Low-dose methylphenidate appears to help patients with attention deficit hyperactivity disorder by increasing sensitivity of neurons in the prefrontal cortex
Research with rats strongly suggests that low-dose methylphenidate
helps patients with attention deficit hyperactivity disorder by increasing the
sensitivity of neurons in the prefrontal cortex while producing little effect
elsewhere in the brain, according to an article published online June 26 by Biological
Psychiatry.
"It's the higher doses of these drugs that are normally
associated with their effects as stimulants, those that increase locomotor activity,
impair cognition and target neurotransmitters all over the brain," said psychologist
Craig Berridge, coauthor of the paper. "These lower doses are diametrically
opposed to that. Instead, they help the PFC better do what it's supposed to do."
In 2006, University of Wisconsin-Madison psychology researchers
David Devilbiss and Craig Berridge reported that therapeutic doses of methylphenidate
boosted neurotransmitter levels primarily in the prefrontal cortex, suggesting
a selective targeting of this region of the brain. Since then, the researchers
have focused on how methylphenidate acts on prefrontal neurons to enhance cognition.
In the current work, the researchers studied prefrontal
neurons in rats under a variety of doses, including one that improved the animals'
performance in a working memory task of the type that patients clinically have
trouble completing. Using a sophisticated new system for monitoring many neurons
at once through a set of microelectrodes, the scientists observed both the random,
spontaneous firings of these neurons and their response to stimulation of the
hippocampus.
When the researchers recorded electrical output from individual neurons, they
found that while cognition-enhancing doses had little effect on spontaneous activity,
the neurons' sensitivity to signals coming from the hippocampus increased dramatically.
Under higher, stimulatory doses, on the other hand, prefrontal neurons stopped
responding to incoming information.
"This suggests that the therapeutic effects of Ritalin [methylphenidate]
likely stem from this fine-tuning of prefrontal cortex sensitivity," said
Berridge. "You're improving the ability of these neurons to respond to behaviorally
relevant signals, and that translates into better cognition, attention and working
memory." Higher doses associated with drug abuse and cognitive impairment,
in contrast, impair functioning of the prefrontal cortex.
More intriguing still were the results that came from tuning into the entire
region of neurons at once. When groups of neurons were firing together strongly,
methylphenidate reinforced the coordinated activity. At the same time, the drug
weakened activity that was not well coordinated at baseline. These findings suggest
that methylphenidate strengthens dominant and important signals within the cortex,
while lessening weaker signals that may act as distractors.
"These results show a new level of action for cognition-enhancing doses
of methylphenidate that couldn't have been predicted from single neuron analyses,"
he Berridge said. "So, if you're searching for drugs that might replace it,
this is one effect you could potentially look for."
The researchers hope the current findings will help clarify how neurons encode
complex behavior and cognition.
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