Biochemistry & Pharmacology: Open Access
Open Access
ISSN: 2167-0501
ISSN: 2167-0501
Zheng-Xiong Xi
Pharmacologist, Intramural Research Program
Zheng-Xiong Xi, a pharmacologist at the National Institute on Drug Abuse in Baltimore, explains that the main receptor in the endocannabinoid system, CB1, interferes with brain levels of dopamine, a chemical associated with reward-seeking behavior, pleasure, and motivation. Activating CB1 jump-starts a chain reaction that culminates in an excess of dopamine floating around between neurons. “The dopamine produces a good feeling, a rush, euphoric effects,” Xi says.
A few years ago, Xi was studying this phenomenon in mice, hoping to find a pill to treat addiction to dopamine-boosting drugs such as cocaine. Scientists suspected that rimonabant, which decreases CB1 activity, dampens appetite by decreasing dopamine levels and taking the rush out of eating. Xi was looking for a compound that would have the same effect on cocaine users. Without the high, he theorized, cocaine might lose its appeal.
In studying the endocannabinoid system, Xi tested THC, the active compound in marijuana. THC is thought to produce euphoric feelings by increasing CB1 activity and causing dopamine levels to rise. Instead he saw the opposite effect. “We found that at higher doses it produced a decrease,” Xi says. “So how did this happen?”
When Xi tried THC on mice lacking CB1 receptors, he found the same response: Dopamine dropped. Could THC be acting on the other receptor in the endocannabinoid system, CB2? It was an odd question, since CB2 receptors were not thought to reside in the brain. “For years people didn’t believe that they really existed there,” Sharkey says. But when Xi tested THC in mice without the CB2 receptor, it had no effect at all. CB2 was clearly involved.