The Neurobiology of Substance Dependence

Implications for Treatment

THOMAS R. KOSTEN TONY P. GEORGE HERBERT D. KLEBER

Tolerance, dependence, and addiction are all manifestations of brain changes resulting from chronic substance abuse and involve different brain pathways than those subserving acute drug reinforcement. Acute drug reinforcement appears to share a final common dopaminergic pathway from the ventral tegmental area of the brain to the nucleus accumbens. These acute processes are relatively unimportant for pharmacotherapy of dependence and addiction; instead, the neurobiology of changes associated with chronic use forms the basis for rational pharmacotherapy. This translation of neurobiology into effective treatments has been most successful for opioids, with more limited success for alcohol, nicotine, and stimulant dependence. Opioid treatments such as metha-done, levo-alpha-acetyl methadol (LAAM), buprenorphine, and naltrexone act on the same brain structures and processes as addictive opioids, but with protective or normalizing effects. This concept of normalization is critical for effective treatments and is illustrated in this chapter, with opioids as the primary example. As we understand the molecular biology of dependence more fully, normalization appears to be a process very similar to learning and may involve similar changes in gene activation and neuronal long-term potentiation (LTP) and long-term depression (LTD) that appear to underlie learned behaviors and emotional states.

While the individual patient, rather than his or her disease, is the appropriate focus of treatment for substance abuse, an understanding of the neurobiology of dependence and addiction can clarify the rationales for treatment methods and goals. Patients who are informed about the brain origins of addiction also can benefit from understanding that their addiction has a biological basis and does not mean that they are "bad" people.

Brain abnormalities resulting from chronic use of nicotine, stimulants, opioids, alcohol, hallucinogens, inhalants, cannabis, and many other abused substances are underlying causes of dependence (the need to keep taking drugs to avoid a withdrawal syndrome) and addiction (intense drug craving and compulsive use). Most of the abnormalities associated with dependence resolve after detoxification, within days or weeks after the substance use stops. The abnormalities that produce addiction, however, are more wide-ranging, complex, and long-lasting. They may involve an interaction of environmental effects—for example, stress, the social context of initial opiate use, and psychological conditioning—and a genetic predisposition in the form of brain pathways that were abnormal even before the first dose of opioid was taken. Such abnormalities can produce craving that leads to relapse months or years after the individual is no longer opioid-dependent.

In this chapter we describe how drugs affect brain processes to produce drug liking, tolerance, dependence, and addiction. Although these processes are highly complex, like everything that happens in the brain, we try to explain them in terms that can be understood by patients. We also discuss the treatment implications of these concepts. Pharmacological therapy directly offsets or reverses some of the brain changes associated with dependence and addiction, greatly enhancing the effectiveness of behavioral therapies. Although researchers do not yet have a comprehensive understanding about how these medications work, it is clear that they often renormalize brain abnormalities that have been induced by chronic, high-dose abuse of various substances.

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