When placed in a maze that normal mice negotiate in less than three minutes, the knockout mice became distracted-performing extraneous activities such as sniffing and rearing-and they failed to finish in less than five minutes. The knockout mice also seemed unable to suppress inappropriate impulses-another hallmark of ADHD.
Surprisingly, the knockout mice were still calmed by Ritalin®, Dexedrine® and other stimulants even though they lacked the protein target on which Ritalin® and Dexedrine® were thought to act. "That caused us to look for other systems that these stimulants might affect," says Caron.
To test whether the stimulants interact with dopamine through another mechanism, the researchers administered Ritalin® to the normal and knockout mice and monitored their brain levels of dopamine. Ritalin® boosted dopamine levels in the normal mice, but it did not alter dopamine levels in knockout mice. That result implied that "Ritalin® could not be acting on dopamine," says Caron.
Next, the researchers gave the knockout mice a drug that inactivates the norepinephrine transport protein. With transport disabled, norepinephrine levels increased as expected, but the boost in norepinephrine did not ameliorate the symptoms of ADHD as it should. This suggested to Caron's team that Ritalin® exerted its effects through another neurotransmitter.
They then studied whether the stimulants altered levels of the neurotransmitter serotonin. The scientists administered Prozac®-a well-known inhibitor of serotonin reuptake-to the knockout mice. After ingesting Prozac®, the knockout mice showed dramatic declines in hyperactivity.
"This suggests that rather than acting directly on dopamine, the stimulants create a calming effect by increase serotonin levels," Caron says.
"Our experiments imply that prop
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Contact: Jim Keeley
keeleyj@hhmi.org
301-215-8858
Howard Hughes Medical Institute
14-Jan-1999