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In 1990, one of us has published with colleagues a paper suggesting that a specific genetic abnormality has been linked to alcoholism (Blum et al. 1990). Unfortunately, it has often been erroneously reported that they had found the gene for alcoholism, "which implies that there is a one-to-one between a gene and a specific behavior. These misinterpretations are common, readers will recall accounts of an obesity gene, "or a gene of personality. Needless to say, there is no such thing as a specific gene for alcoholism, obesity or a particular type of personality. However, it would naive to suggest otherwise, that these aspects of human behavior are not associated with specific genes. Instead, the question is to understand how certain genes and behavioral traits are linked.

Over the last five years we have continued the association between certain genes and various behavioral disorders. In molecular genetics, an association refers to an important impact on the statistical a genetic variant (allele) among genetically unrelated individuals with a particular disease or condition, compared to a population witness. During our work we discovered that the genetic anomaly previously found to be associated with alcoholism is also with increasing frequency in people with other addictions, compulsive or impulsive disorders. The list is long and remarkable that includes alcoholism, addiction, smoking, compulsive overeating and obesity, attention deficit disorder, Tourette syndrome and pathological gambling.

We believe that these disorders are linked by a common biological substrate, a "wired" in the brain of the system (composed of cells and molecules signaling) that offers fun in the process of rewarding certain behavior. See how people react positively to the safety, warmth and stomach full. If these needs are threatened or are not met, we experience discomfort and anxiety. A chemical imbalance innate alters the intercellular signaling in the brain reward processes could supplant an individual's sense of well-being with anxiety, anger or desire for a substance that can alleviate the negative emotions. This chemical imbalance manifests itself in one or more behavioral problems for which one of us (Blum) coined the term "syndrome reward."

This syndrome involves a form of sensory deprivation of the brain's pleasure mechanisms. It can be manifested in relatively mild or severe forms that follow as a consequence of the inability of an individual biochemical draw reward of the ordinary, everyday activities. We believe we have found at least one genetic aberration that leads to impaired in the brain reward pathways. It is a variant of the gene coding for the dopamine D2 receptor, called A1 allele. It is same genetic variant that we found associated with alcoholism. In this review we will consider the evidence that suggests that the allele A1 is also associated with a range of impulsive, compulsive and addictive behaviors. The concept of a syndrome that unites these disorders reward and can explain how simple genetic anomalies give rise to complex aberrant behavior.

The pleasure and reward in the brain was discovered by accident in 1954. The American psychologist James Olds process of studying rat brain alert, when he mistakenly placed the electrodes in part of the limbic system, a group of deep structures of the brain that are generally believed to play a role in emotions. When the brain is wired so that the animal could stimulate this area by pressing a lever, Olds found that rats press the lever almost without interruption, until 5000 times per hour. Animals do stimulate to the exclusion of everything but sleep. They would even endure the pain and enormous difficulties for the opportunity to support the lever. Olds had clearly found an area in the limbic system that provided a reward for these animals.

Research on human subjects revealed that electrical stimulation of certain brain areas (hypothalamus median) has produced a sense of quasi-orgasmic sexual arousal (Olds and Olds, 1969). While some other regions of the brain are stimulated, a person experienced a type of vertigo that banned the negative thoughts. These discoveries demonstrated that pleasure is a distinct neurological function that is related to a complex reward and reinforcement system (Hall, Bloom and Olds, 1977).

During research for several decades on the biological basis of chemical dependency has been able to establish some brain regions and neurotransmitters involved in reward. In particular, it appears that dependence on alcohol, opiates and cocaine is based on a common set of biochemical mechanisms (Cloninger 1983, Blum et al. 1989). A neuronal circuit deep in the brain involving the system limbic and two regions called the nucleus accumbens and the globus pallidus appears to be critical in the expression of reward for people who take these drugs (Wise and Bozarth 1984). Although each substance of abuse appears to act on different parts of the circuit, the end result is the same: dopamine is released in the nucleus accumbens and the hippocampus (Koob and Bloom, 1988). Dopamine appears to be the main neurotransmitter of reward at these reinforcement sites.

Although the system of neurotransmitters involved in the biology of reward is complex, at least three other neurotransmitters are known to be involved several sites in the brain: serotonin in the hypothalamus, the enkephalins (opioid peptides) in the ventral tegmental area and nucleus accumbens, and the inhibitory neurotransmitter GABA in the ventral tegmental area and nucleus accumbens (Stein and Belluz 1986, Blum 1989). Interestingly, the glucose receptor is an important link between the serotonergic system and opioid peptides in the hypothalamus. An alternative reward circuit involves the release of norepinephrine in the hippocampus from neuronal fibers that originate in the locus coeruleus.

In a normal person, these neurotransmitters work together in a cascade of excitation or inhibition between complex stimuli and complex responses that lead to a feeling of well-being, the ultimate reward (Cloninger 1983, Stein and Belluz 1986, Blum and Koslowski, 1990). In the cascade theory of reward, a disruption of these intercellular interactions results anxiety, anger and other "bad feelings" or a desire for a substance that alleviates these negative emotions. Alcohol, for example, is known to activate the norepinephrine system in the limbic circuitry by intercellular cascade that includes serotonin, opioid peptides and dopamine. Alcohol may also act directly by producing Neuroamine that interact with opioid receptors or with systems dopamine (Alvaksinen et al. 1984; Blum and Kozlowski 1990). In the cascade theory of reward, genetic anomalies, prolonged stress or long-term abuse of alcohol can lead to an autonomous model of abnormal cravings in animals and humans.

Support the cascade theory can be derived from a series of experiments on strains of rats that prefer alcohol water. Compared with normal rats, rats, alcohol preferring to have fewer serotonin neurons in the hypothalamus, higher levels of enkephalin in the hypothalamus (because less is released), over the nucleus accumbens GABA neurons (which inhibit the release dopamine), a reduced supply of dopamine in the nucleus accumbens and a lower density of dopamine D2 receptors in certain regions of the limbic system (Russell, Lanin and Taljaard 1988, McBride et al. 1990; Zhou et al. 1990; McBride et al. 1993).

These studies suggest a cascade into four parts where there is a reduction in the amount of dopamine released in an area of key awards in the consumption of alcohol in rats preferred. The administration of substances that increase the supply of serotonin in the synapse or that directly stimulate the dopamine D2 reduce craving for alcohol (McBride et al. 1993). For example, D2 receptor agonists reduce alcohol consumption in rats who prefer alcohol, whereas dopamine D2-receptor antagonist increased consumption of alcohol among these inbred animals (Dyr and al. 1993).

Support for the cascade theory of alcoholism in human beings is in a series of clinical trials. When amino acid precursors of neurotransmitters (serotonin and dopamine) and a drug that promotes enkephalin activity were given to alcoholics, individuals have experienced fewer cravings for alcohol, a reduction in the incidence of stress, a higher probability recovery and reduced relapse rates (Brown et al. 1990; Blum and Tractenberg 1988; Blum, Briggs and Tractenberg 1989). In addition, the notion that Dopamine is the "final common pathway" for drugs such as cocaine, morphine and alcohol is supported by recent studies of Jordi Ortiz and his colleagues at Yale University School of Medicine and the University of Connecticut Health Center Services. These authors have shown that the use chronic cocaine, morphine or alcohol results in the biochemical adaptations in the limbic dopamine system. They suggest that these adaptations can cause changes in structural and functional properties of the dopaminergic system.

We believe that the biological substrates of reward underlying addiction to alcohol and other drugs are also the basis of impulsive, compulsive disorders and addiction including deficiency syndrome reward.

A change in one gene involved in the expression of molecules in the cascade of reward could predispose an individual to alcoholism. Indeed, the evidence for a genetic basis to alcoholism has steadily accumulated the past five decades. The first report of studies on laboratory mice by the American psychologist L. Mirone 1952. Mirone found that being given the choice, certain mice preferred alcohol to water. McLearn Gerald at the University of California at Berkeley has taken this step more the production of inbred mice (strain C57), which had a marked preference for alcohol. Alcohol preferring C57 strain bred true through successive generations, it was the first clear indication that alcoholism has a genetic basis (McLearn and Rodgers 1959).

The first evidence that alcoholism has a genetic basis of human beings, in 1972, scientists at the Washington School of Medicine University in St. Louis found that adopted children whose biological parents were alcoholics are more likely to have an alcohol problem than those born to parents who are not alcoholics (Schuckit, Goodwin and Winokur 1972). In 1973, Goodwin and Winokur, working at the Institute Psykologisk Copenhagen, studied 5,483 men in Denmark who had been adopted in infancy. They found that the son born of alcoholic fathers were three times more likely to become alcoholics than the son of alcoholic fathers.

In the late 1980s research on the inheritance of alcoholism suggested that there may be significant genetic differences between alcoholics and nonalcoholics (Cloninger, Bohman and Sigvardsson, 1981; Goodwin 1979). One of us (Blum) and his colleagues suspected that the activity of the chemical signaling molecules in pathways brain reward could be involved. In two years, we have compared eight genetic markers associated with various neurotransmitters (serotonin including endogenous opioids, GABA, transferrin, acetylcholine, alcohol dehydrogenase and aldehyde dehydrogenase). In each case, we were unable to find a direct link between genetic markers and alcoholism.

The possibility of investigating a marker gene arose after the ninth Olivier Civelli of the Vollum Institute of Oregon University cloned and sequenced the gene for a form of dopamine D2 receptor. The D2 receptor is one of at least five dopamine receptors physiologically distinct (D1, D2, D3, D4 and D5) found on synaptic membranes of neurons in the brain (Sibley and Monsma 1992). Previous studies had established that D2 receptors are expressed in neurons in the brain cortex and the limbic system, including the nucleus accumbens, amygdala and hippocampus. Because they are the same brain areas (except cortex) is believed to be involved in the cascade of reward, work Civelli has provided the opportunity to examine a major contender molecular genetic aberrations in alcoholics.

The technique we used to distinguish between the D2 receptor gene alcoholics and nonalcoholics is based on the detection of polymorphisms of restriction fragment length (RFLP). This approach involves the use of enzymes DNA-cutting (restriction endonucleases) that cleave the DNA molecule at specific nucleotide sequences. If there are differences DNA between two individuals such that the restriction enzyme cuts DNA at different points in (or near) a gene, the fragments result of their genes are different lengths. These different fragments, or polymorphisms, are identified by the use of a DNA probe radiolabeled, in this case a short sequence of D2-receptor gene that binds to a complementary DNA sequence on the fragments. fragments different lengths radioactive mean a difference in the cleavage sequence recognized by the restriction enzyme (Grandy et al. 1989).

The restriction enzyme (Taq 1) cuts the nucleotide sequence of a site just outside the coding region of the gene D2 receptor. The product of the Taq 1A polymorphisms. To date, there are four known alleles Taq 1A, A1, A2, A3 and A4 alleles. The alleles A3 and A4 are rare, while the A2 allele is found in nearly 75 percent of the population in general and about the A1 allele 25 per cent of the population.

In 1990, we used the Taq I enzyme in search of Taq AI polymorphisms in DNA extracted from the brains of deceased alcoholics and a control population of non-alcoholics. The results are striking: In our sample of 35 alcoholics we found that 69 percent had the A1 allele and 31 percent had the A2 allele. In 35 non-alcoholics, we found that 20 percent had the A1 allele and 80 percent had the A2 allele.

Since our 1990 study, some laboratories have failed to find a link between the A1 allele and alcoholism. However, a review of their work show that their samples are not limited to forms severe alcoholism, which we believe to be a criterion of distinction. In our original study, more than 70 percent of alcoholics showed liver cirrhosis, a disease of alcoholism and chronic severe suggestive. Furthermore, negative studies failed to adequately assess controls to eliminate alcoholism, drug abuse and other behaviors of reward. " In this regard, and Shirley Katherine Neiswanger Hill of the University of Pittsburgh recently found a strong association of the A1 allele and alcoholism and suggested that the failures early were the result of a miscalculation of a true phenotype in controls (Neiswanger, Kaplan and Hill, 1995). In To date, 14 independent laboratories have supported the conclusion that the A1 allele is a causative factor in severe alcoholism, but perhaps not in milder forms (Blum and Noble, 1994). These results do not prove that the A1 allele of the gene of dopamine D2 receptor is the only Because of heavy drinking, but they are a strong indication that the A1 allele is involved in alcoholism.

More evidence the role of the biology of alcoholism is the efforts to find markers that could indicate electrophysiological predisposition to disease causing dependence. A marker is the latency and magnitude of the positive 300 milliseconds (P300) wave, an indicator of general activity Electrical the brain that is evoked by a specific stimulus, such as a tone. It turns out that the anomalies in the electrical activity of brain evident in the young son of alcoholic fathers. Their P300 waves are markedly reduced in amplitude compared to the P300 wave of the son of alcoholic fathers. These results raised the question of whether this deficit had been transferred from father to son and if the deficit does predispose the son of Substance Abuse the future (Begleiter, Porjexa, Bihari and Kissin 1984).

The experiments conducted since then have answered both questions. The alcoholic fathers had the same deficit P300 wave seen in their son, and son have increased drug-seeking behaviors (including alcohol and nicotine) compared to the son of alcoholic fathers. In addition, the son of alcoholic fathers had an atypical neurocognitive profile (Whipple, Parker and Noble, 1988). It now appears that children with P300 abnormalities are more likely to abuse drugs and tobacco during the later years (Berman, Whipple, Fitch and Noble, 1993).

Remarkably, Noble and his colleagues found an association between the A1 allele and a prolonged latency of P300 wave in children of alcoholics (Noble et al., 1994). Two of us (Blum and Braverman) has extended this work and observed a similar correlation between the allele A1 and a prolonged P300 latency in a neuropsychiatric population. Subjects who are homozygous for the A1 allele showed significantly prolonged P300 latency compared with carriers A1/A2 and A2/A2.

Cocaine can bring intense, but temporary, pleasure to the user. The next day that the dependence and severe psychological and physiological damage. Various psychosocial theories have been advanced to account for the abuse of cocaine and other illicit drugs. Unlike alcohol, where in addition to empirical evidence involving hereditary factors, relatively little is known about the genetics of addiction to cocaine in humans. However, some recent studies have suggested that hereditary factors are involved in the use and abuse of cocaine and other illicit drugs.

Studies of adopted children, for example, show that biological history of problems drinking among parents predicted an increased tendency to abuse of illicit drugs among children (Cadoret, Froughton, O'Gorman and Heywood, 1986). Of Similarly, family studies of cocaine addicts have a high percentage of the first or second degree relatives who have been diagnosed as alcoholics (Miller, Gold, Belkin and Klaha 1989 Wallace, 1990).

Behavioral abnormalities such as conduct disorder (in which children violate social norms and the rights of others) and antisocial personality (the adult equivalent of behavioral disorders) are often found be associated with alcohol and drug problems. Several researchers have found that the sociopathic behavior in children predicts a trend towards behavior of antisocial personality disorder, alcohol abuse and addiction later in life. An analysis of 40 studies showed a strong correlation positive association between alcohol and drug abuse, alcoholism and between the antisocial personality, and between drug abuse and personality Antisocial (Schubert et al. 1988).

Although there is little data on the genetics of addiction to cocaine, Many scientific data are available on the effects of cocaine on brain chemistry. The current view is that the system that uses dopamine in the brain plays an important role in the rewarding effects of cocaine. In animals, for example, the main place where cocaine takes effect is the receptor gene D2 dopamine on chromosome 11 (Koob and Bloom, 1988). Recently, George Koob and his colleagues at the Scripps Research Institute in La Jolla, California found evidence suggesting that the gene for dopamine D3 receptors is a primary site for the effects of cocaine. The exact effect of cocaine on the expression genes is unknown. However, we know that D2 receptors are decreased by chronic administration of cocaine, which can induce a serious thirst for cocaine and, eventually, the dreams of cocaine (Volkow et al. 1993).

A recent study by Ernest Noble of the University of California at Los Angeles and Blum found that about 52 percent of cocaine users have the A1 allele of the gene of the dopamine D2 receptor, cons only 21 percent of nonaddicts. The prevalence of the A1 allele increased significantly with three risk factors: alcohol and drug abuse by parents; the activity of the cocaine consumed by addicts (intranasal versus "crack") and deviant behavior in early childhood, such as conduct disorder. In fact, if the cocaine has three of these risk factors, the prevalence of the A1 allele is 87 percent. These results suggest that behavioral problems in children may indicate a genetic predisposition to drug or alcohol (Noble et al. 1993).

A recent survey by the National Institute of Drug Abuse five independent studies have shown that the A1 allele also associated with polydrug use (Uhl, Blum, Noble and Smith, 1993). The A1 allele is also associated with an increased amount of money spent on drugs by people dependent poly (Comings et al. 1994).

Although not displayed in the same light as cocaine and other illicit drugs, smoking is another form of chemical dependency. Most attempts to quit smoking are associated with withdrawal symptoms characteristic of the other chemical addictions. Although environmental factors may be important determinants of cigarette consumption, there is strong evidence that the acquisition of the habit of smoking and persistence are strongly influenced by hereditary factors.

Of particular importance are studies of identical twins, which show that when one twin smokes and the other tend to smoke. This is not the case in non-identical twins. In a study of twins, Dorit Carmelli of the Stanford Research Institute and colleagues examined a national sample of male twins were veterans of the Second World War. A unique aspect of this study is that twins were interviewed twice, in 1967-68 and again 16 years later. This allowed an examination of genetic factors in all aspects of smoking initiation Maintenance and quit. In general, what happens to an identical twin who happened to another, including the model term of not smoking, smoking and then quit. The absence of these similarities in a control population of twins suggests a strong biogenetic in smoking behavior (Swan et al. 1990).

Animal studies have suggested that the dopaminergic pathways of the brain may be involved. For example, administration of nicotine to rodents disrupts the metabolism of dopamine in the reward centers of the brain to a greater extent than administration of alcohol.

In this spirit, one of us (Comings) and his colleagues studied the impact of allele A1 in a population of Caucasian smokers. These smokers do not abuse alcohol or other drugs, but he has at least one unsuccessful attempt to stop smoking. It was found that 48 percent of smokers carried the A1 allele. The higher the prevalence of the A1 allele, as had earlier been age of onset of smoking, the greater the amount of tobacco smoked and the difficulty in trying to stop smoking. In another sample Caucasian smokers and non-smokers, Noble and his colleagues found that the prevalence of the A1 allele was higher among current smokers, lower among those who had quit smoking and lower among those who had never smoked (Noble et al., 1994).

Obesity is a disease that takes many forms. Once thought to be primarily environmental, it is now regarded as having two genetic and environmental components. In a Swedish study of adoption, for example, the weight of adult adoptees was strongly related the BMI-biological parents-and body mass index of adoptive parents. Links to genetic factors and environmental factors have been spectacular. Other studies of adopted children and twins suggest that heredity is an important factor development of obesity, the small environment, so that has little or no influence. In addition, the distribution of fat around the body also was found that the hereditary elements. The legacy of the subcutaneous fat distribution is genetically separable fat body stored in other compartments (among the viscera of the abdomen, for example). It has been suggested that there is evidence genes for both single and multiple defects (Bouchard, 1995).

Given the complex array of metabolic systems that contribute to overeating and obesity, it is not surprising that a number of neurochemical abnormalities have been implicated. Indeed, at least three of these genes have been found: one associated with the production of cholesterol, one with fat transport and one related to the production of insulin (Bouchard, 1995). The ob gene and its protein product leptin were also involved in the regulation of feeding behavior long-term (Zhang et al. 1994). More recently, another protein, glucagon-like peptide 1 (GLP-1) was found to be involved in the regulation of short-term feeding behavior (Turton et al. 1996). The relationship between leptin and GLP-1 is unknown. The ob gene may be involved in the selection of animal fat, but perhaps not in the intake of carbohydrates, appears to be governed by the dopaminergic system system. It is possible that the ob gene is functionally related to opioid systems peptodergic involved in reward.

Whatever the relationship between these systems, the complexity of compulsive Eating Disorders indicates that more than one defective gene is involved. Indeed, the relationship between compulsive overeating and drug addiction to alcohol is well documented (Krahn, 1991, Newman and Gold, 1992). neurochemical show that pleasure-seeking behavior is a common denominator of addiction to alcohol, drugs and carbohydrates (Blum et al. 1990). Alcohol, drugs and carbohydrates all cause the release of dopamine in the primary zone of reward the brain, the nucleus accumbens. Although the precise localization and specificity of pleasure inducing properties of alcohol, drugs and food are still being debated, it is generally accepted that they function by dopaminergic pathways in the brain. Other studies suggest the participation of at least three other neurotransmitters serotonin, GABA and opioid peptides.

Variants of the gene of the dopamine D2 receptor appear to be risk factors for obesity. The A1 allele was present in 45 percent of obese subjects, compared to 19 percent of the nonobese subjects (Noble, Noble and Ritchie, 1994). In addition, the A1 allele was not associated with a number of other risks metabolic and cardiovascular diseases, including high levels of cholesterol and hypertension. However, when the profile of the subject factors as parental obesity, a later onset of obesity and carbohydrate preference, the prevalence of A1 allele rose to 85 percent. More recently another study showed a significant association between genetic variants of the D2 receptors and obese subjects (Comings et al. 1993).

There is also an increased prevalence of A1 allele in obese subjects with severe alcohol and substance abuse (Blum et al. 1996a). When obesity, alcoholism and drug abuse have been found in a patient, the incidence the A1 allele rose to 82 percent. In contrast, the allele had an incidence of zero percent for non-obese patients who are also not addicts and had no family history of substance abuse. The presence of gene variants of dopamine D2 receptors increases the risk obesity and related behaviors.

Pathological gambling, in which a person becomes obsessed with the act of risking money or property for a greater "earnings", occurs at a rate of less than two percent in the general population. Although the most socially acceptable of behavioral addictions, pathological gambling has many affinities with alcohol and drug abuse. Clinicians have noted the similarity between the excited state of the player and the euphoric "high" of cocaine or drug addict. Pathological gamblers express a need to separate the "feeling" the game, they develop tolerance in that they must take more risks and make greater paris achieve a level of excitement desired, and they experience withdrawal symptoms of type (anxiety and irritability) when no "action" is available (Volberg and Steadman, 1988). Indeed, there is a typical course of progression through four stages of the syndrome-compulsive game: winning, losing, desperation and hopelessness, a series is not uncommon to other addictive behaviors.

Could be the ways of dopamine in the brain is involved in gambling? A recent study of Caucasian pathological gamblers found that 50.9 percent achieved the A1 allele of the dopamine D2 receptor (Comings and al. 1996b). The more serious the gambling problem, the more likely that the individual was carrying the A1 allele. Finally, in a population of men with drug problems who were also pathological gamblers in the incidence of the A1 allele rose to 76 percent.

This disorder is most common among school-age boys, who are at least four times more likely to express symptoms that are girls. These children have difficulty applying themselves to tasks that require sustained mental effort, they can be easily distracted, they may have difficulty to sit without agitation and they may miss impulsive responses in the classroom or not to wait their turn. Although normal children sometimes display these symptoms, attention deficit disorder is diagnosed when the behavior of the persistence and severity hinders development child's social and education.
Early speculation on the causes of attention deficit disorder concentrated on sources potential stress in the child of the family, including marital discord, parental neglect, psychiatric illness, alcoholism or drug addiction. It gradually became clear, however, that stress within the family can not explain the incidence of the disease. There is now little doubt that the disorder has a genetic basis.

Evidence to support this notion comes from models of inheritance in families of children with the disease and Studies of identical twins. For example, consider the case where brothers and sisters and half brothers and sisters (who have only half of the identity genetic brothers and sisters) are both raised in the same family environment. If the behavioral symptoms of attention deficit disorder have been "learned" in the family, then the incidence of the disease should be the same for all brothers and sisters for the half-brothers and sisters. In fact, half-brothers and sisters of children with attention deficit disorder have a significantly lower incidence of disease brothers and sisters (Lopez 1965). In another study, investigators found that if one identical twin had an attention deficit disorder, there was a 100 percent probability that the other also had the disorder. In contrast, the incidence of concordance in identical twins was only 17 percent. This result was supported by two other independent studies of identical twins (Willerman 1973). Finally, one of us (Comings) and colleagues found that the A1 allele of the gene of dopamine D2 receptor is present in 49 percent of children with attention deficit disorder, deficit compared to only 27 percent of controls (Comings et al., 1991).

Some other recent studies have linked deficiency disorders of attention with another disorder impulsive Tourette's syndrome. More than 100 years, the French neurologist Gilles de la Tourette described a condition that has been characterized swearing by compulsive tics multiple muscle and loud noises. He noted that the disease usually appear in children 7 to 10 years, boys more likely to be affected than girls. Gilles de la Tourette suggested that the state can be inherited.

In the early 1980 one of us (Comings) and his colleagues studied 246 families in which at least one family member had Tourette's. Study revealed that almost all the syndrome of Gilles de la Tourette are genetic (Comings et al. 1991). Further studies also found that there was a high incidence of impulsive, compulsive, dependency, mood and anxiety disorders on both sides of the family the patient, (Comings and Comings, 1987). The A1 allele has been implicated in a recent report shows that nearly 45 percent of people diagnosed with the disorder Tourette was carrying the abnormal gene (Comings et al. 1991). In addition, the A1 allele had the highest incidence higher among those who had the most severe manifestations of disease.

As mentioned earlier, the syndrome of Gilles de la Tourette appears to be closely coupled to attention deficit disorder. In studies of both disorders, it was found that 50 to 80 percent of people with Tourette syndrome also had an attention deficit disorder. In addition, a growing number of parents of individuals Gilles de la Tourette also had attention deficit disorder (Knell and Comings 1993). It now appears that the syndrome of Gilles de la Tourette is a complex disease which may include attention deficit disorder behavior disorder, obsessive compulsive and addictive disorders and other related disorders. The tight coupling between these disorders has led one of us (Arrivals) to propose that Tourette syndrome is a severe form of attention deficit disorder (Comings and Comings 1989, Comings 1995).

The high frequency of A1 allele in individuals with Tourette syndrome and Deficit Disorder the attention raises the question of whether other genes affecting dopamine function might also be involved in these disorders. Two other which were considered are the gene for the enzyme dopamine B-hydroxylase, which converts dopamine to norepinephrine, and the gene carrier dopamine, which takes dopamine in the presynaptic terminal after it is released into the synapse. In both cases, variant forms of these genes are associated Syndrome Gilles de la Tourette (Comings et al. 1996c). The abnormality of dopamine B-hydroxylase gene (the "DBH Taq B1" allele) has also been associated with learning disabilities, conduct disorders and substance abuse, while the variant of the dopamine transporter (The "10" repeat these alleles) was also associated with alcohol abuse, depression and obsessive-compulsive disorder. This observation was supported by other work showing that the allele 10 Repeat for the dopamine transporter gene has been associated with attention deficit disorder (Cook et al. 1995). In addition, high levels of dopamine transporter molecule have been found in the brains of patients with Tourette syndrome (Malison et al. 1995).

If these dopamine-related molecules are indeed associated various disorders, we would expect to have more than one variant would increase the severity or the likelihood of suffering disorder. Indeed, such is the case: The severity of attention deficit disorder, conduct disorder, substance abuse and mood disorders gradually increased from exercising any of those genes to those who carried all three genes (Comings et al. 1996c).

Given the high prevalence of attention deficit disorders in children, and its frequent association with alcoholism, drug and other behavioral disorders, there may be disorder of childhood attention deficit is a cause predisposing to various disorders in adults. For example, there is a significant correlation between hyperactivity disorder and attention deficit drug abuse adult (Gittleman, Mannuzza, Shenker and Bonagura 1985).

The A1 allele has a behavioral risk factor that is evident not only in substance addiction and attention deficit disorders, but also in antisocial behavior, conduct disorder and violent or aggressive behavior. In a recent study the A1 allele was present in 60 percent of a population sample of young adolescents between 12 and 18 who were diagnosed as "pathologically violent" subjects (Blum, unpublished). A variant of the dopamine transporter gene (10 WIND Repeat) was present in 100 percent of teens. Of these 70 percent had the form known as 10/10 while 30 percent made in the form 10 / 9 allele. Another study revealed that 59 percent of Vietnam veterans with Post Traumatic Stress Disorder has also directed the A1 allele, compared to only 5 percent Veterans who were exposed to similar stress, but have not developed the disorder (Comings, Muhleman and Gysin 1996).

Why A1 allele to be predisposed to a range of disorders associated with reward deficiency syndrome? People with the A1 allele of D2 receptors have for about 30 percent less than those with the A2 allele (Noble et al. 1991). Since the receptor gene D2 control the production of these receptors, the results suggest that the A1 allele is responsible for the reduction of receptors. One somehow we do not yet understand, carrying the A1 allele reduces gene expression compared to D2 allele A2. Perhaps a regulatory site of the D2 receptor gene is assigned in A1 carriers.

Less number of dopamine D2 receptors in the brain A1 allele carriers may result in lower levels of dopamine activity in the parts of the brain involved in reward. A1 carriers can not be sufficiently rewarded by stimuli that A2 carriers find satisfying. This can result in the persistent cravings or stimulus-behavior Search A1 carriers. Moreover, because dopamine is known to reduce stress, people who carry the A1 allele may have difficulty coping with the pressures of normal life. In response to stress or desires, A1 carriers may turn to other substances or activities that release additional quantities of dopamine in an attempt to obtain temporary relief. Alcohol, cocaine, marijuana, nicotine, and carbohydrates (like chocolate) all cause the release of dopamine in the brain and cause a temporary relief of thirst. These substances can be used alone or in combination to a certain extent interchangeable.

Although we believe that the D2 receptor gene plays a critical role in reward syndrome, other genes (such as gene carrier dopamine) are probably involved in the different manifestations of the syndrome. Scientists from Israel and the National Institutes of Health Mental recently shown that genetic variation in the gene for dopamine D4 receptor is associated with people who are novelty (or sensation) Applicants (Ebstein et al. 1996 and Benjamin et al. 1996). Both studies were undertaken to test the hypothesis advanced by Robert Cloninger University of Washington that the novelty-seeking behavior is modulated by the brain how cells process dopamine. Richard Ebstein and his colleagues at Herzog Memorial Hospital in Jerusalem found that novelty seekers, who tended to be excessive, exploratory erratic, irritable, angry and extravagant, were much more likely to have a longer version of the receptor gene from persons who were not seeking novelty. The subjects with the short version of the gene scored lower on the criterion of novelty seeking and tend to be reflective, rigid, loyal, stoic, slow tempered and frugal. Jonathan Benjamin and his colleagues have found similar results in their sample of 315 American subjects.

The laboratory work of Benjamin and Ebstein's providing support to the earlier work of Susan George and associates at the University of Toronto who found a strong association between the D4 gene variants and alcoholism and addiction to nicotine. The D2 receptor gene and the D4 receptor gene have nucleotide sequences are quite similar and have similar physiological functions. In this regard, it is surprising that researchers at the University of California, Los Angeles has found an association between the A1 allele and individuals who were classified as sensation seekers "and were characterized by restlessness, impulsivity, irritability and hot anger "(Compton et al. unpublished). All these studies support the link between the syndrome and the reward dopaminergic system.

In the U.S. alone there are 18 million alcoholics, 28 million children of alcoholics, 6 million cocaine addicts, 14.9 million people who abuse other substances, 25 million people dependent on nicotine, 54 million people who have at least 20 percent overweight, 3.5 million children of school age with an attention deficit disorder or the syndrome of Gilles de la Tourette, and about 448,000 problem gamblers. We believe that recognition of the role of dopamine D2 receptor and in the manifestation of these addictions and disorders is the first step towards a rational treatment for a devastating problem in our society.

There are reasons believe that a pharmacological approach could help people with the reward deficiency syndrome. It is tempting to speculate that the sensitivity of pharmacological alcoholic dopamine agonists (bromocriptine, bupropion, and N-propylnor-apomorphine) may be partly determined by the individual genotoype D2. We A1 carriers expect to be pharmacologically more responsive to D2 agonists, particularly in the treatment of alcoholics or people dependent stimulant. At least one study has shown that direct microinjection of the D2 agonist-n-propylnor apomorphine in the rat nucleus accumbens significantly suppresses symptoms of the animal after the withdrawal of opiates (Harris and Aston-Jones, 1994).

A recent double-blind study demonstrates the usefulness of this approach in humans (Lawford et al. 1995). The D2 agonist bromocriptine or placebo was administered to alcoholics who were A1 allele (A1/A1 and A1/A2 genotypes) or who did the A2 allele (A2/A2). The greatest improvement in reducing the desire and of anxiety was found among the A1 carriers were treated with bromocriptine. The attrition rate was higher in A1 carriers who were treated with placebo.

These results provide an important justification for the testing of DNA genetic variants for the dopamine D2 receptor or other genetic variants linked to tertiary treatment of alcoholism. Unlike some other complex diseases such as Alzheimer's disease, early identification and treatment of alcohol and drugs can sometimes affect During the devastating addictions. Consider the success of self-help programs like Alcoholics Anonymous and Narcotics Anonymous, psychopharmacological treatment adjuvant, or Neuroregulation brainwave training and electrophysiological stimulation. Identifying individuals with the A1 allele has the potential to help individuals before alcohol or substance abuse affects their lives. We anticipate the possibility for better treatment, new forms of prevention and elimination social stigma attached not only to alcohol but also to related "reward seeking" behavior constituting syndrome reward.

About the Author

Tamea Sisco is a licensed Addictionologist specializing in the restoration of the balance of brain chemistry to combat addiction.

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