- 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 ).
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- 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."
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- 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.
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- A Pragmatic Paradox
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- 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.
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- "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."
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- 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.
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- 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.
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- 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.
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- Startling Results
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- 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.
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- 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.
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- 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.
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- The two theories opposed each other. But Volkow was
unfazed. "We had to let the data speak for itself," she said.
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- 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.
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- 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?
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- Capturing The Answer
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- 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.
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- 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.
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- 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.
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- 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.
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- 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 ).
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- 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."
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- http://www.mapinc.org/drugnews/v01.n1542.a02.html
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