 |
 |
|
|
By Richard Karel
Two new studies in the journals Nature Neuroscience and Nature pose a potentially revolutionary challenge to the primacy of the dopamine hypothesis of cocaine addiction.
For more than a decade, research on cocaine has converged around the hypothesis that the drug's reinforcing effects are inextricably tied to its capacity to bind directly to the dopamine transporter (DAT), thus blocking dopamine reuptake and raising extracellular concentrations of released dopamine. High levels of extracellular dopamine are one of the measurable effects of cocaine administration in laboratory animals and have been seen as the key to the drug's stimulating and reinforcing properties.
Scientists had long known that cocaine has a greater affinity for the serotonin transporter than the DAT, but they had assumed that serotonin merely modulated the primary reinforcing effects of extracellular dopamine. The new research, however, suggests that the dopamine system, while relevant to cocaine's reinforcing effects, is but part of a more complex series of neuro-cellular systems in which serotonin plays a far more significant role than previously supposed.
If these findings are replicated, they will force a reappraisal of the dopamine hypothesis and undoubtedly trigger a scramble for new approaches to the study of drug addiction.
The most startling of the two studies, titled "Cocaine self-administration in dopamine-transporter knockout mice," was published in the June 1998 Nature Neuroscience. Principal investigator Marc Caron, Ph.D., a neurobiologist at Duke University Medical Center in Durham, N.C., and lead researcher Beatriz Rocha, M.D., Ph.D., an assistant professor at the University of North Texas Health Science Center in Fort Worth, and colleagues, employed a genetic engineering technique known as "knockout" in which mice are bred to lack a specific neuroanatomical structure (in this case the dopamine transporter), believed responsible for a given behavior or symptom of disease. The hypothesis, quite simply, was that if the DAT was responsible for cocaine's reinforcing effects, then mice without the DAT would not self-administer a cocaine solution when given the chance. But that wasn't what happened.
Instead, the mice repeatedly self-administered cocaine, just like mice with normal DAT systems.
"It is remarkable that the DAT-knockout mice, which are already under the influence of the primary pharmacological action of cocaine, elevated dopamine, still self-administer the drug," the authors observe. They conclude that "the molecular targets for cocaine and the pathways that underlie the acquisition and maintenance of the drug-taking behavior in DAT-knockout mice must involve neuronal pathways other than the dopamine system."
The researchers speculate that the serotonin transporter plays a critical role in cocaine's reinforcing effects.
One scientist who has been instrumental in advancing the dopamine hypothesis of addictive drug reinforcement is George Koob, Ph.D., a professor of neuropharmacology at the Scripps Research Institute in La Jolla, Calif.
"I don't know how to interpret the knockout of the transporter," Koob told Psychiatric News. "The theory is that is the way cocaine works, but maybe cocaine does other things to the dopamine neuron."
There may be "compensatory changes occurring in other transmitter systems," he continued. "People have hypothesized there can be multiple, parallel reward systems as opposed to an in-series dopamine reward circuit. If you're going to look for changes that occur in addicts, then you may have to look at these other pathways as well."
The DAT paper complements a study in the May 14 issue of Nature on how cocaine affects mice engineered to lack one of the 14 serotonin receptors. In that study ("Increased vulnerability to cocaine in mice lacking the serotonin-1B receptor"), Rocha and principal investigator Rene Hen, Ph.D., an associate professor of pharmacology in psychiatry at the Center for Neurobiology and Behavior at Columbia University in New York, and colleagues, found that the serotonin receptor-knockout mice were more sensitive to cocaine's reinforcing effects than normal mice. This finding appears to contradict earlier research, which found that stimulating serotonin receptors mimicked some effects of cocaine while blocking those receptors lessened the effects of cocaine.
The authors speculate that the serotonin receptor-deficient mice developed some sort of compensatory mechanism that sensitized them to cocaine. Another possibility is that prior studies of the interaction of cocaine and serotonin systems were compromised by the lack of receptor specificity of some of the drugs used in the experiments, said Francis White, Ph.D., of the department of cellular and molecular pharmacology at Chicago Medical School in a commentary accompanying the Nature article.
George Uhl, M.D., Ph.D., is director of the molecular neurobiology branch at the National Institute on Drug Abuse, one of the first laboratories to clone the dopamine receptor. Earlier work on DAT-knockout mice found that the mice had a much diminished locomotor response to cocaine. But those findings, said Uhl, were over-generalized to suggest that the mice were invulnerable to cocaine's reinforcing effects.
The new research suggests that "dopamine still could participate in the drug's rewarding effects in normal animals and humans, but that it's not the only possible mechanism for cocaine reward," Uhl commented. "And this is somewhat surprising considering" prior research. Earlier work with mice engineered to have extra DAT found that the animals were extra-sensitive to cocaine's reinforcing effects, he noted. So while the prior evidence is not disproved, the new findings "will require us to rethink these classical paradigms."
Although the use of genetically engineered mice is an invaluable tool for researchers trying to elucidate the role of specific brain systems, it is possible and indeed likely that brain systems work differently in normal animals, Uhl observed. Generalizing from animals to humans is even more tentative, due to the complexity of human behavior, he added.