Scripps study suggests potential target for drugs to combat alcohol addiction

Researchers show a direct cellular interaction between the endocannabinoid system and alcohol in the brain, and find that that the endocannabinoid system may actually be able dampen the effects of alcohol as well

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LA JOLLA, Calif.—Some people enjoy a glass of wine at home in the evenings or in social settings. Others find they cannot function without it. While previous studies in the field of neurobiology has confounded theories about this disparity, researchers at the Scripps Research Institute have made a breakthrough in the understanding of the area of the brain that is associated with alcoholism.

For the first time, the Scripps team has shown a direct cellular interaction between the endocannabinoid system—a group of neuromodulatory lipids and their receptors that are involved in a variety of physiological processes including appetite, pain-sensation, mood and memory—and alcohol in the brain. Specifically, they showed that the endocannabinoid system is active in the central amygdala (CeA), the brain region known to play a key role in the processing of memory, emotional reactions and addiction formation.

The discovery, which is detailed in a study published in the journal Neuropsychopharmacology on May 12, "will change a lot in the field," says Scripps Research Associate Professor Marisa Roberto, who is focused on the study of role the amygdala plays on the effects of drug abuse.

"When I came to Scripps, nothing was known about this at the cellular level," Roberto says. "Our research is centered on uncovering the physiologic mechanisms that underlie the effects of acute and chronic ethanol on CeA neurons and particularly on the γ-aminobutyric acid (GABA) and glutamatergic systems. We are the first to make this discovery. I'm confident it will have a huge impact."

The researchers used electrophysiological techniques in brain slices to test the response of brain cells from the rat central amygdala. The cells responded to an agonist mimicking the action of endocannabinoids in the brain. Increasing the agonist resulted in a bigger effect, whereas an inhibitor reversed this response.

The evidence of active CB1, the most common type of endocannabinoid receptors, in the CeA was "compelling," Roberto says.

"It was beautiful," she says, clearly enthusiastic about the finding. "The effect of alcohol on this area of the brain was clear, and it was remarkable how strong and consistent it was."

Roberto says arriving at these findings "wasn't easy at all," but the Scripps team's work should put to rest more than 10 years of controversy in the field of neurobiology. Not only is it the first time a study has shown a direct cellular interaction between endocannabinoids and alcohol in the brain, it also overturns the conclusions of a paper published by a European group in the Journal of Neuroscience in 2001. This paper claimed that CB did not exist in the central amygdala.

"Aside from the 2001 study, there hasn't been much physiology in the central amygdala done before this," Roberto points out. "But as we have shown, this region of the brain is important, not just in alcoholism, but for other drugs of abuse."

In addition to that groundbreaking discovery, the researchers also found that the endocannabinoid system can dampen the effects of alcohol, suggesting a new direction for the development of drugs to combat alcohol addiction. The researchers examined the transmission of a particular neurotransmitter called gamma amino butyric acid (GABA), the main inhibitory neurotransmitter in the brain. Neurons in every brain region use GABA to fine-tune signaling throughout the nervous system. Previous studies by the Scripps Research scientists indicated that GABA plays a critical role in alcohol dependence and other addictions.

For this study, the scientists applied the CB1 agonist on cells from the central amygdala, which decreased GABA transmission. When the scientists proceeded to put ethanol on top, the effect of ethanol was abolished. When the team reversed the order of application, GABA transmission first went up with the application of ethanol, then down with the application of the CB1 agonist.

The researchers will now attempt to differentiate the cellular effects of the endocannabinoid system and CB1 ligands and their modulation by both acute and chronic alcohol treatment. This may lead to a better understanding of the cellular mechanisms of addiction and dependence, Roberto says.

"The exact presynaptic mechanisms affected by ethanol and cannabinoids to alter GABA release remain to be determined," the researchers concluded. "CB1 and ethanol may act on common signaling pathways to regulate the release of GABA, as suggested in the cerebellum, where activation of presynaptic protein kinase A (PKA) is necessary for the ethanol-induced increase in spontaneous GABA release. CB1 activation is well known to inhibit adenylate cyclase and decrease PKA activity, and the mechanism of the cannabinoid-induced decrease of spontaneous GABA release in cerebellar neurons seems to involve PKA. Therefore, the adenylate cyclase/PKA pathway may be a common signal transduction pathway targeted in opposite ways by eCBs and ethanol to regulate GABA release."

Another potential candidate is protein kinase C epsilon (PKCe), the researchers note.

"We recently determined that a PKCe signaling pathway is activated by ethanol to augment GABA release in CeA," they add. "PKCe reportedly negatively regulates the affinity of WIN2 at CB1, although a possible modulation of eCB activity at CB1 by
PKCe is uncertain. Nonetheless, these two kinases seem to be interesting candidates to participate in the opposite regulation of GABA release by ethanol and eCBs, and a combined crosstalk between PKA and PKCe to regulate ethanol and eCB effects is also possible."

The study, "The Endocannabinoid System Tonically Regulates Inhibitory Transmission and Depresses the Effect of Ethanol in Central Amygdala," was supported by the National Institutes of Health's National Institute on Alcohol Abuse and Alcoholism. Roberto's co-author was Paul Schweitzer, associate professor of the neurobiology of addiction at Scripps Research.

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