Cocaine's action in the brain requires more or other sites than researchers previously believed, or an unidentified means of action, according to scientists at the National Institute on Drug Abuse (NIDA), National Institutes of Health. A team led by Dr. George Uhl and Dr. Ichiro Sora of NIDA's Intramural Research Program found that cocaine could still elicit drug-seeking behavior in mice lacking the genes for either the dopamine transporter (DAT knockout mice) or the serotonin transporter (5-HTT knockout mice). These transporters had been believed to be the critical brain sites involved in the experiences of drug euphoria, reward, and ultimately addiction. Yet the two strains of knockout mice, lacking genes for the "reward" transporters, remain sensitive to the rewarding effects of cocaine. Thus, other brain mechanisms must be involved also in the brain's response to drugs or be able to compensate when the primary mechanisms are not operating fully.
"These findings suggest we should expand our search for new target sites in the brain for developing successful therapies for cocaine addiction," said Dr. Alan I. Leshner, Director of NIDA.
"Many studies have pointed to dopamine, and possibly serotonin, transporters as the key reward sites associated with drug abuse and addiction. Now we have to cast the net beyond dopamine or serotonin transporters alone if we are to help cocaine addicts overcome uncontrollable craving and improve their treatment outcome."
In a study published in the June 23 Proceedings of the National Academy of Sciences, researchers set out to determine whether eliminating dopamine or serotonin transporters could affect cocaine reward--a key step in developing a model to study medications for cocaine addiction. Drug reward in the two knockout strains of mice was assessed by the "conditioned place preference" test. DAT and 5-HTT mice as well as normal, control mice are allowed on day 1 to move freely in a plexiglass chamber with two distinct compartments; one has a wire-mesh floor and the other has bedding material on its floor. The mice generally spend most of their time in the compartment with the bedding. Starting on day 2, the mice receive four conditioning sessions during which they are given, alternately, injections of saline while restricted to the bedding compartment or injections of cocaine or methylphenidate (both are stimulant drugs) while restricted to the wire-mesh compartment.
Twenty-four hours after the last conditioning session and after the acute effects of the drug wear off, the mice are allowed to enter either compartment. In this study, researchers found that DAT and 5-HTT knockout mice each showed a significant increase in preference for the wire-mesh compartment, which was the compartment associated with the drug. This finding indicates that cocaine and methylphenidate are still rewarding drugs to these mice, even thoughthey lack the key proteins associated with the rewarding and reinforcing effects of the drugs (the dopamine or serotonin transporters).
Dr. Uhl observed that, given these results, "Cocaine appears to act on a richer array of brain sites than those previously identified as having a role in drug reward and addiction. Any medication used in cocaine treatment may also have to act on these brain sites."
The research team included investigators from NIDA's Intramural Research Program, the Intramural Research Program of the National Institute of Mental Health, and the Department of Psychiatry at the University of Wuerzburg in Germany.