Deciphering the mechanisms of reciprocal regulation or interdependence at the cannabinoid CB1 receptors and cyclooxygenase-2 level: Effects on mood, cognitive implications, and synaptic signaling

The lipid endocannabinoid system refers to endogenous cannabinoids (eCBs), the enzymes involved in their synthesis and metabolism, and the G protein-coupled cannabinoid receptors (GPCRs), CB1, and CB2. CB1 receptors (CB1Rs) are distributed in the brain at presynaptic terminals. Their activation induces inhibition of neurotransmitter release, which are gamma-aminobutyric acid (GABA), glutamate (Glu), dopamine, norepinephrine, serotonin, and acetylcholine. Postsynaptically localized CB1Rs regulate the activity of selected ion channels and N-methyl-D-aspartate receptors (NMDARs). CB2Rs are mainly peripheral and will not be considered here. Anandamide metabolism, mediated by cyclooxygenase-2 (COX-2), generates anandamide-derived prostanoids. In addition, COX-2 regulates the formation of CB1 ligands, which reduce excitatory transmission in the hippocampus (HC). The role of CB1Rs and COX-2 has been described in anxiety, depression, and cognition, among other central nervous system (CNS) disorders, affecting neurotransmission and behavior of the synapses. This review will analyze common pathways, mechanisms, and behavioral effects of manipulation at the CB1Rs/COX-2 level.