Neuropharmacology of the endocannabinoid signaling system-molecular mechanisms, biological actions and synaptic plasticity

Abstract

The endocannabinoid signaling system is composed of the cannabinoid receptors; their endogenous ligands, the endocannabinoids; the enzymes that produce and inactivate the endocannabinoids; and the endocannabinoid transporters. The endocannabinoids are a new family of lipidic signal mediators, which includes amides, esters, and ethers of long-chain polyunsaturated fatty acids. Endocannabinoids signal through the same cell surface receptors that are targeted by Delta(9)-tetrahydrocannabinol (Delta(9)THC), the active principles of cannabis sativa preparations like hashish and marijuana. The biosynthetic pathways for the synthesis and release of endocannabinoids are still rather uncertain. Unlike neurotransmitter molecules that are typically held in vesicles before synaptic release, endocannabinoids are synthesized on demand within the plasma membrane. Once released, they travel in a retrograde direction and transiently suppress presynaptic neurotransmitter release through activation of cannabinoid receptors. The endocannabinoid signaling system is being found to be involved in an increasing number of pathological conditions. In the brain, endocannabinoid signaling is mostly inhibitory and suggests a role for cannabinoids as therapeutic agents in central nervous system (CNS) disease. Their ability to modulate synaptic efficacy has a wide range of functional consequences and provides unique therapeutic possibilities. The present review is focused on new information regarding the endocannabinoid signaling system in the brain. First, the structure, anatomical distribution, and signal transduction mechanisms of cannabinoid receptors are described. Second, the synthetic pathways of endocannabinoids are discussed, along with the putative mechanisms of their release, uptake, and degradation. Finally, the role of the endocannabinoid signaling system in the CNS and its potential as a therapeutic target in various CNS disease conditions, including alcoholism, are discussed.

Keywords: Alcoholism; CB1 receptors; CNS; alcohol-drinking behavior; endocannabinoids; reward; synaptic plasticity; therapy.

Fig. (1)

Schematic summary of CB1 receptor signaling. CB1 receptors are 7-transmembrane domain, G-protein-coupled proteins located in the cell membrane. The Ca²⁺ channels inhibited by CB1 receptors include N-, P/Q- and L-type channels. Actions on Ca²⁺ channels and adenylyl cyclase (AC) are thought to be mediated by the α subunits of the G-protein, and those on GIRK and PI3K by the αβ subunits. Inhibition of AC and the subsequent decrease in cAMP decreases activation of cAMP-dependent protein kinase A (PKA), which leads to decreased phosphorylation of the K⁺ channels. Stimulatory effects are shown by a (→) sign and inhibitory effects by a (⊥) sign.

Fig. (2)

Molecular structure of endocannabinoids. These endocannabinoids share a polyunsaturated fatty acid moiety (arachidonic acid) and a polar head group consisting of ethanolamine or glycerol.

Fig. (3)

The potential pathways of anandamide biosynthesis. Stimulation of adenylate cyclase and cAMP-dependent protein kinase potentiate the Nacyltransferase (Ca²⁺-dependent transacylase, NAT). A fatty arachidonic acid chain is transferred by NAT from the sn-1 position of phospholipids to the primary amine of phosphatidylethanolamine, in a Ca²⁺-dependent manner, forming an N-arachidonyl phosphatidylethanolamine (N-ArPE). This N-ArPE intermediate is then hydrolyzed by a phospholipase D (PLD)-like enzyme to yield the anandamide (AEA). In addition, possible alternative pathways for AEA formation from N-ArPE are shown. Once synthesized, AEA can transported to the outside of the cell through a process that has not yet been well characterized. AMT, anandamide membrane transporter.

Fig. (4)

Scheme illustrating the potential mechanism of anandamide uptake and degradation. Anandamide can be internalized by neurons through a yet unidentified transport mechanism, “the endocannabinoid transporter”. Once inside a neuron, AEA is rapidly cleaved by the hydrolytic enzyme fatty acid amide hydrolase (FAAH), releasing arachidonic acid (AA) and ethanolamine (EA). Alternatively, different lipoxygenases (LOXs) and cyclooxygenase-2 (COX-2) can metabolize AEA, generating hydroxyl derivatives of AEA (HAEAs) and prostaglandins-ethanolamides (PG-EAs), respectively. On the other hand, in FAAH (-/-) mice, AEA is converted into PC-AEA by an unidentified biosynthetic pathway, and PC-AEA can in turn be catabolized to AA by choline-specific phosphodiesterase (NPP6). AMT, anandamide membrane transporter.

Fig. (5)

The biosynthetic pathways of 2-arachidonylglycerol. Intracellular Ca²⁺ initiates 2-AG biosynthesis by inducing the formation of diacylglycerol (DAG) in the membrane either by stimulating the phosphatidyl-inositol-phospholipase C (PI-PLC) pathway, or the formation of phosphatidic acid (PA), and the subsequent activation of phosphatidic acid hydrolase. 2-AG is the product of DAG-lipase acting on DAG. The second pathway involves hydrolysis of PI by phospholipase A1 (PLA1) and hydrolysis of the resultant lyso-PI by a specific lyso-PLC. In certain conditions, 2-AG can also be synthesized through the conversion of 2-arachidonyl lysophosphatidic acid (LPA) by phosphatase to yield 2-AG. Once synthesized, 2-AG can transported to the outside of the cell through a process that has not yet been characterized. AMT, anandamide membrane transporter.

Fig. (6)

Schematic summary of 2-AG uptake and degradation. 2-arachidonylglycerol can be internalized by neurons through a yet unidentified transport mechanism, “the endocannabinoid transporter”. Once inside neurons, 2-AG can be hydrolyzed by hydrolytic enzymes, fatty acid amide hydrolase (FAAH) or monoacylglycerol (MAGL) lipase. Alternatively, 2-AG can be metabolized to 2-arachidonyl LPA (2-AG-LPA) through the action of monoacyl glycerol kinase(s) (MAGLK). 2-AG-LPA is then converted into 1-steroyl-2-arachidonyl PA. 1-steroyl-2-arachidonyl PA is further utilized in the de novo synthesis of PC and PE. Furthermore, 2AG is metabolized by enzymatic oxygenation of 2-AG by COX-2 into PGH2 glycerol esters (PG-G). AMT, anandamide membrane transporter.

Fig. (7)

Schematic diagram to illustrate the role of AEA and CB1 receptors on excitatory and inhibitory neurotransmission. Depolarization of a postsynaptic neuron leads to Ca²⁺ influx through voltage-gated channels and causes the generation and the release of endocannabinoids such as anandamide (AEA). The mechanism through which Ca²⁺ promotes endocannabinoid release is not yet known. The released endocannabinoids then activate the CB1 receptors (CB1R) at presynaptic terminals and suppress the release of glutamate (left) or GABA (right) by inhibiting Ca²⁺ channels [146, 151, 264]. GluR, Glutamate receptors.

Fig. (8)

Molecular structure of CB1 receptor-selective antagonist/inverse agonist, rimonabant. Rimonabant (SR141716A) is highly potent and selective CB1 receptor ligand that readily prevents and reverses CB1 mediated effects both in vitro and in vivo [148].