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URL:
http://www.mapinc.org/drugnews/v01.n1542.a02.html
Newshawk: John Markes
Pubdate: Wed, 22 Aug 2001
Source: Journal of the American Medical Association (US)
Copyright: 2001 American Medical Association.
Contact: JAMA-letters@ama-assn.org
Website: http://jama.ama-assn.org/
Details: http://www.mapinc.org/media/219
Author: Brian Vastag
PAY ATTENTION: RITALIN ACTS MUCH LIKE
COCAINE
WASHINGTON - Advanced imaging research has answered a 40-year-old question
about methylphenidate ( Ritalin ), which is taken daily by 4 million to 6
million children in the United States: how does it work? The answer may
unsettle many parents, because the drug acts much like cocaine, albeit
cocaine dripped through molasses ( J Neurosci. 2001;21:RC121 ).
Taken orally in pill form, methylphenidate rarely produces a high and has not
been reported to be addictive. However, injected as a liquid it sends a
jolt that "addicts like very much," said Nora Volkow, MD, psychiatrist
and imaging expert at Brookhaven National Laboratory, Upton, NY.
"They say it's like cocaine."
Acknowledged as leaders in the field of brain imaging of drug effects, Volkow
and colleagues have spent several years tracing the effects on the brain of drugs
of addiction, using positron emission tomography ( PET ) and other advanced
techniques. Among their long list of findings, they've identified the
brain's dopamine system as a major player in compulsive behavior, including
drug taking and overeating.
A Pragmatic Paradox
Building on that base, Volkow, associate laboratory director for life
sciences at Brookhaven, hit the trail of a legal stimulant. Although
they have used it to treat attention-deficit/hyperactivity disorder ( ADHD )
for 40 years, psychiatrists and pharmacologists have never known how or why
it worked. Chemically similar to cocaine and other stimulants,
methylphenidate presents a pragmatic paradox: it decreases activity and
increases the ability to concentrate in people with ADHD, but in studies,
about half of those without ADHD find it unpleasant, like drinking too much
coffee.
"I've almost been obsessed about trying to understand [methylphenidate]
with imaging," said Volkow at a recent media conference. "As
a psychiatrist, sometimes I feel embarrassed [about the lack of knowledge]
because this is, by far, the drug we prescribe most frequently to
children."
So the team went to work with PET scans to examine the dopamine system, which
stimulates reward and motivation circuits during pleasurable experiences
eating, having sex, learning. To pick one of many pleasures, tasting
chocolate ice cream will trigger cells in the basal ganglia to release
dopamine molecules. These float across the synapse to neurons in a reward
circuit. Receptors on these cells sop up the dopamine, activating
signals that translate to "this experience is worth paying attention
to." Too much signal and the experience feels unpleasant,
overstimulating. Too little, and the experience elicits a yawn; no pleasure,
only boredom and distraction.
Volkow wanted to know how methylphenidate affects this signal. But
instead of focusing on dopamine receptors, she tracked another part of the
system. After the pleasure signal is sent on its way, dopamine
molecules recycle back to the neurons that produced them. There,
transporters also called autoreceptors act as vacuum cleaners, scouring the
synapse for another go-around.
Earlier research had shown that cocaine blocks about 50% of these
transporters, leading to a surfeit of dopamine in the synapse and a hit of
pleasure. Because of methylphenidate's chemical similarities to
cocaine, pharmacologists thought that it might work in the same way, only
less potently, blocking fewer transporters. Animal studies with high
doses of methylphenidate indicated that this could be the case.
Startling Results
Using a radiotracer, [11C]raclopride, that labels dopamine transporters, the
team scanned 11 healthy men who took various doses of oral
methylphenidate. The results were shocking.
"We were surprised as hell," said Volkow. "We didn't
expect this." Instead of being a less potent transport inhibitor than
cocaine, methylphenidate was more potent. A typical dose given to
children, 0.5 mg/kg, blocked 70% of dopamine transporters. "The
data clearly show that the notion that Ritalin is a weak stimulant is
completely incorrect," Volkow said.
More pondering led the team to consider two theories. Methylphenidate
could be blocking the recycling of dopamine exactly as cocaine does, leading
to strong signals that would yield a high and lead to addiction. But
this did not jibe with four decades of clinical experience.
So they considered another possibility. Perhaps methylphenidate seeps
into the brain slowly, and as one by one the drug molecules block the
transporters, dopamine cells shift gears. Like a union foreman yelling
to an assembly line to slow down, the cell interprets the transporter
congestion as a signal that too much dopamine is being produced. The
neuron cranks down production, sending less dopamine into the synapse,
suppressing the reward signal.
The two theories opposed each other. But Volkow was unfazed.
"We had to let the data speak for itself," she said.
That meant measuring the amount of dopamine floating in the synapses.
Fortunately, the investigators had at hand another radioactive label that
binds only to open dopamine receptors. A weak PET signal would mean low
numbers of open receptors, which in turn would mean that large amounts of dopamine
occupied the synapse.
After combining data from the volunteers, the team got its second
surprise. Those who took methylphenidate displayed high levels of
extracellular dopamine just like people using cocaine. But if
methylphenidate works like cocaine, why aren't millions of US children
getting high and becoming addicted?
Capturing The Answer
The answer came after Volkow combined her results with those from another
research team. In 1999, Darin Dougherty, MD, and colleagues at
Massachusetts General Hospital and Harvard University Medical School reported
that people with ADHD have many more dopamine transporters than those without
the condition ( Lancet. 1999;354:2132-2133 ). This surplus
increases the collective cleaning power of each cell; as dopamine fires into
the synapse it is quickly sucked back, before it can home in on reward
circuit receptors. "There isn't enough time for it to produce a
signal," said Volkow.
It finally started to make sense. Children with ADHD produce weak dopamine
signals, meaning that usually interesting activities provide fewer
rewards. In effect, their attention circuitry is underfed. At the
same time, they experience a related effect: random, distracting neuron
firing. Or, as Volkow put it, more noise and less signal. This
background hum interferes with concentration, making the child more
distractible.
Methylphenidate flips the relationship, upping the signal and reducing the
noise. After someone swallows methylphenidate, it enters the
bloodstream and eventually finds the brain, where it blocks dopamine
transporters and increases attention signaling. Again, cocaine acts the
same way. But the two drugs differ in a significant way:
methylphenidate takes about an hour to raise dopamine levels, whereas inhaled
or injected cocaine hits the brain in seconds. "It is the speed at
which you increase dopamine that appears to be a key element of the addiction
process," said Volkow.
While the team is unclear on why this speed factor is so important, future
research will focus on it. They also plan to map dopamine levels in
volunteers who have ADHD when they are at rest or while concentrating.
Other research will search for molecular tools to screen children for
dopamine transporter levels; those with high levels could be identified early
and encouraged with behavioral solutions before methylphenidate is
prescribed. "We know that social interactions can increase
dopamine receptors," said Volkow, but whether better interplay also
affects transporter levels is unknown.
The long-term dopamine effects of taking methylphenidate for years, as many
do, are another unknown. The only two large epidemiological studies
conflict. One reports more drug addiction in children with ADHD who
took methylphenidate compared with children with ADHD who took no drug ( J
Learn Disabil. 1998;31:533-544 ); the other shows the opposite result (
Pediatrics. 1999;104:e20 ).
Because people with low levels of dopamine receptors are at risk for drug
addiction, Volkow said that researchers need to understand if methylphenidate
can alter the whole dynamic of the dopamine pathway. "Could
chronic use of Ritalin make you more vulnerable to decreased dopamine brain
activity as cocaine does? It's a key question nobody has answered."
MAP posted-by: Beth
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