2002), and chronic alcoholics show a similar finding (Lingford-Hughes et al., 1998). These differences in the brain's executive inhibitory circuitry might explain why substance abusers find it so difficult to inhibit or manage their cravings for drugs. Glutamate-enhancing drugs, such as modafinil, might ultimately play a role in bolstering prefrontal function (Dackis & O'Brien, 2003a).

As with some of the previously discussed findings, it is not possible to tell from a cross-sectional imaging study of addicted adults whether an observed brain difference predates the long history of drug use or whether it reflects the impact of long-term drug exposure. Studies with primates do show that chronic exposure to stimulants can undermine frontal inhibitory functions (Jentsch, Olaussen, De La Garza, & Taylor, 2002), which may help explain the poor frontal function in some human cocaine users. But the primate findings do not preclude the possibility that adolescents with poorer frontal function may be at early risk for making poor choices regarding drug experimentation or other risky behaviors. Such adolescents would be very poorly equipped for handling the motivational significance of drug and drug cues. Consistent with this latter notion, childhood psychiatric disorders such as ADHD and conduct disorder are risk factors for adolescent substance abuse (Biederman, Wilens, Mick, Spencer, & Faraone, 1999; Wilens, Faraone, Biederman, & Gunawardene, 2003), and both these disorders are associated with frontal deficiencies (Biederman et al., 1999). Even children who fail to meet the full clinical criteria for ADHD or conduct disorder may have some degree of frontal impairment that would increase their risk for managing the pull of rewarding drugs and their associated cues. The neurological basis of adolescent vulnerability is reviewed in more detail by Chambers, Taylor, and Potenza (2003).

Although addiction has a very long human history, we have only recently acquired the technology to measure alterations in the living human brain that contribute to addiction vul nerability. Within the past two decades, human brain imaging techniques have revolutionized the field of psychiatric and neurological research, allowing us to visualize both the structure and the function of living human brains. Imaging research has also begun to identify differences in the reward and executive inhibitory brain systems of addicted individuals that may be critical in addiction vulnerability.

Most of the brain imaging research in addiction has been conducted with addicted adults, posing a difficulty in applying these findings to the adolescent brain. For instance, which of the brain differences observed in adults may have existed in childhood and adolescence, as a vulnerability that predated and perhaps even predisposed the person to drug addiction? Alternatively, which brain differences in the addicted adult brain result from years of exposure to the drug of abuse? Imaging studies at only one time point in adulthood have trouble answering this important “chicken-or-the-egg” question. Imaging studies in adolescents who are at risk for drug use but have not yet begun to use the drug will be critical in analyzing the findings in adult brains. The approach in this overview is to highlight several recent findings from brain imaging in addicted adults that may provide clues about the vulnerability to addiction in adolescence. Using the framework of reward and inhibition, this overview will also identify gaps in our current knowledge and potential implications of the brain findings for treatment and prevention.

A large body of neuroscience research, only partially reviewed in this section, supports the notion that addiction is a disease that disrupts brain pleasure centers, including the extended amygdala and its numerous connections with other reward-related systems. Neurobiological research has provided an understanding of brain mechanisms that can guide medication development and potentially improve outcome. While the anatomy and circuitry of reward neurocircuits have been largely delineated, we know little about molecular changes within these regions that mediate the transition into addiction, enhance relapse vulnerability, and produce hedonic dysregulation. Nevertheless, the disease concept of addiction is supported by its strong biological basis, which is conclusively demonstrated by several lines of animal and human research. Although addictive drugs produce pleasure by activating brain reward circuits, their long-term effect is to inhibit these regions, leading to hedonic dysregulation and unpleasant emotional states. The short-term fix of more drug use provides temporary relief but then merely worsens this vicious cycle. Animal models of addiction have identified specific neurochemical alterations in reward-related and stress-related systems that contribute to dysphoric motivational states associated with drug abstinence, and the pharmacological reversal of these neuroadaptations is a promising strategy to improve outcome in clinical practice. Human studies likewise demonstrate functional and structural brain abnormalities associated with addiction, especially in the prefrontal cortex and amygdala, although the issue of causality has not been adequately addressed. Are these abnormalities produced by repeated drug administration, or do they predate and even contribute to addictive vulnerability? Can they be normalized with abstinence or through specific interventions? Will brain abnormalities identified through imaging techniques eventually serve to identify individuals who are most at risk of developing addiction? The issue of vulnerability is particularly important to identify adolescents who might benefit from specific interventions, be they preventive or therapeutic. Unfortunately, prodigious gaps exist in our knowledge of the neurobiology of addiction in adolescents, which represents an important area for future re-search.

Research using both animal and human models is advancing our understanding of the role of genetic factors in substance use. Animal models of drug addiction can manipulate genetic factors through selective breeding or “knock-outs” (mice that are lacking a critical gene) to explore general and specific genetic effects on behavioral responses to drugs and propensity to self-administer drugs. As reviewed by Ponomarev and Crabbe (2002), this line of research has generated important knowledge about the role of genetic factors in initial sensitivity to drugs, neuroadaptive changes from chronic exposure, withdrawal syndromes, and reinforcing effects. Of particular relevance to adolescent substance use, animal research is elucidating how the adolescent brain may be especially vulnerable to the stimulating effects of both novel environment and drugs of abuse (Laviola, Adriani, Terranova, & Gerra, 1999). This work suggests that adolescence is a critical period during which exposure to drugs may interfere with more adap