Genetic basis for susceptibility to alcohol abuse confirmed

A new set of experiments in mice confirms that a brain receptor associated with the reinforcing effects of marijuana also helps to stimulate the rewarding and pleasurable effects of alcohol.

The research, which was conducted at the U.S. Department of Energy's Brookhaven National Laboratory and was published online September 2, 2005, by the journal Behavioural Brain Research, confirms a genetic basis for susceptibility to alcohol abuse and also suggests that drugs designed to block these receptors could be useful in treatment.

"These findings build on our understanding of how various receptors in the brain's reward circuits contribute to alcohol abuse, help us understand the role of genetic susceptibility, and move us farther along the path toward successful treatments," said Brookhaven's Panayotis (Peter) Thanos, lead author of this study and many others on "reward" receptors and drinking (see: http://www.bnl.gov/bnlweb/pubaf/pr/PR_display.asp?prID=05-49 and , http://www.bnl.gov/thanoslab).

Earlier studies in animals and humans have suggested that so-called cannabinoid receptors known as CB1 -- which are directly involved in triggering the reinforcing properties of marijuana -- might also stimulate reward pathways in response to drinking alcohol. Thanos' group investigated this association in two experiments.

In the first experiment, they measured alcohol preference and intake in mice with different levels of CB1 receptors: wild type mice with normal levels of CB1; heterozygous mice with approximately 50 percent levels; and so-called knockout (KO) mice that lack the gene for CB1 and therefore have no CB1 receptors. All mice were given a choice of two drinking bottles, one with pure water and one with a 10 percent alcohol solution -- approximately equivalent to the alcohol content of wine. Mice with the normal levels of CB1 receptors had a stronger preference for alcohol and drank more than the other two groups, with the CB1-deficient mice showing the lowest alcohol consumption.

After establishing each group's level of drinking, the scientists treated animals with a drug known to block CB1 receptors (SR141716A) and tested them again. (These animals were also compared with animals injected with plain saline to control for the effect of the injection.) In response to the CB1 receptor-blocking drug, mice with normal and intermediate levels of receptors drank significantly less alcohol compared to their pre-treatment levels, while KO mice showed no change in drinking in response to the treatment.

In the second experiment, the scientists compared the tendency of wild type and KO mice to seek out an environment in which they had previously been given alcohol. Known as "conditioned place preference," this is an established technique for determining an animal's preference for a drug.

Animals were first conditioned to "expect" alcohol in a given portion of a three-chambered cage while being given an injection of saline in the opposite end, and then monitored for how much time they spent in the alcohol chamber "seeking" the drug. Wild type animals, with normal levels of CB1, spent more time in the alcohol-associated chamber than the saline chamber, showing a decided preference, while KO mice (with no CB1 receptors) showed no significant preference for one chamber over the other.

"These results support our belief that the cannabinoid system and CB1 receptors play a critical role in mediating the rewarding and pleasurable properties of alcohol, contributing to alcohol dependency and abuse," Thanos said.

In addition, the fact that the mice with intermediate levels of CB1 exhibited alcohol preference and intake midway between those with high levels of receptors and those with none suggests that the genetic difference between strains quantitatively influences the preference for and the amount of alcohol consumed. "These results provide further evidence for a genetic component to alcohol abuse that includes the CB1 gene -- the same gene that is important for the behavioral effects of marijuana," Thanos said.

While it remains unclear exactly how CB1 triggers the rewarding effects of alcohol, one possibility is that activation of the CB1 receptor somehow blocks the brain's normal "stop" signals for the production of dopamine, another brain chemical known to play a role in addiction. Without the stop signal, more dopamine is released to produce a pleasure/reward response.

Since blockade of the CB1 receptor with SR141716A appears to effectively reduce alcohol intake and preference, this study also suggests that such CB1 receptor-blocking drugs might play an important role in the future treatment of alcohol abuse.