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, 7 (8), 769-79

The Endocannabinoid Signaling System: A Potential Target for Next-Generation Therapeutics for Alcoholism


The Endocannabinoid Signaling System: A Potential Target for Next-Generation Therapeutics for Alcoholism

Balapal S Basavarajappa. Mini Rev Med Chem.


Research into the endocannabinoid signaling system has grown exponentially in recent years following the discovery of cannabinoid receptors (CB) and their endogenous ligands, such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG). Important advances have been made in our understanding of the endocannabinoid signaling system in various aspects of alcoholism, including alcohol-seeking behavior. Alcohol increases the synthesis or impairs the degradation of endocannabinoids, leading to a locally elevated endocannabinoid tone within the brain. Elevated endocannabinoid tone might be expected to result in compensatory down-regulation of CB1 receptors or dampened signal transduction. Following release, endocannabinoids diffuse back to the presynaptic neuron where they act as short-range modulators of synaptic activity by altering neurotransmitter release and synaptic plasticity. Mice treated with the CB1 receptor antagonist SR141716A (rimonabant) or homozygous for a deletion of the CB1 receptor gene exhibit reduced voluntary alcohol intake. CB1 knockout mice also show increased alcohol sensitivity, withdrawal, and reduced conditioned place preference. Conversely, activation of CB1 receptor promotes alcohol intake. Recent studies also suggest that elevated endocannabinoid tone due to impaired degradation contributes to high alcohol preference and self-administration. These effects are reversed by local administration of rimonabant, suggesting the participation of the endocannabinoid signaling system in high alcohol preference and self-administration. These recent advances will be reviewed with an emphasis on the endocannabinoid signaling system for possible therapeutic interventions of alcoholism.


Fig. (1)
Fig. (1). Molecular structures of endocannabinoids that are known to bind to brain cannabinoid receptors
These endocannabinoids share a polyunsaturated fatty acid moiety (arachidonic acid) and a polar head group consisting of ethanolamine or glycerol.
Fig. (2)
Fig. (2). A hypothetical model for the action of endocannabinoids on excitatory and inhibitory neurotransmission through retrograde messenger activity
Depolarization of postsynaptic neuron causes the generation and release of endocannabinoids such as anandamide (AEA). 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.
Fig. 3
Fig. 3. Neural reward circuits important in endocannabinoid action in modulation of the addiction-related effects of drugs of abuse including alcohol
The ventral tegamental area (VTA) contains both dopamine (DA) and γ-aminobutyric acid (GABA) neurons that innervate the nucleus accumbens (NAc), prefrontal cortex (PFC), amygdala (Amyg), and other forebrain targets not shown in the diagram. The glutamatergic (GLU) projections from the PFC to the NAc and the VTA are shown. In the VTA, glutamate inputs from the PFC synapse on mesoaccumbens GABA neurons and mesoprefrontal DA neurons. CB1 receptors are located on presynaptic glutamatergic and GABAergic neurons but not on dopaminergic neurons in the VTA. Activation of CB1 receptors in the VTA by endocannabinoids (EC; broken arrows) produces inhibition of GABA release and removes the inhibitory effect of these GABAergic cells on dopaminergic neurons. The activation of dopaminergic neurons facilitates the release of EC from dopaminergic cells. These EC acting in a retrograde manner on presynaptic CB1 receptors, inhibit both inhibitory (GABA) and excitatory inputs to VTA dopaminergic neurons. In the NAc, EC inhibit glutamatergic neurons through a retrograde manner acting mainly on CB1 receptors on the axon terminals of glutamatergic neurons. This inhibition of glutamate release results in activation of VTA dopaminergic neurons by indirectly inhibiting the GABAergic neurons that originate in the NAc and project to the VTA. CB1 receptors on the glutamatergic projections from the PFC would be important to modulate motivation to seek the drug, including alcohol. Opioid interneurons modulate GABA-inhibitory action on the VTA and influence the firing of norepinephrine (NE) neurons in the locus ceruleus (LC). Serotonergic (5-HT) projections from the raphe nucleus (RN) extend to the VTA and the NAc.

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