A number of recent reports underscore how much various drugs and stress can cause lasting changes to brains, and particularly to younger brains that are still developing. Adolescent brains even appear to be more vulnerable in some cases than younger brains. First off, here is a report on stress-induced permanent changes to the hippocampus.

Studies by Susan Andersen, PhD, of McLean Hospital in Belmont, Mass., and colleagues show that stressful events experienced during adolescence can lead to enduring changes in brain structure in adulthood. This work is the first to demonstrate that exposure to a significant stress during adolescence can impact neuronal connections in the adult brain.

The researchers found that adult rats exposed to a social stress during adolescence (ages approximating 13 to 15 years in humans) showed a significant decrease in a specific protein found in the hippocampus, a brain region important for learning and memory. In fact, the loss of this protein, synaptophysin, is at least as great as that occurring in animals exposed to more severe stressors at a younger age, suggesting that adolescents may be more vulnerable to the effects of stress than younger animals.

Under typical conditions, synaptophysin, which is often used as an index of the number of neuronal connections, or synapses, reaches a peak during young adulthood (approximately ages 18 to 20), with the rise occurring primarily during adolescence. The team tested whether a social stress during this key developmental period might alter this pattern. A control group of rats was housed with their peers, and an experimental group of rats was housed individually during adolescence; individual housing in normally social animals such as rats is a stressful experience. The brains of both groups were then examined during young adulthood. The team found that rats exposed to the social stressor did not show the normal increase in synaptophysin during this period. These data suggest that social stress during adolescence causes either a loss of synapses or a decrease in the synaptophysin protein.

The researchers then compared the loss of synaptophysin in rats that were stressed during adolescence with rats that experienced significant stress during ages comparable to childhood. The stressor used for this age group was repeated maternal separation (RMS). The scientists found no significant difference in synaptic density between rats that had social stress during adolescence or rats that had early RMS. However, the density of synapses in the hippocampus of both groups was reduced significantly when compared with control rats.

These findings are the first to demonstrate that exposure to a significant stress during adolescence can have enduring consequences on the connections formed in the hippocampus in adulthood. These data may suggest why early traumatic stress, such as physical or sexual abuse or neglect, is associated with a decrease in the size of the hippocampus in adulthood.

“These preclinical data suggest that stress experienced early in life alters the normal developmental trajectory of the hippocampus, but that these changes are not apparent until later in life,” says Andersen.

Adolescent brains undergo a great amount of change and therefore anything that interferes with development during that stage has the potential of creating lasting impacts on cognitive function. See the previous post Adolescence Is Tough On The Brain for reports on some of the changes that happen in adolescence.

So what to do about stress causing harmful effects on the brain? Picture at some point in the future nanotech sensors injected into a child's body to provide Mom and Dad with a daily report of whether the kid is feeling enough stress for it to have a harmful effect on cognitive development. If that happens the kid will be put in stress-dampening drugs in order to protect the brain. Sound far-fetched? Sensors will eventually become sensitive enough, small enough, and sufficiently long lasting for that part of this scenario to work. A sensor reader could be mounted on the front door or perhaps in internal house rooms with the sensor data getting routed to the house computer. As Amy Arnsten explains in the following article, drugs with the desired effects already exist.

Amy F.T. Arnsten wrote an interesting article a few years ago in J Am Acad Child Adolesc Psychiatry that explains a different mechanism by which stress causes the result of catecholamines which produce temporary or even permanent changes to the prefrontal cortex.

Animals or humans with lesions to the PFC exhibit poor attention regulation, disorganized and impulsive behavior, and hyperactivity. Recent research in animals indicates that exposure to stress can produce a functional “lesion” of the PFC. During stress exposure, catecholamines are released in both the peripheral and central nervous systems. In the periphery, the catecholamines norepinephrine and epinephrine are released from the sympathetic nervous system and adrenal gland, respectively. These catecholamine actions serve to “turn on” our heart and muscles and “turn off” the stomach to prepare for fight-or-flight responses during stress.

In the brain, high levels of the catecholamines dopamine and norepinephrine are released in the PFC during stress exposure, even during relatively mild psychological stress. As basal levels of dopamine and norepinephrine have essential beneficial influences on PFC function, it was originally presumed that high levels of catecholamine release during stress might facilitate PFC function. However, research in monkeys and rats demonstrated the contrary: exposure to stress impairs the working memory functions of the PFC.

If you read Arnsten's full article you will see where she talks about drugs that can prevent the damage caused by catecholamines released during stress. Keep that in mind when reading below how nicotine can provide the brain with protection against stress. Nicotine, being an addictive drug that also causes other and perhaps undesireable changes to the brain, is far from the ideal compound to use for stress protection. But it does point the way toward the development of compounds that would provide stress protection without the various harmful side-effects caused by nicotine.

Nicotine causes changes in fetal brains.

The children of women who smoke during pregnancy have been found to be at greater risk for a wide variety of emotional and behavioral disorders, such as attention deficit hyperactivity disorder (ADHD) and conduct disorder. Now, new animal studies from the Yale University School of Medicine demonstrate that the effects of developmental nicotine on emotional learning last into adulthood.

“If we can identify the mechanism for this long-term behavioral change, we may be able to develop new therapies for human emotional disorders that are linked to prenatal nicotine exposure,” says Sarah King, PhD.

For their most recent study, King and her colleague, Marina Picciotto, PhD, used an animal model of emotional learning known as passive avoidance. This model measures how long an animal avoids a dark chamber in which it had previously received a mild electric shock. King and Picciotto found that nicotine-treated mice showed a hypersensitive response and avoided the dark compartment longer than non-exposed mice.

This response was identical to one the researchers had reported on previously (Journal of Neuroscience, May 2003) in genetically altered mice that lack high affinity nicotine receptors as a result of a knockout mutation. “We believe that nicotine exposure during development— the same kind of exposure that occurs in mothers who smoke during pregnancy — disrupts normal nicotine receptor activity, much like the knockout mutation, and that this leads to altered emotional learning in adulthood,” says King.

King and Picciotto have also identified a novel brain circuit — glutamate neurons, which originate in the cortex and project to the thalamus (corticothalmic neurons) — as the likely site where changes occur in the brain during early nicotine exposure. They are currently working to identify the molecular changes that developmental exposure to nicotine triggers in the corticothalamic neurons.

Each year, about 2 million teenagers become regular smokers, according to the American Lung Association. Because the brain continues to develop during adolescence — and beyond — scientists at George Mason University decided to investigate the effect that exposure to nicotine during adolescence has on later behavioral functioning. The researchers implanted 46 rats with small minipumps that dispensed either 3 or 6 mg of nicotine per kilogram of body weight per day — or no nicotine at all (controls). When the animals reached adulthood, they were tested for spatial learning and memory.

Nicotine made a significant difference in the animals’ performance in the tests. Low and high doses of nicotine altered behavior in opposite directions: The low-dose group tended to learn faster and the high-dose group tended to learn slower than the control animals. “Whether performance improved or declined is probably less important than the demonstration that nicotine does produce long-lasting changes in the animals’ performance, presumably reflecting long-lasting effects on brain development,” says Robert Smith, PhD.

Although this research was done in rats, the processes of brain development are similar in humans, which leads Smith to believe that teenagers who smoke aren’t risking only addiction, but also lasting changes in the development of their brains. Smith and his colleagues are now examining the genetic mechanisms that are involved in producing this lasting change in behavior.

During times of stress, smokers tend to increase the number of cigarettes they light up — perhaps as a form of self-medication to counteract the harmful effects of stress on the brain. Stress, which may range from mild anxiety to posttraumatic stress disorder, has been shown to impair normal brain function, including learning and memory.

Researchers in the laboratories of Karim Alkadhi, PhD, at the University of Houston College of Pharmacy recently studied the effect of nicotine on stress-induced memory impairment in rats. They found that when stressed animals were given nicotine, they performed significantly better at short-term memory tests than stressed animals not given the chemical. In fact, the nicotine-treated stressed animals performed the same as unstressed (control) animals.

“Our findings are important to the understanding of the mechanism by which nicotine repairs stress-damaged brain function,” says Abdulaziz Aleisa, a doctoral student at UH. “This research may eventually help in the designing of new, safe approaches to the treatment of Alzheimer’s and Parkinson’s diseases — approaches that mimic the beneficial effect of nicotine on stress.”

Before you start thinking that nicotine would be great to give to adolescents to learn more quickly check out an previous post: Early Nicotine Exposure Increases Nicotine Craving. Nicotine is one of many addictive drugs which cause problems. See also: Adolescent Mice More Sensitive To Addictive Drugs.

Also, note the opposite effects of the lower and higher nicotine doses on speed of learning. The brain is a finely balanced device. Likely some day it will become possible to use drugs to guide brain development to improve long-term memory and other cognitive abilities. But there are more ways to go wrong than to go right with this kind of intervention and at this point there are no clear safe ways to try to guide brain development to yield some desired outcome.

Not all drug use during adolescence primes the brain to want more drugs later in life. The same Susan Andersen mentioned above has previously found evidence that Ritalin given to juveniles may decrease their desire for cocaine later in life.

December 2, 2001 -- Belmont, MA -- Exposure to Ritalin early in life may make one less vulnerable to the allure of cocaine later, according to a new report by McLean researchers. Susan Andersen, PhD, William Carlezon, PhD, and their colleagues found adult rats that were given Ritalin as juveniles spent less time seeking out cocaine than did their Ritalin-free peers. Moreover, in some cases, the rats appeared to actively avoid places where they had been exposed to cocaine in the past.

The findings, which appear in the Dec. 3 online version of Nature Neuroscience, could help resolve several controversies surrounding the use of Ritalin, or methylphenidate, a stimulant prescribed for children who have an abnormally high level of activity or attention deficit hyperactivity disorder (ADHD).

Also see a more recent report on Ritalin's effect on long term drug and alcohol use: Ritalin For Children Reduces Later Alcohol and Drug Abuse.