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DSM-IV-TR defines 11 classes of commonly abused substances (see 6.07 Addiction). These include alcohol, amphetamine and amphetamine-like compounds, caffeine, cannabis, hallucinogens, inhalants, nicotine, opioids, phencyclidine, and the class of drugs defined as sedatives, hypnotics, or anxiolytics. Substance dependence is defined as a pattern of repeated self-administration that can result in tolerance, withdrawal, or compulsive drug-taking behavior, and has as a basis an anhedonia, the inability to gain pleasure from normally pleasurable experiences. Tolerance is evident as either a need for increased amount of substance to produce a desired effect, or the diminished effect of the same dose of substance over time. All substances of abuse produce tolerance, but the actual degree of tolerance varies across classes. Withdrawal involves maladaptive physiological changes that occur with declining drug concentrations. These changes tend to be unpleasant and produce cognitive and behavioral consequences that lead the individual to seek to maintain a constant dosing regimen. This can lead to compulsive drug-taking behavior that can include the individual taking large amounts of drug over a long period of time, spending significant amounts of time seeking a supply of substance, a reduction in time spent in social, occupational, or recreational activities, and an inability to stop or decrease drug use despite frequent attempts. This leads a situation of hedonic dysregulation with associated hypofrontality, a decrease in prefrontal cortex function, and cell loss and remodeling.

Statistics compiled by the National Institute on Drug Abuse (NIDA) indicate that the prevalence of substance abuse and the cost of this disorder are considerable. In 1994, an estimated 9.4% of the US population was involved in substance abuse. Since most of the drugs of abuse are illegal, prevalence estimates often come from either treatment program data or an assessment of the incarcerated population. In 2003, 1.7 million people were admitted to publicly funded treatment programs. A survey of 14 major metropolitan areas between 2000 and 2002 found that 27-49% of male arrestees tested positive for cocaine. Substance abuse is also surprisingly common in school-aged children, with 2004 estimates of 8.4% of 8th-graders reporting illicit drug use during the last 30 days, a number that rises to 23% in the 12th grade population. The cost to society is estimated to be in excess of $320 billion annually with significant amounts going directly to healthcare costs and law enforcement. Additionally, a large proportion of healthcare costs are due to medical complications associated with the substance abuse. For example, intravenous drug use is the major vector for transmission of human immunodeficiency virus (HIV), accounting for one-third of all acquired immune deficiency syndrome (AIDS) cases, and is reaching epidemic proportions.13

Current approved treatments for substance abuse are directed at decreasing craving and preventing relapse. These include methadone and buprenorphine treatment for heroin addiction, and naltrexone for the treatment of alcohol abuse. Currently no drug is approved for the treatment of cocaine addiction, although several, including disulfiram and modafinil, have shown promise in randomized control trials. Notably, none of these compounds was developed for their potential to treat substance abuse. This stems in part from the persistent and ill-informed prejudice that addicts use compounds like methadone as a surrogate 'crutch.' It is clearly evident from the current statistics that substance abuse represents a major unmet medical need and a significant opportunity for future drug development.

The prognosis for addicted individuals varies significantly depending on the class of abuse substance and the degree of available psychological and social support. For example, nicotine addicts have several over-the-counter options that have been proven effective and the recent approval of the neuronal nicotinic receptor agonists. The availability of treatment combined with strong social pressure to stop smoking leads to a relatively good prognosis. On the other hand, the prognosis for cocaine addicts is poor due to the fact that they are less likely to seek medical attention and have relatively few pharmacological treatments available.

Ongoing areas of research that may yield new treatments for substance abuse include novel DAT inhibitors with different pharmacokinetic and pharmacodynamic properties to cocaine, new classes of k-receptor opioid ligands and modulators of regulator of G protein signaling (RGS) protein function.

In addition to substance abuse there a number of addictions some of which are included in DSM-IV-TR under the classification of impulse control disorders which include kleptomania, pathological gambling, pyromania, and tricotillomania. Interestingly, recent reports have described an increase in compulsive gambling in Parkinson's disease patients receiving DA agonist treatment.

Addictions that may be added to these disorders include nymphomania, compulsive shopping, and overeating, all of which, in excess, lead to behaviors that are both illogical and harmful. Returning to the anhedonia context of addiction behaviors, the inability to gain pleasure from normally pleasurable experiences, it is debatable whether the milder forms of addiction are not in fact manifestations of depression. In this context, it is noteworthy that current medications for the treatment of obesity, the impulse dyscontrol related to food consumption, are antidepressants.

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