“Alcoholism is a complex disorder affecting modern society in many ways, yet there are few effective treatment strategies currently available.”
“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.”
“Overwhelmingly, recent studies suggest that cannabinoids and alcohol activate similar reward pathways. The CB1 receptors also seem to regulate the reinforcing properties of alcohol. The discovery of cannabinoid receptors and their endogenous ligands set a landmark in cannabinoid research. These discoveries impacted significantly on alcohol research, too, since there is now considerable evidence that endocannabinoid signaling plays a key role in alcohol addiction, and this has promising clinical consequences. The purpose of this article is to analyze the interaction between alcohol and endocannabinoid signaling, paying particular attention to the reward mechanism. Therapeutic aspects driving from these new insights are also discussed.”
“THERAPEUTIC OPPORTUNITY”
“Although the detailed physiology, biochemistry and pathophysiology of the endocannabinoid signaling system have not been fully investigated, there is already overwhelming evidence to indicate that pharmacological modulation of the endocannabinoid signaling system could provide new treatments for a number of disease states, including alcohol addiction. Recently it was reported that rimonabant holds an important therapeutic role in treating liver fibrosis and alcohol abuse accounts for more than half of the prevalence of liver fibrosis and cirrhosis in the western world. Therefore, it is important to examine whether alcohol-induced liver fibrosis and cirrhosis results in increased endocannabinoid levels and rimonabant reverses alcohol-induced liver fibrosis/cirrhosis. In terms of drug development, the CB1 receptor antagonist rimonabant has progressed furthest and is in late phase III trials for the treatment of obesity and as an aid for smoking cessation. An NIAAA clinical study of the effectiveness of rimonabant to reduce voluntary alcohol drinking has progressed to phase I trials. Pending results of the clinical trials, rimonabant could become an important addition to the limited arsenal of effective treatments for alcoholism. During drug abuse there are changes in endocannabinoid levels in various brain regions. Therefore, drugs which regulate the level of endocannabinoids by inhibiting their metabolism (FAAH inhibitors such as URB597) or uptake (AM404) could locally target sites while limiting effects in uninvolved cognitive areas to produce a higher therapeutic value. Cannabinoid interactions with the dopamine system have been offered as a possible mechanism for some of the therapeutic potential of cannabinoid-based drugs in alcoholism. A recent study provides evidence of the ability of CB1 receptor antagonist to mitigate alcohol-withdrawal symptoms, and block the formation of physical dependency by inhibiting alcohol intake. Recent data on the role of CB1 receptors in alcohol drinking behavior, including alcohol tolerance as discussed in the earlier sections, clearly suggest that agents such as CB1 receptor antagonists, including rimonabant, will be promising therapeutic agents for the treatment of alcoholism.”