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Interaction of genes and environment

alcohol, or other drugs*is a strong developmental marker for progression to polysubstance use, as well as eventual abuse (maladaptive patterns of use) and dependence (persis- tence of use despite problems).

Second, early-onset substance use also conveys risk for

other poor outcomes in adolescence and adulthood beyond the development of substance use disorders. Odgers et al14 reported that exposure to alcohol and illicit substances in early adolescence is associated with a range of negative developmental events including early pregnancy, herpes infection, and crime. A key contribution of this paper was to demonstrate that these associations hold even after accounting for history of conduct problems. For example, they reported that nearly half of those studied who experi- enced early exposure to substances did not have a history of conduct problems, and yet were at heightened risk for the developmental and health risks noted above.

Third, recent conceptual papers have argued that early exposure to substances may have profound adverse effects on brain development in adolescence that potentiate the risk for dependence. For example, there is increasing recognition that alcohol use in adolescents may have potentially toxic effects on brain plasticity and maturational processes including differentially shaping reward centers via dopaminergic re- sponsivity, resultant cascading effects on the circuitry under- lying addictive tendencies, and impact of stress-related hormonal production.4,1517 Thus, from the neurobiological perspective, early-onset use may influence the likelihood of eventual dependence.

Fourth, recent longitudinal studies have illuminated that early-onset substance use is associated with rapid escalation of use.18 For example, Wittchen et al have shown that first alcohol or nicotine use occurring between 10 and 16 years of age leads to a high risk of transition to regular substance use and substance use disorders in the first 3 years of onset. These authors thus suggest that ‘‘the time windows for targeted intervention to prevent progression to malignant patterns in adolescence are critically small’’ (p. S16).

Taken together, current empirical and conceptual thinking supports the need for intervention targeted at youth who have initiated substance use at an early age. In particular, we propose that focusing on adolescents in middle school provides a strong opportunity to permit the most efficacious use of targeted intervention before the rapid transitions to more problematic use occur.


on to progress to eventual abuse and dependence? No. Prospective studies show that there are separable trajectories, such that a number of youth either stop using substances or escalate only into sporadic or nonproblematic use. The 51

intervention perspective is, in principle, most concerned with adolescents who will progress to later abuse and dependence*but how exactly can these youth be teased apart from the majority that will not suffer from eventual substance use issues?

One focus has been to examine indicators of subjective

reactivity to initial use*work conducted on tobacco use serves to illustrate the principle. Adolescents vary in their subjective reactions to their first puff, and puffs, of a cigarette. Some say that they don’t react much at all. Some report very strong negative reactions (eg, coughing, nausea, etc.). And some will tell you that they had immediate positive reactions (eg, relaxation, a ‘‘buzz’’). As you might expect, youth with initial positive reactions to a cigarette might be particularly sensitive to the reward properties of nicotine and at risk not only to continue to try smoking but rapid escalation to higher levels of use, and there is certainly evidence in the literature that this is so.19

There has also been somewhat controversial work done over

the past decade that suggests that these initial reactions to cigarettes may be the first signals of nicotine dependence. The conventional wisdom about nicotine dependence was that it was an eventual consequence of years of smoking for some individuals, and it would not be expressed until adulthood. As a result, symptoms of dependence were traditionally not measured in smoking studies unless the participants were adults. However, more recent studies that have measured symptoms of dependence do find that adolescents endorse symptoms even before they have devel- oped a pattern of regular use. The provocative finding has been that some adolescents can report symptoms of depen- dence even after their first puff of a cigarette and certainly with low levels of smoking.2022 The overall point is that some adolescents may be at differentially high risk for responding physiologically to the addictive properties of substances, and as such there is an urgency to attempt to intervene early enough to try to curb their progression to higher and more problematic use. Given this, I turn to genetically informative studies, which are designed to elucidate how environmental and genetic factors come together to either buffer or promote risk for substance use and progression to higher and more problematic levels of use.

The empirical yield from genetically-informative studies There have been numerous studies of adolescent substance

use using genetically informative designs. Most of these have relied upon the classical twin method that compares identical and fraternal twins. Some have included expansions of this design to incorporate nontwin biological siblings, as well as half-siblings, and biologically unrelated siblings. A number of studies have included retrospective reports of adolescent use by adults; that said, there are also a number of prospective studies of adolescents that directly measure adolescent use. These studies have been conducted not just with samples of adolescents in the United States, but include

M&B 2011; 2:(1). July 2011

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