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388 REVERSIBLE DISORDERS OF BRAIN DEVELOPMENTChapter 17Brain Development as a VulnerabilityFactor in the Etiology of SubstanceAbuse and AddictionCharles P. O’BrienSubstance Abuse and AddictionThe concept of addiction as a brain disease has had a major impact on understandingand treating patients with this disorder. Abraham Wikler was the first to recognizethat addiction was fundamentally a learned response. His pioneering animalexperiments showed that removal of the drugs from the body did not eliminatethe conditioned reflexes that had been developed over years of drug use (Wikler,1965). Studies in human subjects demonstrated that the effects of drugs could beconditioned and that craving and withdrawal symptoms reported by drug freeaddicts when they were exposed to drug associated cues followed the laws of classicalconditioning (C. P. O’Brien, Greenstein, Ternes, McLellan, & Grabowski,1979; C. P. O’Brien, Testa, O’Brien, Brady, & Wells, 1977). More recently, theseconditioned, involuntary responses were found to have consistent representationin the brain (Childress et al., 1999) and changes in brain receptors accompaniedthese long-term behavioral effects (Volkow, Fowler, & Wang, 2004).The vast majority of substance abusers begin their drug use prior to the age of25 and most prior to age 21 (figure 17-1; Wagner & Anthony, 2002). Thus adolescenceis a critical period for the development of abuse and addiction. This appliesboth to legal drugs, such as nicotine and alcohol, and illegal drugs, such asmarijuana, cocaine, heroin, and methamphetamine. The Monitoring the Future388