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.

The Endocannabinoid System: A Promising Target for the Management of Type 2 Diabetes

“…The EC system has first emerged as a major neuromodulatory system in the brain [1,2], where ECs act as retrograde neurotransmitters (or messengers) that inhibit synaptic activity [4,5].…”

“…Unlike neurotransmitter molecules that are typically held in vesicles before synaptic release, ECs are synthesized on demand in response to acute stimulation within the plasma membrane [3,5,7]. This response is mediated through increased intracellular calcium concentrations.…”

“…Indeed, cannabinoid (CB) receptors, especially CB1 receptors, participate in the physiological modulation of many central and peripheral functions [3]. The tremendous increase in the understanding of the molecular basis of CB activity [4][5][6] has encouraged many pharmaceutical companies to develop synthetic CB analogues and antagonists, leading to an explosion of basic research and clinical trials [7][8][9][10][11]. For instance, it is reasonable to hypothesize that the attenuation of EC system overactivity would have therapeutic benefit in treating disorders that might have a component of excessive appetite drive, such as obesity and related disturbances [9,[11][12][13][14][15][16].…”

Addictive Drugs and Synaptic Plasticity

“…The eCBs as ligands for these CB1 and CB2 receptors are a family of lipidic mediators that signal through the same cell surface receptors that are targeted by Δ9-THC. Unlike neurotransmitter molecules that are typically held in vesicles before synaptic release, eCBs are liberated directly after synthesis and, once released, travel in a retrograde direction to suppress presynaptic neurotransmitter release through activation of CBRs (Basavarajappa, 2007).…”

“…Additionally, the eCB signaling system is being found to be involved in an increasing number of neuropathological conditions, with widespread roles being invoked in neurodegenerative disorders. The fact that eCB signaling is mostly inhibitory, imparts eCBs with the ability to modulate synaptic efficacy with a wide range of functional consequences and provides unique therapeutic possibilities in central nervous system (CNS) diseases, including alcoholism, Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis (see Basavarajappa, 2007;Basavarajappa et al, 2009 for reviews).…”