Brain doubles up on marijuanalike agents

As neuroscientists have slowly lifted the veils from the chemistry of the brain, they've realized that many powerful, and illegal, psychoactive drugs mimic natural compounds used by the nervous system.

 Take marijuana, whose primary active ingredient is delta-9-tetrahydrocannabinol, also known as THC. In 1992, researchers found that THC and anandamide, a naturally occurring brain chemical, bind to the same proteins on the surface of brain cells.

 Investigators now report that the brain makes a second THC-like compound, called sn-2 arachidonylglycerol, or 2-AG, and it does so in much greater quantities than anandamide. Moreover, the scientists offer several pieces of evidence suggesting that 2-AG plays a role in memory, which may help explain the short-term memory loss often produced by smoking marijuana.

 The new study is not the first to bring 2-AG to neuroscientists' attention. In 1995, a research group in Israel and another in Japan discovered that 2-AG binds to the same surface proteins -- the cannabinoid receptors -- on brain cells as anandamide does, but not as tightly.

 Yet doubts remained as to whether the brain uses 2-AG. While the Japanese group had offered some evidence that the brain employs 2-AG, the Israeli group found the compound in intestinal tissue, not in the nervous system.

 Danieli Piomelli of the Neurosciences Institute in San Diego recalls that he was very skeptical that 2-AG played any role in the brain. In what he expected would be a short task, he asked his research group to demonstrate that 2-AG is not present in the brains of rats.

 Instead, as the group reports in the Aug. 21 Nature, 2-AG turned out to be 170 times more abundant than anandamide.

 The researchers believe that 2-AG can prove difficult to detect in the brain because the compound degrades rapidly after death. Piomelli's team avoided that problem by quick-freezing brain tissue within 10 seconds of a rat's death and then analyzing the tissue.

 Other investigators, including the leader of the Israeli group, have also established that the compound is made by the central nervous system. "It's in the brain in high amounts," says Raphael Mechoulam of the Hebrew University of Jerusalem.

 The existence of 2-AG may help account for some aspects of marijuana biochemistry that anandamide cannot explain. The smoking of marijuana can produce many effects, including pain relief, motor impairment, appetite stimulation, and loss of recent memories.

 Investigators have struggled to link anandamide to memory formation, notes Piomelli. In contrast to anandamide, 2-AG is made by the hippocampus, a brain region crucial to memory. The investigators also observed in test-tube experiments that 2-AG inhibits a phenomenon called long-term potentiation, a strengthening of links between brain cells that may help memories form.

 While this finding may suggest at first glance that 2-AG impairs memory formation, Piomelli notes that people do not normally store every fact related to a particular memory. The brain forgets all aspects of a memory except those it somehow deems crucial, he says. The chemical 2-AG may play a role in that deliberate forgetting, speculates Piomelli.

 Through studying 2-AG and anandamide, scientists hope to develop drugs that ease pain or muster other therapeutic, marijuanalike actions without the accompanying memory loss or motor impairment. "Our goal is understanding the underlying biology in order to make more selective drugs," says Piomelli.

 The influence of 2-AG may go beyond the brain. In addition to intestinal tissue, "we have found it in the spleen and pancreas," says Mechoulam, noting that cells in all three sites also have cannabinoid receptors.