Drug Rehab

Tame Sisco

Many people's lives have been affected in some way by REWARD Syndrome (RDS), either as a child, parent, sibling or spouse. Unfortunately, one third of the population expresses one or another form of reward deficiency syndrome behavior.

addicted to battle cravings on medical a daily basis, and reward deficiency disorders that afflict as many as 100 million people in the U.S. The relationship between low levels of dopamine and addictive behavior is key to help doctors treat patients in a primary care setting.

A comprehensive diagnostic drug and alcohol treatment clinic which is dedicated to the growing population of this devastating disease must implement effective technologies for the treatment of this disease. The use of Diagnostic genetic testing when necessary to try alcohol genetic predispositions. We are fortunate in this treatment is offered in the state of Colorado. Change and repair of the biochemistry of the brain by understanding the genetics of DNA that contains the gene birth of addiction. At last we are fighting the war against addiction.

In 1990 one of us published a paper with colleagues suggesting that a specific genetic defect related to alcoholism (Blum et al. 1990). Unfortunately, often wrongly reported that they had found the gene for alcoholism, "which implies that a relationship exists one-on-one between a gene and a specific behavior. misinterpretations are common-readers may recall the accounts of an obesity "gene" or a personality gene. " "Needless to say that there is such thing as a specific gene for alcoholism, obesity or a particular personality type. However, it would be naive to assert the contrary, these aspects of human behavior are not associated with any particular gene. Rather, the issue at hand is to understand how certain genes and behavioral traits are connected.

In the last five years we have carried out the association between different genes or behavioral disorders. In molecular genetics, an association refers to a statistically significant incidence of a genetic variant (an allele) among genetically unrelated individuals with a particular illness or condition, compared with a control population. In the course of our work we have discovered that the genetic anomaly previously were considered related to alcoholism are also more frequent among people with other addictive disorders, compulsive or impulsive. The list is long and remarkable "that with alcoholism, drug abuse, 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 "hard-wired" system in the brain (made up of cells and molecules signaling) that provides the pleasure in the process of rewarding certain practices. Consider how people respond positively to the safety, warmth and full stomach. If these needs are threatened or not met to be, we experience discomfort and anxiety. An inborn chemical imbalance that alters signaling intercellular in the brain's reward process could impersonate a person's sense of well being with anxiety, anger or a craving for a substance that can alleviate the emotions negative. This chemical imbalance manifests as one or more behavioral problems for which one of us (Blum) has coined the term "syndrome reward deficiency. "

This syndrome is a form of sensory deprivation of the brain's pleasure mechanisms. It can manifest in a relatively are minor or serious consequence of the biochemistry of an individual's inability to obtain the reward from ordinary activities every day. We believe we have discovered at least one genetic aberration that leads to an alteration in brain reward pathways. It is a variant of the gene for the dopamine D2 receptor, called the A1 allele. This is the same genetic variant previously considered related to alcoholism. In this review we will examine evidence suggesting that the A1 allele is also associated with a spectrum of impulsive behavior, compulsive and addictive. The concept of a syndrome that links reward to these disorders and may explain how simple genetic anomalies give rise to complex aberrant behavior.

The pleasure and reward system in the brain was discovered by accident in 1954. The American psychologist James Olds studying the process of rat brain alert when mistakenly placed the electrodes in a part of the limbic system, a group of structures deep within the brain generally believed to play a role in emotion. When the brain was wired so that the animal could stimulate this area by pressing a lever, Olds found that rats press the lever almost nonstop, up to 5,000 times per hour. Animals that are stimulated with the exclusion of everything else, except sleep. It could even endure tremendous pain and difficulties for a chance to press the lever. Olds had clearly found an area in the limbic system which provide a powerful reward for these animals.

Research on humans showed that electrical stimulation of certain brain regions (medial hypothalamus) produces a feeling of almost orgasmic sexual arousal (Olds and Olds 1969). If some areas of the brain were stimulated, an individual experienced a type of dizziness that banished to negative thoughts. These findings demonstrate that pleasure is a distinct neurological function is linked to a complex reward reinforcement system (Hall, Bloom and Olds, 1977).

During the past several decades research on the biological basis of chemical dependency has been established some brain regions and neurotransmitters involved in reward. In particular, it is that dependence on alcohol, opiates and cocaine is based on a common set biochemical mechanisms (Cloninger 1983, Blum et al. 1989). A neuronal circuit deep in the brain that affect the limbic system and two regions called the nucleus accumbens and globus pallidus appears to be critical in the expression of reward for people taking these drugs (Wise and Bozarth 1984). Although each substance abuse appears to act on different parts of this circuit, the end result is the same: dopamine is released in the nucleus accumbens and the hippocampus (Koob and Bloom, 1988). Dopamine seems to be the primary 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 in several places 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 Belluzi 1986, Blum 1989). Interestingly, the glucose receptor is an important link between the serotonergic system and opioid peptides in the hypothalamus. An alternative reward circuitry 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, leading to a feeling of well being, the final reward (Cloninger 1983, Stein and Belluzi 1986, Blum and Koslowski 1990). In the cascade theory of reward, a disruption of these interactions, results in 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 through an intercellular cascade that includes serotonin, dopamine and opioid peptides. The alcohol may act directly through the production of neuroamines that interact with opioid receptors or dopaminergic systems (Alvaksinen et al. 1984; Blum and Kozlowski 1990). In the cascade theory of reward, genetic anomalies, prolonged stress or long-term alcohol abuse can lead to a self-sustaining pattern of abnormal cravings in animals and humans.

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

These studies suggest a cascade of four parts in which there is a reduction in the amount of dopamine released in a key area in reward alcohol-preferring rats. The administration substances that increase the supply of serotonin in the synapse, or that directly stimulate dopamine D2 receptors to reduce craving for alcohol (McBride et al. 1993). For example, D2 receptor agonists reduce alcohol intake among alcohol-preferring rats, whereas the D2 dopamine antagonist-receptor increase the consumption of alcohol in these inbred animals (Dyr et al. 1993).

Support for the cascade theory of alcoholism in humans is in a series of clinical trials. When amino acid precursors of certain neurotransmitters (serotonin and dopamine) and a drug that promotes enkephalin activity were given to alcoholics, people experienced fewer cravings for alcohol, a reduction in the incidence of stress, greater chance of recovery and a reduction in relapse rates (Brown et al. 1990; Blum and Tractenberg 1988, Blum, Briggs and Tractenberg 1989). Furthermore, the notion that dopamine is the "final common pathway" of drugs such as cocaine, morphine and alcohol is supported by recent studies by Jordi Ortiz and his colleagues at Yale University School of Medicine and the University of Connecticut Health Services Center. These authors showed that chronic use of cocaine, morphine or alcohol results biochemical adaptations in the limbic dopamine system. Suggest that these adaptations may result in changes in structural and functional properties of the dopaminergic system.

We believe that the biological substrates of reward that underlie addiction to alcohol and other drugs are also the basis of impulsive, compulsive and addictive includes reward deficiency syndrome.

An alteration in any of the genes that are involved in the expression of molecules in the cascade reward might predispose an individual to alcoholism. In fact, the evidence for a genetic basis for alcoholism has accumulated steadily over the last five decades. The first report comes from studies in laboratory mice by the American psychologist L. Mirone in 1952. Mirone found that, given a choice, prefer certain mice alcohol to water. Gerald McLearn at the University of California at Berkeley is a step further by producing an inbred mouse (C57 strain) that had a marked preference for alcohol. The 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 in humans occurred in 1972 when scientists from the School of Medicine at Washington University in St. Louis found that adopted children whose biological parents were alcoholics were more likely to have a drinking problem than those born to alcoholic parents (Schuckit, Goodwin and Winokur, 1972). In 1973, Goodwin and Winokur, working at the Institute Psykologisk Copenhagen, Denmark studied 5483 men had been taken in early childhood. They found that children born of alcoholic parents had three times more likely to become alcoholics than children of nonalcoholic parents.

In the late 1980s research on the inheritance of alcoholism suggests 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 the brain's reward pathways may be involved. During two years compared eight genetic markers associated with various neurotransmitters (including serotonin, endogenous opioids, GABA, transferrin, acetylcholine, alcohol dehydrogenase and aldehyde dehydrogenase). In each case, we failed to find a direct link between genetic markers and alcoholism.

The opportunity to investigate genetic marker ninth came after Olivier Civelli of the Vollum Institute at Oregon University cloned and sequenced the gene in a D2 receptor of dopamine. The D2 receptor is one of at least five physiologically distinct dopamine receptors (D1, D2, D3, D4 and D5) are in synaptic membranes of neurons in the brain (Sibley and Monsma 1992). Previous studies had shown that D2 receptors are expressed in neurons in the cerebral cortex and the limbic system, including the nucleus accumbens, amygdala and hippocampus. Because these are the same brain areas (with the exception of the cortex) that are believed to be involved in the cascade of reward, Civelli work provided the opportunity to investigate a molecular candidate important genetic aberrations among alcoholics.

The technique used to distinguish between the D2 receptor gene in alcoholics and nonalcoholics is based on the detection of polymorphisms fragment length restriction (RFLP). This approach involves the use of DNA-cutting enzymes (restriction endonucleases) that cut the DNA molecule at specific sequences of nucleotides. If there are genetic differences between individuals so that a restriction enzyme cuts along their DNA at different points (or near) a gene, the resulting fragments their genes will be of different lengths. These different fragments, or polymorphisms, are identified by the use of a radiolabeled DNA probe, in this case a short sequence D2 receptor gene-which binds to a complementary DNA sequence of the fragments. Radiolabeled fragments of different lengths make a difference in the division sequence recognized by the restriction enzyme (Grandy et al. 1989).

The restriction enzyme (Taq 1) short nucleotide sequence at a site outside the region that encodes the D2 receptor gene. This produces the Taq 1A polymorphisms. To date there are four Taq 1A allele is known, A1, A2 alleles, A3 and A4. The A3 and A4 alleles are rare, while the A2 allele is found almost 75 percent of people in general and the A1 allele in 25 percent of population.

In 1990 I used to look Taq Taq AI polymorphisms in the DNA extracted from the brains of people deceased alcoholics and nonalcoholic control population. The results were striking: In our sample of 35 alcoholics found that 69 percent had 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 connection between the A1 allele and alcoholism. However, a review of their work shows that their samples were not limited to severe forms of alcoholism, which we believe is an important criterion to distinguish. In our original study, more than 70 percent of alcoholics had liver cirrhosis, a disease of alcoholism suggest severe and chronic. Moreover, negative studies do not adequately assess controls to eliminate alcoholism, drug abuse and other related "reward behaviors." In this sense, Katherine Neiswanger and Shirley Hill, University of Pittsburgh recently found a strong association of the A1 allele and alcoholism, and suggested that the early failures were the result of poor assessment of a true phenotype controls (Neiswanger, Kaplan and Hill 1995). To date, 14 independent laboratories have supported the conclusion that the A1 allele is a causal factor in severe forms of alcoholism, although perhaps not in milder forms (Blum and Noble, 1994). These findings do not prove that the gene A1 allele of dopamine D2 receptor is the sole cause severe alcoholism, but they are a powerful indication that the A1 allele is involved in alcoholism.

In addition evidence for the role of biology in alcoholism comes from efforts to find electrophysiological markers that may indicate a predisposition to addictive disorder. A marker is as latency and magnitude positive than 300 milliseconds (P300) wave, a general indicator of brain electrical activity that is evoked by a specific stimulus, such as a tone. It turns out that abnormalities in brain electrical activity are evident in young children of alcoholics. Their P300 waves are markedly reduced compared with the amplitude P300 wave of the children of alcoholic parents. These results raised the question whether this deficit had been transferred from father to son and if this deficit could predispose a child to substance abuse in the future (Begleiter, Porjexa, Bihari and Kissin 1984).

The experiments conducted since then have responded to both questions. Alcoholic parents have the same deficit of P300 seen in their children, and children showed an increase in drug-seeking behaviors (including alcohol and nicotine) compared to children of alcoholics. Moreover, children of alcoholic parents have an atypical neurocognitive profile (Whipple, Parker and Noble, 1988). Now it seems that children with P300 abnormalities are more likely to abuse drugs and snuff in recent years (Berman, Whipple, Fitch and Noble 1993).

Surprisingly, 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) extended his work and observed a similar correlation between A1 allele and a prolonged P300 latency in a neuropsychiatric population. Subjects who are homozygous for the A1 allele showed significantly prolonged P300 latency compared with A1/A2 and A2/A2 carriers.

Cocaine can bring intense, but temporary, pleasure to the user. The consequences are severe addiction and psychological and physiological damage. Various theories Psychosocial that advance to the account of the abuse of cocaine and other illicit drugs. In contrast to alcoholism, where growing empirical evidence is that they involve factors heritable, relatively little is known about human genetics of cocaine dependence. However, 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 a biological substance of alcohol problems in parents predicts an increased tendency toward illicit drug abuse in children (Cadoret, Froughton, O'Gorman and Heywood 1986). Similarly, family studies of cocaine addicts show a high percentage of first or second grade who have been diagnosed as alcoholics (Miller, Gold, Belkin and Klaha 1989; Wallace 1990).

Abnormal behavior as a disorder of conduct (in which children violate the social norms and the rights of others) and personality antisocial (the equivalent adult behavior disorder) is often associated with alcohol and drug problems. Several researchers have pointed out that sociopathic behavior in children predicts a trend toward antisocial personality, alcohol and drug problems in years of life. An analysis of 40 studies showed a strong positive correlation between the alcoholism and drug abuse, including alcoholism and antisocial personality, and between drug abuse and antisocial personality (Schubert et al. 1988).

Although little is known about the genetics of cocaine dependence, a large amount of scientific data 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 pleasurable effects of cocaine. In animals, for example, the principal location where cocaine comes into force is the gene for the dopamine D2 receptor on chromosome 11 (Koob and Bloom, 1988). Recently George Koob and colleagues at the Scripps Research Institute in La Jolla, California, have found evidence that the dopamine D3 receptor gene is a primary site of the effects of cocaine. The exact effect of cocaine on gene expression is unknown. However, we do know that D2 receptors are reduced with chronic administration of cocaine, which can cause intense desire for cocaine and, possibly, 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 approximately 52 percent of cocaine addicts have the A1 allele of the dopamine receptor gene D2, compared to only 21 percent of those not addicted. A1 allele prevalence increases significantly with three risk factors: parental alcoholism and drug abuse, the power of the cocaine used by the addict (intranasal compared to "crack" cocaine), and early childhood behavior off, such as conduct disorder. In fact, if the cocaine addict has three of these risk factors, the prevalence of A1 allele rises to 87 percent. These findings suggest that childhood behavior disorders may signal a genetic predisposition to addiction to drugs or alcohol (Noble et al. 1993).

A recent poll by the National Institute of Drug Abuse five independent studies demonstrated that the A1 allele is also associated with the dependence of various substances (Uhl, Blum, Noble and Smith, 1993). The A1 allele is also associated with an increase in the amount of money spent for drug dependent persons by various substances (Comings et al. 1994).

Although not visible in the same light as the use of cocaine and other illicit drugs, smoking is another form of chemical dependency. The Most attempts to quit are associated with withdrawal symptoms typical of other chemical addictions. Although environmental factors may be decisive in consumption of cigarettes, there is strong evidence that the acquisition of smoking and persistence are strongly influenced by hereditary factors.

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

Animal studies have suggested that dopaminergic pathways of the brain can be involved. For example, administration of nicotine to rodents disturbs the metabolism of dopamine in the reward centers of the brain to a greater degree as the administration of alcohol.

With this in mind, one of us (arrivals) and colleagues investigated the effect of A1 allele in a population of white smokers. These smokers not abuse alcohol or other drugs, but losing has made at least one attempt to quit smoking. It turned out that 48 percent of smokers carried the A1 allele. The higher prevalence A1 allele, the former was the age of onset of smoking, the greater the number of smokers and the greater the difficulty in trying to quit smoking. In another sample of Caucasian smokers and nonsmokers, Noble and his colleagues found that the prevalence of A1 allele was higher in current smokers, lower in those who had stopped smoking and lowest in those who had never smoked (Noble et al. 1994).

Obesity is a disease that comes in many forms. Once you create all the environment, is now considered that both genetic and environmental components. In an adoption study in Sweden, for example, the weight of the adult adoptees was strongly related to body mass index of the biological parents and body mass index of adoptive parents. Links to both genetic factors and environmental, were dramatic. Other studies of adoptees and twins suggest that inheritance is an important factor for the development of obesity, the environment, while that children have little or no influence. Moreover, the distribution of fat around the body also found that the hereditary elements. The inheritance distribution of subcutaneous fat is genetically separable from body fat stored in other compartments (between the viscera in the abdomen, for example). It has been suggested that evidence for both single and multiple abnormal genes (Bouchard 1995).

Given the complex set of metabolic systems that contribute overeating and obesity, it is not surprising that a number of neurochemical defects have been implicated. In fact at least three such genes have been found: one associated with the production cholesterol, a fat transport and one related to the production of insulin (Bouchard 1995). The ob gene and its protein product leptin also have been implicated in the regulation of feeding behavior duration period (Zhang et al. 1994). More recently, another protein-like peptide Glucagon-1 (GLP-1) has been found to be involved in the regulation of short-term feeding behavior (Turton et al. 1996). The relationship between leptin and GLP-1 is not known. The ob gene may be involved in the selection of animal fat, but perhaps not in the intake of carbohydrates, which appears to be regulated by the dopaminergic system. It may be that the ob gene is functionally linked to peptodergic opioid systems involved in reward.

Whatever the relationship between these systems, the complexity of the compulsive eating disorders suggests that more than one defective gene is involved. In fact, the relationship between binge eating and drug and alcohol addiction is well documented (Krahn 1991, Newman and Gold 1992). Neurochemical studies show that the pleasure-seeking behavior is a common denominator for addiction to alcohol, drugs and carbohydrates (Blum et al. 1990). Alcohol, drugs and carbohydrates all cause dopamine release in the primary area of the brain's reward, the nucleus accumbens. Although the location precise and specific nature of the pleasure-inducing properties of alcohol, drugs and food are still being debated, there is general agreement that work through of dopaminergic pathways in the brain. Other studies suggest the participation of at least three other neurotransmitters serotonin, GABA and opioid peptides.

Gene variants of dopamine D2 receptor appear to be risk factors for obesity. The A1 allele was present in 45 percent of obese people compared with 19 percent of nonobese subjects (Noble, Noble and Ritchie, 1994). Moreover, the A1 allele was not associated with a number of other metabolic and cardiovascular risks, including levels high cholesterol and high blood pressure. By contrast, when the profile of the subject includes factors such as parental obesity, a later onset of obesity and preference for carbohydrates, the prevalence of A1 allele rose to 85 percent. More recently, another study found a significant association between variants the D2 receptor gene and obese subjects (Comings et al. 1993).

There is also a higher prevalence of A1 allele in obese subjects who have severe alcohol and drug dependence (Blum et al. 1996a). When obesity, alcoholism and drug addiction were found in one patient, the incidence of A1 allele rose to 82 percent. By contrast, the allele had an incidence of zero percent in non-obese patients also do not abuse substances and had no history family substance abuse. The presence of gene variants of dopamine D2 receptor increases the risk of obesity and related behaviors.

Gambling in which a person becomes obsessed with the fact risking money or possessions for more "rewards", occurs at a rate two percent less than in the general population. Though it is the socially acceptable behavioral addictions, compulsive gambling has many affinities with alcohol and drug abuse. Clinicians have emphasized the similarity between the excited state of the player and the euphoric "high" from cocaine addict or substance abuser. Pathological gamblers express a desire different for the "feel" games of chance, develop tolerance in that they have to take more risks and make larger bets to reach a desired level of emotion, and experience symptoms similar to withdrawal-(anxiety and irritability) when no "action" is available (Volberg and Steadman 1988). In fact, there is a typical course of progression through four stages of the syndrome of compulsive gambling: winning, losing, desperation and hopelessness of the series one is not uncommon for other addictive behaviors.

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

About the Author

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

Portland Rehab Centers De Paul Treatment Center, Inc.