Long-term effects of alcohol abuse during adolescence
        In addition to reacting differently to the acute, or initial, effects of alcohol, it appears that adolescents are also affected differently than adults by repeated, heavy drinking. Many adolescents engage in a pattern of chronic intermittent exposure (CIE) sometimes referred to as binge drinking. Chronic intermittent exposure is a special case of chronic alcohol administration that involves discrete, repeated withdrawals. There is compelling evidence that it is the repeated withdrawals from alcohol that are responsible for many of the CNS effects of chronic alcohol exposure. For example, in laboratory animals, repeated withdrawals from alcohol result in a higher rate of seizures during withdrawal than are observed after continuous exposure of the same duration (Becker and Hale, 1993). The association of repeated withdrawals with withdrawal seizure susceptibility is also indicated in humans. In studies of alcohol detoxification, patients with a history of previous detoxifications were more likely to exhibit seizures during withdrawal (Brown et al, 1988). Although these data from human studies are correlational, the convergence of these findings with those from animal models strongly suggests that discrete, repeated withdrawals from alcohol exposure presents a unique risk for subsequent neurobehavioral impairments.
       There is mounting evidence that repeated exposure to alcohol during adolescence leads to long-lasting deficits in cognitive abilities, including learning and memory, in humans. Much of this work has been pioneered by Drs. Susan Tapert and Sandra Brown, alcohol researchers at the University of California , San Diego (UCSD). Drs. Tapert and Brown have conducted a series of studies examining the impact of alcohol abuse on neuropsychological functioning in adolescents and young adults. In one such study (Brown et al., 2000), adolescents in an in-patient substance abuse treatment program, at least three weeks sober, were compared to controls from the community on a battery of neuropsychological tests. Ages ranged from 15-16. Frequent drinkers (100 or more total drinking sessions), particularly those that had experienced alcohol withdrawal, performed more poorly than controls on several tests, including tests of learning, memory, and visuospatial functioning.
       In a longitudinal study of subjects recruited from treatment programs (ages 13-19), Dr. Tapert and her colleagues observed that a return to drinking after the program led to further decline in cognitive abilities, particularly in tests of attention, over the next four years (Tapert et al., 1999). Once again, withdrawal from alcohol was a powerful predictor of such impairments. Similarly, Tapert and colleagues (2002) assessed neuropsychological functioning and substance use involvement at seven time points during an eight year period in subjects beginning, on average, at the age of 16 and ending at 24. Many of the subjects were initially assessed while in treatment and then tracked after their stay in the facility ended. Others were recruited from the community and then followed during the eight year period. Cumulative levels of substance use, including alcohol use, were correlated with impairments in verbal learning and memory during the final assessment. That is, the heavier one was involved in substance use during adolescence, the lower their scores on tests of learning and memory at year eight, when subjects were in their early twenties. Heavier drinking alone was associated with lower scores on tests of attention, and experiencing withdrawal symptoms from alcohol predicted additional deficits in visuospatial abilities. These studies suggest that heavy use of alcohol and other drugs during the teenage years predicts lower scores on test of memory and attention when one is in their early-mid twenties.
       Research by Dr. Tapert and her colleagues clearly suggests that alcohol use during the teen years, particularly when such use is heavy enough to result in withdrawal symptoms upon cessation of drinking, negatively impacts memory and attention, abilities necessary for negotiating the tasks of adolescence and successfully making the transition into adulthood. These impairments presumably stem from changes in brain function, and that is exactly what additional projects by Tapert and Brown have observed. The authors have conducted several studies employing fMRI to investigate changes in brain activity following alcohol abuse during the teen years. While MRI is used to create images of the anatomy of the brain, fMRI is used to measure changes in oxygen levels in the brain over time, like while subjects perform different tasks. The changes in oxygen levels are used to measure, indirectly, changes in brain activity. In one study on this topic (Tapert et al., 2001), alcohol-dependent young women and healthy controls between the ages of 18-25 performed tests of working memory and vigilance (attention) while brain oxygen levels were measured using fMRI. The sample sizes were not quite big enough to detect significant impairments in working memory, though a clear trend toward such impairments was observed. However, alcohol-dependent subjects exhibited significantly less brain activity while performing the working memory task. Weaker activity was observed in several parts of the frontal lobes and in the parietal lobes. Alcohol-dependent subjects performed just fine during the vigilance task, and their brain activation during the task appeared normal. Such data suggest that the trend toward impaired working memory and the week brain activity that went with it can not simply be explained by lack of interest or motivation on the part of the subject.
       A subsequent study with alcohol-dependent young women showed that alcohol-related cues (e.g., words associated with drinking) elicited craving and led to greater increases in brain activity in a variety of regions relative to controls (Tapert et al., 2004), thus establishing a link between craving for alcohol and brain function in key areas and indicating that the brains of alcohol-dependent young women function differently than their peers.

       As discussed previously, 15-16 year olds in in-patient treatment for alcohol-dependence perform more poorly on test of memory and attention than healthy control subjects from the surrounding community. The image above shows representative brain images from such subjects. Details regarding the image can be found in the caption. This image appeared in an information sheet from the Society for Neuroscience entitled, Brain Briefings: Brains on Alcohol . Additional images based on Tapert's and Brown's research can be found on the Alcohol Policy Solutions website.        
        Research with human adolescents clearly suggests that alcohol abuse during the teen years has deleterious effects. For obvious legal and ethical reasons, there are limits to the amount of control a researcher can exert on the variables that might impact the magnitude of the adolescent's impairments or the time course of the recovery. Many researchers have turned to rodents to address these issues. In one of our recent studies, we observed what we believe is a striking, long-term effect of developmental alcohol exposure in rats (White et al, 2002c). We found that CIE treatment (5.0 g/kg IP, every 48 hrs for 20 days) during adolescence interferes with the normal increase in sensitivity to alcohol-induced motor impairments that occurs between adolescence and adulthood. As expected, under control conditions (i.e. repeated saline exposure), rats were more sensitive to the effects of alcohol on postnatal day 65 (young adulthood) then they had been on postnatal day 30 (adolescence). This is consistent with the previous reports that rats become more sensitive to the motor impairing effects of alcohol as they progress from adolescence to adulthood (White et al., 2002b). However, animals that received CIE during adolescence did not show the normal pattern of increased sensitivity to alcohol as they aged into adulthood. In these subjects, the impact of acute alcohol on motor coordination remained unchanged before, two days after, and 16 days after CIE treatment. In contrast to the effects of CIE in adolescents, CIE treatment during adulthood had little impact on the subsequent effects of alcohol on motor coordination. This suggests the possibility that the chronic exposure during adolescence may have "locked in" the adolescent insensitivity to alcohol's sedative effects, or at least significantly delayed the normal progression to greater sensitivity in adulthood. The data raise the distinct possibility that repeated exposure to alcohol during adolescence might alter the normal trajectory of brain development in long-lasting, perhaps permanent, ways.

        Long-lasting cognitive deficits have also been observed in rodents exposed to alcohol repeatedly during adolescence. For instance, our preliminary data indicate that CIE treatment in adolescent rats results in exacerbated alcohol-induced learning deficits in adulthood (White et al, 2000). Adolescent and adult subjects were treated with CIE (5.0 g/kg, IP every 48 hrs for 20 days) and then trained on a spatial memory task. All subjects acquired the task at similar rates. However, when their memory was tested under acute alcohol (1.5 g/kg), subjects treated with CIE during adolescence performed more poorly than the other groups. This finding is consistent with a recent report on the impact of alcohol on memory in college students. Weissenborn and Duka (2003) assessed the impact of acute alcohol exposure on memory in college students. Those with a history of binge-pattern drinking performed more poorly while intoxicated than other subjects.
        Cognitive impairments following repeated alcohol exposure and withdrawal may stem from neurotoxicity in the hippocampus and related structures. Crews et al. (2000) reported that adolescent rats exposed to alcohol in a four-day binge pattern suffer extensive brain damage that includes structures that provide the hippocampus with the information that it needs to form memories. This damage was more extensive in adolescent subjects than in adults exposed to alcohol in the same pattern. A study by De Bellis et al. (2000) provides preliminary evidence that, in humans, alcohol abuse during adolescence is associated with a reduction in the volume of the hippocampus. The authors utilized magnetic resonance imagine (MRI) to assess the size of the hippocampus in subjects with adolescent-onset alcohol use disorders and in normal control subjects. Hippocampal volumes were smaller in those who abused alcohol during adolescence, and the amount of apparent hippocampal damage increased as the number of years of alcohol abuse increased (i.e., the longer one abused alcohol, the smaller the hippocampus became). Total intracranial, cortical gray and white matter, corpus callosum and amygdala volumes did not differ between groups. Such data suggest that the adolescent hippocampus is sensitive to the neurotoxic effects of alcohol, and that the earlier in adolescence one begins abusing alcohol, the greater the risk for producing hippocampal damage. However, whether adolescents are truly more vulnerable than adults to hippocampal damage following alcohol exposure remains to be seen.
       Damage to the hippocampus following repeated alcohol exposure might stem from too much activity at the NMDA receptor, a particular type of receptor for the neurotransmitter glutamate, during alcohol withdrawal. Too much activity at these receptors could allow intracellular levels of calcium (Ca2+) to become too high, which can damage and even kill a cell. Evidence for this remains indirect, but such an effect is certainly feasible based on research examining the impact of alcohol on NMDA receptor activity in slices of brain and cultured neurons (Grant et al, 1990; Hoffman and Tabakoff, 1994; Snell et al, 1993; Crews and Chandler, 1993). 
       While the long-lasting effects of alcohol abuse during adolescence might reflect brain damage in the traditional sense, there is certainly reason to believe that such effects might also involve alterations in normal brain development. As discussed above, the adolescent brain is a brain in flux. There are a number of important changes taking place during this stage of development. It is possible that alcohol, and other drugs, alters the course of brain development in a way that might be hard to correct if the abuse persists throughout the adolescence period. Such changes would clearly be considered "damage", but not in the traditional sense of the word (i.e., this type of damage could occur without the death of a single cell).