May 21, 1998 DURHAM, N.C. - When Marc Caron created genetically engineered mice missing a molecule thought to be the main target of cocaine in the brain, he expected the resulting mice would be relatively immune from cocaine's effects. But to his surprise, he and his colleagues at Howard Hughes Medical Institute at Duke University Medical Center found these mice still self-administer cocaine, a behavior akin to addiction in humans.
The researchers said the results, to appear in the June issue of the journal Nature Neuroscience, may cause scientists to rethink how the brain becomes dependent on addictive drugs and could immediately broaden the approach clinicians take in treating cocaine addiction by targeting several neurotransmitters instead of just one, dopamine.
"The surprising thing is that in the absence of the primary target for cocaine, these animals will still self-administer cocaine," Caron said. "This goes against all of the dogma about the reinforcing properties of cocaine. Our results show there is something else going on."
For many years, scientists have theorized that cocaine's addictive properties are related to its effects on dopamine, an essential messenger of the nervous system, particularly in the brain. Normally, brain cells release dopamine and other neurotransmitters such as serotonin, norepinephrine, and GABA (gamma aminobutyric acid) to alert their neighbors about changing conditions - to signal that it is time to run instead of walk, or to remember that red oven coils are burning hot.
Because these neurotransmitters are so critical to the smooth functioning of the nervous system, they are tightly regulated. When a chemical, such as an addictive drug, interferes with this process, the brain can be tricked, causing people or animals to react in strange, uncharacteristic ways.
"The dopamine system has always been thought to be the brain's central reward pathway," said Caron, a Howard Hughes Medical Institute investigator and James B. Duke professor of cell biology. "Nearly all drugs of abuse, from nicotine to heroin, are thought eventually to funnel through this pathway."
The reason cocaine is such a powerfully addictive drug, Caron said, is that it inserts itself directly into essential brain-signaling systems. When a person snorts or smokes cocaine, it travels through the bloodstream and finds its way to the brain, where it nestles into transporters not only for dopamine, but also for serotonin and norepinephrine. Once settled, it effectively shuts down transport mechanisms, so that neurotransmitters sit in the neural synapse signaling neighboring neurons much longer than they should.
Scientists have long thought that it is blockade of the dopamine transporter system that causes people to become addicted. Researchers have focused their attention on dopamine neurons in a part of the brain called the ventral tegmental area (VTA), which projects to the nucleus accumbens, a part of the mesolimbic system, since scientists first showed 20 years ago that destroying this specific area in rats' brains stopped them from self-administering cocaine. In effect, the theory goes, cocaine fools the dopamine system into thinking cocaine is the best "food" it has ever had, and soon it wants more.
"Much of what we know about dopamine's functions comes from studies in which whole neurons are surgically removed or destroyed by chemical compounds," Caron said. "We wanted to use genetics to specifically delete one key element of the dopamine system."
To better understand the specific role of the dopamine transporter in this process, Caron and his colleagues used genetics to create a mouse that lacks the dopamine transporter, the supposed key to cocaine addiction.
Lacking the dopamine transporter - the molecule that normally scavenges dopamine back into the transmitting cell - Caron's genetically altered mice have no way to turn off dopamine signaling and are acutely hyperactive, as though they are on cocaine all the time. Published in the Feb. 15, 1996, issue of the journal Nature, the study first describing the mice showed definitively that the dopamine system is indeed the primary biological pathway of addiction.
In their current research, Caron and his colleagues wanted to see how the mice would react when presented with cocaine.
To do that, Caron collaborated with Dr. Beatrix Rocha of the University of North Texas in Fort Worth. Rocha conducted experiments in which she offered both normal mice and the genetically altered mice cocaine as a reward for pressing a lever. Because the brains of the transporter-deficient mice are in a constant state of stimulation, much like that of an animal permanently on cocaine, the researchers reasoned that the mice would be indifferent to cocaine if they were presented the drug. To their surprise, however, the transporter-deficient animals self-administered cocaine anyway, although they required more cocaine to become "hooked."
Caron and post-doctoral fellows Fabio Fumagalli, Raul Gainetdinov, Sara Jones, Bruno Giros, and Gary Miller then tested other areas of the brain to see which were being stimulated by the cocaine. They found that cocaine was blocking the serotonin transporter in three key brain areas, the anterior olfactory nuclei, piriform cortex, and orbital cortex, that have been shown to be stimulated by other drugs of abuse. For example, lysergic acid diethylamide (LSD) and phencyclidine (PCP) activate serotonin transmission in the piriform cortex.
The findings suggest that in addition to dopamine, serotonin is a key contributor to the reinforcing and addictive properties of cocaine.
Caron's research is further substantiated by a research paper in the May 14 issue of the journal Nature. Dr. Rene Hen of Columbia University, who also collaborated with Rocha, made mice lacking one of the receptors for serotonin. These mutant mice are more aggressive than normal mice. When the mice were allowed to give themselves cocaine, they frantically self-administered the drug, much more so than normal animals.
The Columbia researchers studied the brains of mice missing the serotonin receptor and discovered their brains resembled those of mice accustomed to receiving large amounts of cocaine. In a sense, they are born addicted.
"The serotonin system has been thought to be a minor player in cocaine addiction," Miller said. "People say the dopamine system drives addiction. I think we've shown it is more complicated than that. All the momentum in drug therapies is geared toward the dopamine system, especially the transporter. But a combined therapy that targets both the serotonin and dopamine systems may be worth pursuing."
The research was funded in part by grants from the National Institutes of Health and by unrestricted grants from Bristol Myers Squibb and Zeneca Pharmaceuticals.
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