids

The discovery of (−)-Δ⁹-tetrahydrocannabinol (Δ⁹ THC) as the main psychoactive ingredient in cannabis (marijuana), the cloning of the cannabinoid receptors CB₁R and CB₂R, and the identification of the endocannabinoids as their endogenous ligands has stimulated extensive research on the role of the cannabinoid system in synaptic regulation in the CNS. The 2 major endocannabinoids in the nervous system are 2-arachydonoyl glycerol (2-AG) and N-arachidonoyl ethanolamide (also known as anandamide). They are lipid mediators that are released from neurons on demand in response to excitatory synaptic activity. Endocannabinoids function primarily as retrograde messengers that inhibit neurotransmitter release via presynaptic CB₁Rs, which are distributed primarily in γ-aminobutyric acid (GABA)ergic and to a lesser extent glutamatergic and other presynaptic terminals. Retrograde endocannabinoid signaling participates in several mechanisms of short- and long-term plasticity (depression) of inhibitory and excitatory synapses. Endocannabinoids may also act via postsynaptic CB₁Rs and, in the case of anandamide, also transient receptor potential, vanilloid type 1 (TRPV1) channels. Endocannabinoids also mediate interactions among neurons and different types of glial cells, regulating not only synaptic plasticity but also inflammatory responses in the CNS. By all these mechanisms, endocannabinoids affect the activity of neuronal networks involved in cognition, emotion, addiction and feeding behavior, motor control, and pain processing and participate in the mechanism of neuroprotection. The cannabinoid system thus provides a potential therapeutic target, with consequent increased interest in the use of cannabis for management of selected neurologic conditions. All these topics have been the subject of several comprehensive reviews.^1–8