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The first major blows to the dopamine theory of cocaine addiction came in May and June with articles in the journals Nature and Nature Neuroscience (Psychiatric News, June 19). Now another study, this one in the June 23 Proceedings of the National Academy of Sciences, further undermines the notion that dopamine is the key determinant of cocaine's reinforcing effects and has also called into question the role of serotonin.
The study by Ichiro Sora, M.D., Ph.D., and George Uhl, M.D., Ph.D., of the National Institute on Drug Abuse (NIDA) Molecular Neurobiology Branch, and colleagues, found that genetically engineered mice lacking dopamine transporters (DATs) and another strain lacking serotonin transporters (5-HTTs) remained vulnerable to cocaine's reinforcing effects.
Cocaine blocks the uptake of released dopamine, serotonin, and norepinephrine, and a substantial body of research suggests that blockade of the DAT, perhaps modulated by 5-HTT, explained the drug's addictive properties. Much has been made of dopamine's role in cocaine addiction, since high levels of extracellular dopamine are a hallmark of cocaine administration in mice.
In the two studies summarized in the June 19 Psychiatric News, researchers reported that mice without dopamine transporters remained sensitive to cocaine's reinforcing properties, and that mice without serotonin transporters were particularly vulnerable to the drug's reinforcing effects. These studies set off speculation that the mice developed compensatory mechanisms to offset the loss of dopamine transporters and that perhaps serotonin was more significant as a modulator of cocaine reward than previously thought.
The authors of the current study used a behavioral measure called "conditioned place preference" to assess whether mice without DAT and mice without 5-HTT continued to find cocaine administration psychologically rewarding.
The authors used a two-compartment Plexiglas chamber. One compartment had a wire mesh floor mounted on Plexiglas, the other corncob bedding on Plexiglas. They established that the mice without DAT and those without 5-HTT preferred the corncob bedding to the wire floor, then administered cocaine to the two different strains of mice in the wire-floor compartment. Given access to both compartments, the cocaine-conditioned mice spent more time on the wire floor than on the bedding, indicating that they had developed a preference for the place where they had received cocaine.
The outcomes of these studies suggest that addiction scientists must rethink their current understanding of addiction. "These results have substantial implications for understanding cocaine's actions and for strategies to produce anticocaine medications," state the authors. "Cocaine appears to act on a richer array of brain sites than those previously identified as having a role in drug reward and addiction," principal investigator Uhl commented. "Any medication used in cocaine treatment may also have to act on these brain sites."
Related information can be found at the Web sites of the Proceedings of the National Academy of Sciences at www.pnas.org; NIDA: www.nida.nih.gov; Nature: www.nature.com; and Nature Neuroscience: www.neurosci.nature.com.