NEW ORLEANS — As any parent of a teenager can tell you, there is a lot going on in the brain of an adolescent that we do not understand. Adolescence is a critical period for synaptogenesis – billions of new connections are made throughout the brain during this period – followed by a pruning back that leaves the brain rewired for adulthood. As is true during other critical periods in which the brain is molded, the adolescent brain is highly sensitive to environmental influences, including drugs and stress, and the changes wrought by these influences may be lifelong.
Research presented here at the last year's Annual Meeting of the Society for Neuroscience investigated the responses of the adolescent brain to these influences. On the other hand, according to other data presented here, nicotine – the drug most commonly used by adolescents – may be a valuable treatment for attention deficit hyperactivity disorder (ADHD).
BEHAVIORAL INHIBITION IN ADHD
ADHD is the most common psychological disorder of childhood, occurring in 3 to 5 percent of children. According to Alexandra Potter, PhD, of the Clinical Neuroscience Research Unit at the University of Vermont in Burlington, behavioral inhibition “is increasingly recognized as the core cognitive deficit in ADHD. Behavioral inhibition – defined as the inability to refrain from or delay responding when cued by the environment – is critical for executive functioning, such as planning and achieving goal-directed behavior. These are certainly critical skills, and they are all impaired in ADHD.”
“It's not that they are inattentive, but they are unable to inhibit attention to inappropriate things,” said co-investigator Paul Newhouse, MD, who is the Director of the Research Unit.
“We also know ADHD and smoking are linked,” Dr. Potter said. The prevalence of smoking in adolescents with ADHD is twice that of normal adolescents, a trend that continues into adulthood: 40 percent of adults with ADHD smoke, compared to 26 percent of those without it. “This leads to the theory that perhaps adolescents and adults with ADHD are self-medicating, via nicotine administration,” she said.
The theory makes biochemical sense, according to Dr. Potter, since psychostimulants release catechola-mines, which reliably improve the symptoms of ADHD. Nicotine stimulates the release of dopamine. Nicotine also has positive effects on cognition, particularly on attention.
To test the effect of nicotine on inhibition in ADHD directly, Dr. Potter enrolled eight nonsmoking adolescents with ADHD who were prescreened for impaired behavioral inhibition and who were currently receiving methylphenidate (Ritalin) or another stimulant.
Subjects were given either double placebo, or 7 milligrams of nicotine delivered via transdermal patch plus a placebo pill, or their normal methylphenidate dose plus a placebo patch. Behavioral inhibition was tested using a “stop signal” task, in which a “go signal” – an “X” or an “O” – is presented, and the subject must respond by indicating which is shown.
However, a fraction of the presentations are followed quickly by a stop signal – a tone that signifies the subject should not respond. The longer the delay before the tone, the more inhibitory control is needed to abort the response. A computer adjusts the delay between the stop and go signals so that the subjects successfully inhibit 50 percent of the time.
“Kids with ADHD do really terribly on this task,” said Dr. Newhouse. “In fact in our lab, some of them do so badly, the computer can't even find the interval” that gives the 50-percent success rate.
In this study, the mean delay interval was 290 milliseconds without any medication, compared to 200 milliseconds for age-matched non-ADHD subjects. Dr. Potter found that both methylphenidate and nicotine reduced the mean delay time to within the normal range. The effect was not due to a speeding of reaction time, since the time for response without the stop signal was not affected.
She also examined another cognitive task requiring inhibition, the Stroop task, in which the word for a color is shown in text of another color (for example, the word “red” written in blue letters).
“We know that word reading is a faster process than color naming,” Dr. Potter said, “and so in this test you have to inhibit word reading to respond with color naming. How much does it cost you in reaction time to perform that inhibitional process?” Dr. Potter found that nicotine, but not methylphenidate, significantly improved performance compared to placebo on this task. Nicotine also improved a memory task while methylphenidate did not, and both drugs improved self-rated irritability.
GOOD DRUG, BAD DELIVERY SYSTEM
Drs. Potter and Newhouse both pointed out that these results, while important, are far from a recommendation to use nicotine for ADHD. This was an acute test, and more chronic use of nicotine has not been examined rigorously in these youths – this is the next step in their research. “If this holds up in chronic administration,” said Dr. Newhouse, “it could suggest that one of the reasons ADHD kids persist in smoking is in part because it may improve their cognitive performance” through increasing inhibitory control.
“It would be reckless to suggest nicotine as a therapy at this point,” Dr. Newhouse said. “We're still trying to ask the question, ‘Does this have something to tell us about why these kids smoke at twice the rate of non-ADHD kids?’” he said. “To develop nicotine as a therapeutic strategy, you would need to show it has the same clinical benefits as methylphenidate, without the down sides.”
Nicotine as adolescents usually take it – in cigarettes – obviously could not be recommended as a treatment. “Our lab's phrase is ‘nicotine: good drug, bad delivery system.’” To date, he has not heard of any cases in which an adolescent has used a nicotine patch specifically for cognitive effects.
Dr. Potter noted that animal experiments are needed to “tease apart” the various mechanisms of the effect they have found, which they suspect involves the dopamine system. “We really want to look at what's happening” within the brain, she said, “because we don't have any idea yet.”
BINGE DRINKING AND STRESS
Animal models are playing a critical role in determining the response of the adolescent brain to alcohol and stress, as well. To examine the effects of binge drinking on the brain, Douglas Matthews, PhD, Associate Professor of Psychology at the University of Memphis, treated male rats every 48 hours from postnatal day 30 to day 50, a time in which the rat brain is undergoing developmental changes similar to those of human adolescents, including widespread synaptogenesis.
He found that this chronic intermittent exposure to alcohol caused significant alteration in gene expression in the hippocampus. Specifically, the levels of one subunit of the GABA-A receptor increased by 82 percent, immediately and 15 days later, after the rats had entered adulthood.
Similar changes had previously been reported in brains of chronic alcohol abusers. Hippocampal pyramidal neurons also changed their firing pattern in response to alcohol exposure. Ethanol inhibits the spontaneous activity of these neurons, but chronic intermittent exposure induced tolerance to ethanol, and firing rates increased. These data “strongly suggest that binge alcohol exposure during adolescence alters the neurobiology of the brain,” Dr. Matthews said, and these changes can be long lasting.
The potentially harmful role of stress in development of the adolescent brain was examined by Susan Andersen, PhD, of McLean Hospital in Belmont, MA. Dr. Andersen housed adolescent rats alone, depriving them of their normal social contacts. She found a significant decrease in hippocampal synaptophysin, an index of the number of neural connections, which is known to rise throughout normal adolescence. The synaptophysin deficit was equivalent to that seen in younger rats deprived of interaction with their mothers.
“Our lab studies the effects of child abuse,” Dr. Andersen said, “and it is pretty well established there is lifelong hippocampal damage” from this abuse. “There is not much research examining the effects of a normal childhood followed by a stressful adolescence. Adolescence represents a critical point, where things that happen early on can really set the rest of the developmental trajectory,” she said. “My animals are not regaining that loss” of neural connection.
A GOOD MODEL OF BIOLOGICAL CHANGES
But how relevant can a rodent model of adolescence be, given the enormous differences in time scale – 20 days versus three or more years – between a rat and a human's adolescence? The best data indicate overproduction and elimination of synapses, and there are receptors that change, as well as other findings in parallel in both species, said Dr. Andersen.
Michelle Ehrlich, MD, agrees. “It's looking more and more like adolescence is biological, in terms of pathways and development,” rather than being a mere social construct, she said. Dr. Ehrlich is Professor of Neurology at Jefferson Medical College of Thomas Jefferson University in Philadelphia, PA. “A mouse is not a rat is not an adolescent human,” she cautioned, “but there are similar anatomic and biologic changes.” Changes are especially significant in the dopaminergic midbrain and its connections to the nucleus acumbens reward pathway, she said, with synapse formation and myelination changing rapidly, affecting the way neurons are communicating. Stress or drug exposure during this period may “redefine the setpoint” for the brain's responses.
Dr. Matthews notes that even in complex behaviors such as addiction, there are strong similarities between rodents and people. “In a room full of humans, some will never become addicted, some will. We see exactly the same thing in rats. Some just don't like cocaine. While you have to be careful about rat-human parallels in adolescence, they seem to match up very well.”
Because of the old notion that “the brain is done” by the end of early childhood, there has been very little research on the brain during adolescence. “It's clearly not done,” he said.
ARTICLE IN BRIEF
✓ Research presented at the last Annual Meeting of the Society for Neuroscience in New Orleans investigated the responses of the adolescent brain to drugs, stress, ADHD, and alcohol.