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Drug and alcohol addictions affect more than 30 million people in the USA and Europe.1 The overall cost of drug abuse and addiction in the USA in 1998 was estimated to be greater than $143 billion; estimates include costs associated with loss of productivity, healthcare costs, and other related expenses including those related to the criminal justice system. Based on these data the projected overall cost of addiction for 2006 may exceed $180 billion.

Addictive behaviors are also associated with gambling, shopping, sexual behavior, and eating, although terming these behaviors 'addictions' remains controversial. Hence these will not be discussed further in this chapter but rather the interested reader is referred to relevant reviews.2-4 Nevertheless, the biochemical bases of all addictive disorders appear to have at least some overlap, as do the hypotheses of addiction. Indeed, the questions asked, and the discoveries made, in drug addiction research may be applied toward a better understanding of these other addictive disorders and may be implemented in treatment strategies to prevent secondary medical consequences of these behaviors, such as obesity in overeating disorder.4'5 A list of terms and definitions used in this chapter can be found in Table 1.6

The definition of addiction has permutated over time, and hypotheses related to manifestation are described in Section 6.07.2. However, one guide for clinicians is the DSM-IV Criteria of Addictions (Table 2). As noted, the

Table 1 Definitions of terms used in drug addiction

Craving (formerly called psychological dependence)

Physical or physiological dependence

Substance abuse

Substance dependence

Withdrawal syndrome

An intense desire to reexperience the effects of a psychoactive substance. Craving is a cause of relapse after long periods of abstinence.

Physical tolerance and the withdrawal syndrome.

Priming New exposure to a formerly abused substance. This exposure can precipitate rapid resumption of abuse at previous levels or at higher levels.

Relapse Resumption of drug-seeking or drug-taking behavior after a period of abstinence. Priming, environmental cues (people, places, or things associated with past drug use), and stress can trigger intense craving and cause a relapse.

Reward A stimulus that the brain interprets as intrinsically positive or as something to be attained.

Sensitization The increase in the expected effect of a drug after repeated administration (e.g., increased locomotor activation after the administration of psychostimulants). Sensitization also refers to persistent hypersensitivity to the effect of a drug in a person with a history of exposure to that drug (or to stress). Sensitization may be one of the neurobiologic mechanisms involved in craving and relapse. Behavior characterized by recurrent and clinically significant adverse consequences related to the repeated use of substances, such as failing to fulfill major role obligations, use of drugs in situations in which it is physically hazardous, occurrence of substance-related legal problems, and continued drug use despite the presence of persistent or recurrent social or interpersonal problems. As defined by The Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM-IV), a cluster of cognitive, behavioral, and physiological symptoms indicating that a person is continuing to use a substance despite having clinically significant substance-related problems. For substance dependence to be diagnosed, at least three of the following must be present: symptoms of tolerance; symptoms of withdrawal; the use of a substance in larger amounts or for longer periods than intended; persistent desire or unsuccessful attempts to reduce or control use; the spending of considerable time in efforts to obtain the substance; a reduction in important social, occupational, or recreational activities because of drug use; and continued use of a substance despite attendant health, social, or economic problems. A constellation of signs and symptoms that follows the abrupt discontinuation or reduction in the use of a substance or after blockage of the actions of a substance with antagonists (e.g., naloxone in heroin addiction). The syndrome can also be produced by cues associated with substance use (conditioned withdrawal). Symptoms tend to be the opposite of those produced after short-term exposure to a drug. Withdrawal is one of the causes of compulsive drug-taking behavior and short-term relapse.

Modified from Table 1 in Cami, J.; Farre, M. N. Engl. J. Med. 2003, 349, 975-986.

Table 2 DSM-IV definition of substance dependence (addiction)

A maladaptive pattern of substance use, leading to clinically significant impairment or distress, as manifested by three (or more) of the following, occurring at any time in the same 12-month period:

1. Tolerance, as defined by either of the following:

(a) A need for markedly increased amounts of the substance to achieve intoxication or desired effect.

(b) Significantly diminished effect with continued use of the same amount of the substance.

2. Withdrawal, as manifested by either of the following:

(a) The characteristic withdrawal syndrome for the substance.

(b) The same (or a closely related) substance is taken to relieve or avoid withdrawal symptoms.

3. The substance is often taken in larger amounts or over a longer period than was intended.

4. There is a persistent desire or unsuccessful efforts to cut down or control substance use.

5. A great deal of time is spent in activities necessary to obtain the substance, use the substance, or recover from its effects.

6. Important social, occupational, or recreational activities are neglected or reduced because of substance use.

7. The substance use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance.

Preoccupation with obtai persistent physical or psychological problem

Spiralling distress

S°c/'ai occupational, or recr& activities compromis

Spiralling distress

Addiction

Figure 1 The addiction cycle. (Reprinted from Koob, G. F.; Le Moal, M. Neuropsychopharmacology 2001, 24, 97-129, with permission from Elsevier.)

occurrence of both tolerance and/or dependence are not described as being crucial to the development of addiction, although they are two of several criteria that are regarded as components of the disorder. Rather, this definition emphasizes the loss of control that develops, such that a person will often ingest larger quantities of drug then intended, persistently seek out the drug, be unsuccessful in reducing drug use, and continue using drugs despite adverse physical, social, occupational, and psychological consequences. In other words, drug addicts can exhibit all these behaviors and not demonstrate measurable tolerance or withdrawal symptoms. Figure 1 illustrates the vicious cycle of addiction, where intoxication leads to withdrawal and negative affective states, which then lead to greater drug use in an attempt to ameliorate the spiraling psychological, and in some cases, physical distress.

Addiction to drugs does not typically develop following a single episode of drug use. Rather, addiction develops over a period of time, evolving from sporadic or intermittent use to regular use, and finally, in vulnerable individuals, to addiction.7 Numerous factors influence vulnerability, including genetic factors (40-60%), environmental factors, such as drug availability, socioeconomic status, poor parental support, and stress, as well as comorbid mental illness.8 Although many of the genetic factors that determine vulnerability to addictions remain to be defined, major advances have been made in understanding the brain mechanisms underlying many of the effects of addictive drugs. In particular, many studies indicate that drugs of abuse, despite the differences in their molecular targets, share in common the ability to activate the mesolimbic dopamine system. With cocaine and amphetamine, this results directly from the release of dopamine (DA) from the nerve dopaminergic terminals in the nucleus accumbens (NAc). Other drugs, such as the opioids, increase the firing rate of DA cell bodies located in the ventral tegmentum area (VTA), which project to the NAc via inhibiting GABAergic interneurons that themselves tonically exert inhibitory effects on DA cell bodies.7 The ability of drugs of abuse to release DA in the NAc underlies the ability of these drugs to support self-administration behavior, which is one way to measure the reinforcing nature of these agents. Natural reinforcers, such as food and sex, also release DA in the NAc, but these do not generally lead to addiction perhaps because natural reinforcers produce elevations in DA that are longer in duration and substantially lower in magnitude, and more discrete in terms of anatomical distribution, than drugs of abuse.8 Chronic treatment of rodents with drugs of abuse, because of their common effect on dopaminergic mechanisms, also produce similar long-term changes in brain function via changes in gene transcription.9 These long-term changes in gene expression are thought to contribute to the progression of occasional drug use to addiction.

The central role of DA and the NAc in mediating the rewarding effects of drugs of abuse should not obscure the fact that nondopaminergic brain neurons and circuits contribute to the development and continuance of addictive behavior. For example, chronic stimulant use produces neuronal deficits in serotonergic function that resemble those observed in major depression,10 supporting the hypothesis that nondopaminergic mechanisms substantially contribute to the development of addiction.11 Moreover, Childress (and others) reports that cocaine craving, triggered by cocaine-related cues, is associated with differential activation of limbic structures of the brain.12 Other studies implicate cocaine-associated changes in the frontal orbital cortex and the cingulate cortex as important contributors to cocaine addiction.13 Indeed, Figure 2 emphasizes the fact that many brain circuits besides the well-studied reward circuitry of rodents contribute to addiction in humans. For example, the loss of frontal lobe volume observed in addicts may contribute to their poor judgment and reduced impulse control.

Drug reinforcement (salience attribution)

Reward oil (anterior o prefrontal

Withdrawal

Bingeing (loss of control)

Craving (drug expectation)

(cingulate gyrus, prefrontal cortex, orbitofrontal cortex)

Memory (hippocampus)

Conditioned response (amygdala)

Reward circuits (ventral tegmental area, nucleus accumbens)

Top-down control (frontal cortex)

Figure 2 Integrative model of brain and behavior.13 (Reprinted from Goldstein, R. Z.; Volkow, N. D. Am. J. Psychiat. 2002, 159, 1642-1652, with permission from the American Journal of Psychiatry (Copyright 2002) American Psychiatric Association.)

Addiction to alcohol, opioids, cocaine, and amphetamines, once considered as primarily a legal, social, and moral problem, has finally been recognized as a chronic brain disorder/disease with potentially treatable solutions.1 The combination of pharmacotherapy and psychosocial intervention provides the basis of addiction recovery. However, a clearer understanding of biochemical bases of drug addiction and relapse is required in order to identify targeted and effective treatment strategies. The severe medical consequences of drug abuse and addiction result from neurobehavioral modifications due to chronic drug use. In addition, secondary diseases such as human immunodeficiency virus-acquired immunodeficiency syndrome (HIV-AIDS) or hepatitis B from needle sharing, chronic liver disease from alcohol abuse, and lung cancer from smoking are just a few examples of long-term health problems associated with addiction. As addiction is a compulsive behavioral disorder that is not curbed by negative consequences, the demise of family connections, and loss of employment and income ensures that an addict will continue seeking and taking drugs. Current treatment modalities are discussed in Section 6.07.5. However, the hypotheses addressing the transition from casual drug use to addiction are instructive in order to understand the biochemical processes involved in this disorder and then to further target mechanistically based pharmacotherapies. A list of the primary drugs of abuse that can lead to addiction can be found in Table 3 and their chemical structures are depicted in Figure 3.

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