Reward Deficiency Syndrome
Kenneth Blum, John G.
Cull, Eric R. Braverman and David E. Comings
In 1990 one of us published with his colleagues a paper
suggesting that a specific genetic anomaly was linked to alcoholism (Blum et
al. 1990). Unfortunately it was often erroneously reported that they had
found the " alcoholism gene," implying that there is a one-to-one
relation between a gene and a specific behavior. Such misinterpretations are
common-readers may recall accounts of an " obesity gene," or a
personality gene." Needless to say, there is no such thing as a
specific gene for alcoholism, obesity or a particular type of personality.
However, it would be naive to assert the opposite, that these aspects of human
behavior are not associated with any particular genes. Rather the issue at hand
is to understand how certain genes and behavioral traits are connected.
In the past five years we have pursued the association between certain genes
and various 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 disease or condition,
compared to a control population. In the course of our work we discovered that
the genetic anomaly previously found to be associated with alcoholism is also
found with increased frequency among people with other addictive, compulsive or
impulsive disorders. The list is long and remarkable-it comprises alcoholism,
substance abuse, smoking, compulsive overeating and obesity, attention-deficit
disorder, Tourette's syndrome and pathological gambling.
Figure 1: Reward deficiency syndrome comprises a spectrum of
impulsive, compulsive, addictive and personality disorders that are based on a
common genetic deficiency in the dopamine D2 receptor, according to the
authors. A predictive model based on Bayes's Theorem suggests that an
individual who carries the A1 allele for the dopamine D2 receptor has a 74
percent chance of developing one of the disorders of the reward deficiency
syndrome (Blum et al . 1996b). The type of disorder that is
manifested by any particular individual is determined by other genetic and
environmental factors, which are not yet fully understood.
We believe that these disorders are linked by a common
biological substrate, a " hard-wired" system in the brain (consisting
of cells and signaling molecules) that provides pleasure in the process of
rewarding certain behavior. Consider how people respond positively to safety,
warmth and a full stomach. If these needs are threatened or are not being met,
we experience discomfort and anxiety. An inborn chemical imbalance that alters
the intercellular signaling in the brain's reward process could supplant an
individual's feeling of well being with anxiety, anger or a craving for a
substance that can alleviate the negative emotions. This chemical imbalance
manifests itself as one or more behavioral disorders for which one of us (Blum)
has coined the term " reward deficiency syndrome."
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 an individual's biochemical inability to derive reward from
ordinary, everyday activities. We believe that we have discovered at least one
genetic aberration that leads to an alteration in the reward pathways of the
brain. It is a variant form of the gene for the dopamine D2 receptor, called
the A1 allele. This is the same genetic variant that we previously found to be
associated with alcoholism. In this review we shall look at evidence suggesting
that the A1 allele is also associated with a spectrum of impulsive, compulsive
and addictive behaviors. The concept of a reward deficiency syndrome unites
these disorders and may explain how simple genetic anomalies give rise to
complex aberrant behavior.
The Biology of Reward
The pleasure and reward system in the brain was discovered by accident in 1954.
The American psychologist James Olds was studying the rat brain's alerting
process, when he mistakenly placed the electrodes in a part of the limbic
system, a group of structures deep within the brain that are generally believed
to play a role in emotions. When the brain was wired so that the animal could
stimulate this area by pressing a lever, Olds found that the rats would press
the lever almost nonstop, as many as 5,000 times an hour. The animals would
stimulate themselves to the exclusion of everything else except sleep. They
would even endure tremendous pain and hardship for an opportunity to press the
lever. Olds had clearly found an area in the limbic system that provided a
powerful reward for these animals.
Research on human subjects revealed that the electrical stimulation of some
areas of the brain (the medial hypothalamus) produced a feeling of
quasi-orgasmic sexual arousal (Olds and Olds 1969). If certain other areas of
the brain were stimulated, an individual experienced a type of light-headedness
that banished negative thoughts. These discoveries demonstrated that pleasure
is a distinct neurological function that is linked to a complex reward and
reinforcement system (Hall, Bloom and Olds 1977).
Figure 2: Rat in a Skinner box is a typical laboratory scenario used
in the investigation of reward-seeking behavior. Early studies on
reward-seeking behavior assumed that an animal's response to pleasurable
stimuli was largely learned. Since the 1950s, however, it has become evident
that identifiable structures deep within the brain modulate the animal's experience
of pleasure in response to stimuli associated with food, sex and thirst. Here a
rat can directly stimulate the pleasure regions of the brain by pressing a
lever that activates an electrode in its head. Such animals will stimulate
themselves as many as 5,000 times an hour. (Photograph courtesy of the
During the past
several decades research on the biological basis of chemical dependency has
been able to establish some of the brain regions and neurotransmitters involved
in reward. In particular it appears that the dependence on alcohol, opiates and
cocaine relies on a common set of biochemical mechanisms (Cloninger 1983, Blum et
al. 1989). A neuronal circuit deep in the brain involving the limbic system
and two regions called the nucleus accumbens and the globus pallidus appears to
be critical in the expression of reward for people taking these drugs (Wise and
Bozarth 1984). Although each substance of 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 appears
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 at
several sites in the brain: serotonin in the hypothalamus, the enkephalins
(opioid peptides) in the ventral tegmental area and the nucleus accumbens, and
the inhibitory neurotransmitter GABA in the ventral tegmental area and the
nucleus accumbens (Stein and Belluzi 1986, Blum 1989). Interestingly, the
glucose receptor is an important link between the serotonergic system and the
opioid peptides in the hypothalamus. An alternative reward pathway 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 ultimate reward (Cloninger 1983, Stein and
Belluzi 1986, Blum and Koslowski 1990). In the cascade theory of reward, a
disruption of these intercellular interactions results in anxiety, anger and
other " bad feelings" or in a craving for a substance that alleviates
these negative emotions. Alcohol, for example, is known to activate the
norepinephrine system in the limbic circuitry through an intercellular cascade
that includes serotonin, opioid peptides and dopamine. Alcohol may also act
directly through the production of neuroamines that interact with opioid
receptors or with dopaminergic systems (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 a self-sustaining pattern of
abnormal cravings in both animals and human beings.
Figure 3: Structures deep within the limbic system play a crucial
role in the expression of emotions and the activity of the reward system of the
brain. The experience of pleasure and the modulation of reward is based on a
reward " cascade," a chain of neurons within the limbic system that
interact through various signaling molecules, or neurotransmitters. The authors
propose that a biochemical deficiency in one or more of these neurons or
signaling molecules can supplant an individual's feeling of well being with
anxiety, anger or a craving for a substance that can alleviate the negative
Support for the cascade theory can be derived from a series
of experiments on strains of rats that prefer alcohol to water. Compared to
normal rats, the alcohol-preferring rats have fewer serotonin neurons in the
hypothalamus, higher levels of enkephalin in the hypothalamus (because less is
released), more GABA neurons in the nucleus accumbens (which inhibit the
release of dopamine), a reduced supply of dopamine in the nucleus accumbens and
a lower density of dopamine D2 receptors in certain areas of the limbic system
(Russell, Lanin and Taljaard 1988 McBride et al. 1990 Zhou et al.
McBride et al. 1993).
These studies suggest a four-part cascade in which there is a reduction in the
amount of dopamine released in a key reward area in the alcohol-preferring
rats. The administration of substances that increase the supply of serotonin at
the synapse or that directly stimulate dopamine D2 receptors reduce craving for
alcohol (McBride et al. 1993). For example, D2 receptor agonists reduce
the intake of alcohol among rats that prefer alcohol, whereas D2
dopamine-receptor antagonist increase the drinking of alcohol in these inbred
animals (Dyr et al. 1993).
Support for the cascade theory of alcoholism in human beings is found 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 alcoholic subjects, the individuals experienced fewer
cravings for alcohol, a reduced incidence of stress, an increased likelihood 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" for drugs such as
cocaine, morphine and alcohol is supported by recent studies by Jordi Ortiz and
his associates at Yale University School of Medicine and the University of
Connecticut Health Services Center. These authors demonstrated that the chronic
use of cocaine, morphine or alcohol results in several biochemical adaptations
in the limbic dopamine system. They suggest that these adaptations may result
in changes in the structural and functional properties of the dopaminergic
We believe that the biological substrates of reward that underlie the addiction
to alcohol and other drugs are also the basis for impulsive, compulsive and
addictive disorders comprising the reward deficiency syndrome.
Figure 4: Reward cascade in the limbic system consists of excitatory (blue)
and inhibitory (red) connections between neurons that are
modulated by neurotransmitters. The activation of the dopamine D2 receptor (green)
by dopamine on the cell membranes of neurons in the nucleus accumbens and the
hippocampus is hypothesized by the authors to be the " final common
of the reward cascade. If the activity of the dopamine D2
receptor is deficient, the activity of neurons in the nucleus accumbens and the
hippocampus is decreased, and the individual experiences unpleasant emotions or
cravings for substances that can provide temporary relief by releasing
dopamine. Alcohol, cocaine and nicotine are known to promote the release of
dopamine in the brain. A simplified version of the cascade is presented here.
Disorders of the cells and molecules in the " upstream" part of the
cascade may also disrupt the normal activity of the reward system. The cascade begins
with the excitatory activity of serotonin-releasing neurons in the
hypothalamus. This causes the release of the opioid peptide met-enkephalin in
the ventral tegmental area, which inhibits the activity of neurons that release
the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). The
disinhibition of dopamine-containing neurons in the ventral tegmental area
allows them to release dopamine in the nucleus accumbens and in certain parts
of the hippocampus, permitting the completion of the cascade.
Alcoholism and Genes
An alteration in any of the genes that are involved in the expression of the
molecules in the reward cascade might predispose an individual to alcoholism.
Indeed, the evidence for a genetic basis to alcoholism has accumulated steadily
over the past five decades. The earliest report comes from studies of
laboratory mice by the American psychologist L. Mirone in 1952. Mirone found
that, given a choice, certain mice preferred alcohol to water. Gerald McLearn
at the University of California at Berkeley took this a step farther by
producing an inbred mouse (the 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 human beings came in
1972 when scientists at the Washington University School of Medicine in St.
Louis found that adopted children whose biological parents were alcoholics were
more likely to have a drinking problem than those born to nonalcoholic parents
(Schuckit, Goodwin and Winokur 1972). In 1973 Goodwin and Winokur, working at
the Psykologisk Institut in Copenhagen, studied 5,483 men in Denmark who
had been adopted in early childhood. They found that the sons born to alcoholic
fathers were three times more likely to become alcoholic than the sons of
In the late 1980s research on the inheritance of alcoholism suggested that there
might be important 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 reward pathways of the brain might be involved. Over the course of two
years we compared eight genetic markers associated with various
neurotransmitters (including serotonin, endogenous opioids, GABA, transferrin,
acetylcholine, alcohol dehydrogenase and aldehyde dehydrogenase). In each
instance we failed to find a direct association between the genetic markers and
The opportunity to investigate a ninth genetic marker arose after Olivier
Civelli of the Vollum Institute at Oregon University cloned and sequenced the
gene for one form of the dopamine D2 receptor. The D2 receptor is one of at
least five physiologically distinct dopamine receptors (D1, D2, D3, D4 and D5)
found on the synaptic membranes of neurons in the brain (Sibley and Monsma
1992). Previous studies had established that D2 receptors are expressed in
neurons within the cerebral cortex and the limbic system, including the nucleus
accumbens, the amygdala and the hippocampus. Because these are the same areas
of the brain (with the exception of the cortex) that are believed to be
involved in the reward cascade, Civelli's work provided the opportunity to
investigate an important molecular candidate for genetic aberrations among
Figure 5: Human chromosome number 11 carries the gene that codes for
the dopamine D2 receptor, one of six known dopamine receptors. The gene is
located on the long (q) arm of the chromosome and was cloned and
sequenced in 1990, providing investigators with the opportunity to test for
genetic variations in the population. A 1.5-kilobase sequence taken from one
end of the gene is used as probe to search for variants.
The technique we used to distinguish between the D2 receptor
genes of alcoholics and those of nonalcoholics relies on the detection of
restriction-fragment-length polymorphisms (RFLPs). This approach involves the
use of DNA-cutting enzymes (restriction endonucleases) that cleave the DNA
molecule at specific nucleotide sequences. If there are genetic differences
between two individuals such that a restriction enzyme cuts their DNA along
different points in (or near) a gene, the resulting fragments of their genes
will be of different lengths. These differing fragments, or polymorphisms, are
recognized by the use of a radioactively labeled DNA probe-in this case a short
sequence of the D2 receptor gene-that binds to a complementary DNA sequence on
the fragments. Radiolabeled fragments of different lengths signify a difference
in the cleavage sequence recognized by the restriction enzyme (Grandy et al.
Figure 6: Method of recognizing genetic variations in the dopamine D2
receptor gene relies on the detection of restriction-fragment-length
polymorphisms (RFLPs). DNA is extracted from brain tissue, blood samples or
other body tissues and then cut into many fragments with a restriction enzyme
(such as Taq I), which cleaves the genetic material at a specific
nucleotide sequence. The fragments are separated from each other in a gelatin
solution by an electric current that carries the fragments different distances
according to their lengths and electric charge. The double-stranded DNA
molecules are denatured into single strands before being blotted onto a
membrane to allow further processing. A radioactive probe (a 1.5-kilobase
sequence of the dopamine D2 receptor gene extracted from a known source) binds
to complementary sequences of the single-stranded fragments. The fragments of
the single-stranded DNA that bind the probe are visualized when x-ray film is
exposed to the membrane. Here the genetic variations are revealed in the x-ray
film, producing a DNA fingerprint for each of three individuals (a, b, c)
The restriction enzyme (Taq 1) cuts the nucleotide
sequence at a site just outside the coding region for the D2 receptor gene.
This produces the Taq 1A polymorphisms. To date there are four Taq 1A
alleles known, the A1, A2, A3 and A4 alleles. The A3 and A4 alleles are rare,
whereas the A2 allele is found in nearly 75 percent of the general population
and the A1 allele in about 25 percent of the population.
In 1990 we used the Taq I enzyme to search for Taq IA
polymorphisms in the DNA extracted from the brains of deceased alcoholics and a
control population of nonalcoholics. The results were 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 nonalcoholics we found that 20 percent had the A1 allele
and 80 percent had the A2 allele.
Figure 7: Map of the dopamine D2 receptor gene shows the location of
the genetic variants in the A region(peach) at the 3'
end of the gene. The coding region of the gene contains eight exons (blue) ,
containing nucleotide sequences that code for the structure of the gene, which
are interrupted by introns (gray) , which do not code for the gene.
The A region contains nucleotide sequences that do not code for
the structure of the gene, but may have an important role in regulating the
expression of the gene. The restriction enzyme Taq I cuts the A
region of the gene at several sites (T) , which vary according to
differences in the sequence of the nucleotide base pairs. Four genetic
variations in the A region (the A1, A2, A3 and A4 polymorphisms or
alleles) are produced by the Taq I enzyme. The A3 and A4 alleles
are rare, whereas the A1 allele is present in about 25 percent of the general
population and the A2 allele in nearly 75 percent of the population. The A1
allele is associated with the addictive-impulsive-compulsive disorders of the
reward deficiency syndrome.
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 to be an important distinguishing criterion. In
our original study, over 70 percent of the alcoholics had cirrhosis of the
liver, a disease suggestive of severe and chronic alcoholism. Moreover, the
negative studies failed to adequately assess controls to eliminate alcoholism,
drug abuse and other related " reward behaviors." In this regard,
Katherine Neiswanger and Shirley Hill of the University of Pittsburgh recently
found a strong association of the A1 allele and alcoholism and suggested that
early failures were the result of poor assessment of a true phenotype in the
controls (Neiswanger, Kaplan and Hill 1995). To date, 14 independent
laboratories have supported the finding that the A1 allele is a causative
factor in severe forms of alcoholism, though perhaps not in milder forms (Blum
and Noble 1994). These findings do not prove that the A1 allele of the dopamine
D2 receptor gene is the only cause of severe alcoholism, but they are a
powerful indication that the A1 allele is involved with alcoholism.
Figure 8: DNA fingerprint of an individual carrying the A1 allele of
the dopamine D2 receptor gene (right) contains an extra fragment
that is about 6.6 kilobases in length. The other DNA fingerprint (left)
shows that another individual carries the A2 allele rather than the A1 allele,
since the 6.6-kilobase fragment is absent. The individual with the A1 allele
was an alcoholic, the individual with the A2 allele was not an alcoholic. Many
studies (discussed in the text) now reveal that people who carry the A1 allele
are at risk for developing various disorders associated with the reward
Further evidence for the role of biology in alcoholism comes
from efforts to find electrophysiological markers that might indicate a
predisposition to the addictive disorder. One such marker is the latency and
the magnitude of the positive 300-millisecond (P300) wave, an indicator of the
general electrical activity of the brain that is evoked by a specific stimulus
such as a tone. It turns out that abnormalities in the electrical activity of
the brain are evident in the young sons of alcoholic fathers. Their P300 waves
are markedly reduced in amplitude compared to the P300 waves of the sons of
nonalcoholic fathers. These results raised the question as to whether this
deficit had been transferred from father to son and whether this deficit would
predispose the son to substance abuse in the future (Begleiter, Porjexa, Bihari
and Kissin 1984).
Experiments carried out since then have answered both questions. The alcoholic
fathers had the same P300-wave deficit seen in their sons, and the sons showed
increased drug-seeking behaviors (including alcohol and nicotine) compared to
the sons of nonalcoholic fathers. Moreover, the sons 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 in 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 the P300 wave in children of alcoholics (Noble et
al. 1994). Two of us (Blum and Braverman) extended this work and observed a
similar correlation between the 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 to A1/A2 and A2/A2
Figure 8: DNA fingerprint of an individual carrying the A1 allele of
the dopamine D2 receptor gene (right) contains an extra fragment
that is about 6.6 kilobases in length. The other DNA fingerprint (left)
shows that another individual carries the A2 allele rather than the A1 allele,
since the 6.6-kilobase fragment is absent. The individual with the A1 allele
was an alcoholic, the individual with the A2 allele was not an alcoholic. Many
studies (discussed in the text) now reveal that people who carry the A1 allele
are at risk for developing various disorders associated with the reward
Drug Addiction and Smoking
Cocaine can bring intense, but temporary, pleasure to the user. The aftermath
is addiction and severe psychological and physiological harm. Various
psychosocial theories have been advanced to account for the abuse of cocaine
and other illicit drugs. In contrast to alcoholism, where growing empirical
evidence is implicating hereditary factors, relatively little has been known
about the genetics of human cocaine dependence. 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 a biological background of
alcohol problems in the parents predicts an increased tendency toward illicit
drug abuse in the children (Cadoret, Froughton, O'Gorman and Heywood 1986).
Similarly, family studies of cocaine addicts show a high percentage of first-
or second-degree relatives who have been diagnosed as alcoholics (Miller, Gold,
Belkin and Klaher 1989 Wallace 1990).
Behavioral anomalies such as conduct disorder (in which children violate social
norms and the rights of others) and antisocial personality (the adult
equivalent of conduct disorder) are often found to be associated with alcohol
and drug problems. Several investigators have noted that sociopathic behavior
in children predicts a tendency toward antisocial personality behavior, alcohol
abuse and drug problems later in life. An analysis of 40 studies showed a
strong positive correlation between alcoholism and drug abuse, between
alcoholism and antisocial personality, and between drug abuse and antisocial
personality (Schubert et al. 1988).
Although there is little known about the genetics of cocaine dependence,
extensive 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 pleasurable effects of cocaine. In animals, for
example, the principal location where cocaine takes effect is the dopamine D2
receptor gene on chromosome 11 (Koob and Bloom 1988). Recently George Koob and
his colleagues of the Scripps Research Institute in La Jolla, California, found
evidence suggesting that the dopamine D3 receptor gene is a primary site of
cocaine effects. The exact effect of cocaine on gene expression is unknown.
However, we do know that D2 receptors are decreased by chronic cocaine
administration, and this may induce severe craving for cocaine and possibly
cocaine dreams (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 addicts have the A1 allele of
the dopamine D2 receptor gene, compared to only 21 percent of nonaddicts. The
prevalence of the A1 allele increases significantly with three risk factors:
parental alcoholism and drug abuse the potency of the cocaine used by the
addict (intranasal versus " crack" cocaine) and early-childhood
deviant behavior, such as conduct disorder. In fact, if the cocaine addict has
three of these risk factors, the prevalence of the A1 allele rises to 87
percent. These findings suggest that childhood behavioral disorders may signal
a genetic predisposition to drug or alcohol addiction (Noble et al.
Figure 10: Likelihood of carrying the A1 allele increases as the
number of risk factors increases among cocaine-dependent people. Three risk
factors are especially significant: parental alcoholism and drug abuse, the
potency of the cocaine used by the addict (intranasal versus " crack"
cocaine), and early childhood deviant behavior, such as conduct disorder. The
study included 49 subjects (Noble, Blum and Khalsa 1993).
A recent survey by the National Institute of Drug Abuse of
five independent studies showed that the A1 allele is also associated with
polysubstance dependence (Uhl, Blum, Noble and Smith 1993). The A1 allele is
also associated with an increase in the amount of money spent for drugs by
polysubstance-dependent people (Comings et al. 1994).
Although not viewed in the same light as the use of cocaine and other illicit
drugs, cigarette smoking is another form of chemical addiction. Most attempts
to stop smoking are associated with withdrawal symptoms typical of the other
chemical addictions. Although environmental factors may be important
determinants of cigarette use, there is strong evidence that the acquisition of
the smoking habit and its persistence are strongly influenced by hereditary
Of particular significance are studies of identical twins, which show that when
one twin smokes, the other tends to smoke. This is not the case in nonidentical
twins. In one twin study, Dorit Carmelli of the Stanford Research Institute and
her associates examined a national sample of male twins who were veterans of
World War II. A unique aspect of this study was that the twins were surveyed
twice, once in 1967-68 and again 16 years later. This allowed an examination of
genetic factors in all aspects of smoking-initiation, maintenance and quitting.
In general, whatever happened to one identical twin happened to the
other-including the long-term pattern of not smoking, smoking and then quitting
smoking. The absence of these similarities in a control population of
nonidentical twins suggests a strong biogenetic component in smoking behavior
(Swan et al. 1990).
Animal studies have suggested that the dopaminergic pathways of the brain may
be involved. For example, the administration of nicotine to rodents disturbs
dopamine metabolism in the reward centers of the brain to a greater extent than
does the administration of alcohol.
With this in mind, one of us (Comings) and his colleagues investigated the
incidence of the A1 allele in a population of Caucasian smokers. These smokers
did not abuse alcohol or other drugs, but had made at least one unsuccessful
attempt to stop smoking. It turned out that 48 percent of the smokers carried
the A1 allele. The higher the prevalence of the A1 allele, the earlier had been
the age of onset of smoking, the greater the amount of smoking and the greater
the difficulty experienced in attempting to stop smoking. In another sample of
Caucasian smokers and nonsmokers, Noble and his colleagues found that the
prevalence of the A1 allele was highest in current smokers, lower in those who
had stopped smoking and lowest in those who had never smoked (Noble et al.
Compulsive Bingeing and Gambling
Obesity is a disease that comes in many forms. Once thought to be primarily
environmental, it is now considered to have both genetic and environmental
components. In a Swedish adoption study, for example, the weight of the adult
adoptees was strongly related to the body-mass index of the biological parents and
to the body-mass index of the adoptive parents. The links to both genetic
and environmental factors were dramatic. Other studies of adoptees and twins
suggest that heredity is an important contributor to the development of
obesity, whereas childhood environment has little or no influence. Moreover,
the distribution of fat around the body has also been found to have heritable
elements. The inheritance of subcutaneous fat distribution is genetically
separable from body fat stored in other compartments (among the viscera in the
abdomen, for example). It has been suggested that there is evidence for both
single and multiple gene anomalies (Bouchard 1995).
Given the complex array of metabolic systems that contribute to overeating and
obesity, it is not surprising that a number of neurochemical defects have been
implicated. Indeed at least three such genes have been found: one associated
with cholesterol production, one with fat transport and one related to insulin
production (Bouchard 1995). The ob gene and its product the leptin
protein have also been implicated in regulating long-term eating behavior
(Zhang et al. 1994). Most recently another protein, glucagon-like
peptide 1 (GLP-1) has been found to be involved in the regulation of short-term
eating behavior (Turton et al. 1996). The relationship between leptin
and GLP-1 is not known. The ob gene may be involved in the animal's
selection of fat, but perhaps not in the ingestion of carbohydrates, which
appears to be regulated by the dopaminergic system. It may be that the ob
gene is functionally linked to the opioid peptodergic systems involved in
Whatever the relation between these systems, the complexity of compulsive eating
disorders suggests that more than one defective gene is involved. Indeed, the
relation between compulsive overeating and drug and alcohol addiction is well
documented (Krahn 1991, Newman and Gold 1992). Neurochemical studies 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 reward area of
the brain, the nucleus accumbens. Although the precise localization and
specificity of the pleasure-inducing properties of alcohol, drugs and
food are still debated, there is general agreement that they work through the
dopaminergic pathways of the brain. Other studies suggest the involvement of at
least three other neurotransmitters serotonin, GABA and the opioid peptides.
Variants of the dopamine D2 receptor gene appear to be risk factors in obesity.
The A1 allele was present in 45 percent of obese subjects as compared to 19
percent of nonobese subjects (Noble, Noble and Ritchie 1994). Furthermore, the
A1 allele was not associated with a number of other metabolic and
cardiovascular risks, including elevated levels of cholesterol and high blood
pressure. In contrast, when the subject's profile included factors such as
parental obesity, a later onset of obesity and carbohydrate preference, the
prevalence of the A1 allele rose to 85 percent. More recently another study
found a significant association between genetic variants of the D2 receptor and
obese subjects (Comings et al. 1993).
There is also an increased prevalence of the 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 a patient, the incidence
of the A1 allele rose to 82 percent. In contrast, the allele had an incidence
of zero percent in nonobese patients who were also not substance abusers and
did not have a family history of substance abuse. The presence of the dopamine
D2 receptor gene variants increases the risk of obesity and related behaviors.
Pathological gambling-in which an individual becomes obsessed with the act of
risking money or possessions for greater " payoffs" -occurs at a rate of
less than two percent in the general population. Although it is the most
socially acceptable of the behavioral addictions, pathological gambling has
many affinities to alcohol and drug abuse. Clinicians have remarked on the
similarity between the aroused euphoric state of the gambler and the
of the cocaine addict or substance abuser. Pathological
gamblers express a distinct craving for the " feel" of gambling they
develop tolerance in that they need to take greater risks and make larger bets
to reach a desired level of excitement, and they experience withdrawal-like
symptoms (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 compulsive-gambling syndrome: winning, losing,
desperation and hopelessness-a series not uncommon to other addictive
Might the dopamine pathways in the brain be involved with pathological
gambling? A recent study of Caucasian pathological gamblers found that 50.9
percent carried the A1 allele of the dopamine D2 receptor (Comings et al.
1996b). The more severe the gambling problem, the more likely it was that the
individual was a carrier of the A1 allele. Finally, in a population of males
with drug problems who were also pathological gamblers the incidence of the A1
allele rose to 76 percent.
This disorder is most commonly found among school-age boys, who are at least
four times more likely to express the symptoms than are young girls. These
children have difficulty applying themselves to tasks that require a sustained
mental effort, they can be easily distracted, they may have difficulty
remaining seated without fidgeting and they may impulsively blurt out answers
in the classroom or fail to wait their turn. Although normal children
occasionally display these symptoms, attention-deficit disorder is diagnosed
when the behavior's persistence and severity impedes the child's social
development and education.
Early speculation about the causes of attention-deficit disorder focused on
potential sources of stress within the child's family, including marital
discord, poor parenting, psychiatric illness, alcoholism or drug abuse. It has
become progressively clear, however, that stress within the family cannot
explain the incidence of the disorder. There is now little doubt that the
disorder has a genetic basis.
Evidence in support of this notion comes from patterns of inheritance in the
families of children with the disorder and from studies of identical twins. For
example, consider instances in which full siblings and half-siblings (who have
only half of the genetic identity of full siblings) are both raised in the same
family environment. If the behavioral symptoms of attention-deficit disorder
were " learned" in the family, then the incidence of the disorder
should be the same for full siblings as it is for half-siblings. In fact,
half-siblings of children with attention-deficit disorder have a significantly
lower frequency of the disorder than full siblings (Lopez 1965). In another
study, investigators found that if one identical twin had attention-deficit
disorder, there was a 100 percent probability that the other also had the
disorder. In contrast, the incidence of concordance among nonidentical twins
was only 17 percent. This result has been supported by two other independent
studies of identical twins (Willerman 1973). Finally, one of us (Comings) and
his coworkers found that the A1 allele of the dopamine D2 receptor gene was
present in 49 percent of the children with attention-deficit disorder compared
to only 27 percent of the controls (Comings et al. 1991).
Some other recent work has linked attention-deficit disorder with another
impulsive disorder: Tourette syndrome. More than 100 years ago the French
neurologist Giles de la Tourette described a condition that was characterized
by compulsive swearing, multiple muscle tics and loud noises. He found that the
disorder usually appeared in children between 7 to 10 years old, with boys more
likely to be affected than girls. Tourette suggested that the condition might
In the early 1980s one of us (Comings) and his colleagues studied 246 families
in which at least one member of the family had Tourette disorder. The study
indicated that virtually all cases of Tourette syndrome are genetic (Comings et
al. 1991). Subsequent studies also found that there was a high incidence of
impulsive, compulsive, addictive, mood and anxiety disorders on both sides of
the affected individual's family (Comings and Comings 1987). The A1 allele was
implicated in a recent report showing that nearly 45 percent of the people
diagnosed with Tourette disorder carried the aberrant gene (Comings et al.
1991). Moreover, the A1 allele had the highest incidence among people who had
the severest manifestations of the disorder.
As mentioned earlier, Tourette syndrome appears to be tightly coupled to
attention-deficit disorder. In studies of the two disorders, it was found that
50 to 80 percent of the people with Tourette syndrome also had
attention-deficit disorder. Furthermore, an increased number of relatives of
individuals with Tourette disorder also had attention-deficit/hyperactivity
disorder (Knell and Comings 1993). It now appears that Tourette syndrome is a
complex illness that may include attention-deficit disorder, conduct disorder,
obsessive, compulsive and addictive disorders and other related disorders. The
close coupling between these disorders has led one of us (Comings) to propose
that Tourette syndrome is a severe form of attention-deficit disorder (Comings
and Comings 1989 Comings 1995).
The high frequency of the A1 allele among people with Tourette syndrome and
attention-deficit disorder raises the question of whether other genes affecting
dopaminergic function might also be involved in these disorders. Two others
that have been considered are the gene for the enzyme dopamine B-hydroxylase,
which converts dopamine to norepinephrine, and the gene for the dopamine
transporter, which takes dopamine back into the presynaptic terminal after it
is released into the synapse. In both cases, variant forms of these genes are
associated with Tourette syndrome (Comings et al. 1996c). The anomalous
dopamine B-hydroxylase gene (the " DBH Taq B1" allele) was further
associated with learning disabilities, conduct disorder and substance abuse,
whereas the variant of the dopamine transporter (the " 10 repeat"
allele) was also associated with alcohol abuse, depression and
obsessive-compulsive disorder. This observation was supported by other work
showing that the 10 repeat allele for the dopamine transporter gene was
associated with attention-deficit/hyperactivity disorder (Cook et al.
1995). Moreover, elevated levels of the dopamine transporter molecule have been
found in the brains of patients with Tourette syndrome (Malison et al.
If these dopamine-related molecules are indeed associated with various
behavioral disorders, it might be expected that having more than one variant
would increase the severity or the likelihood of having a disorder. Indeed,
this is the case: The severity of attention-deficit disorder, conduct disorder,
substance abuse and mood disorders progressively increased from individuals
carrying none of the genes to those who carried all three genes (Comings et
Given the widespread prevalence of attention-deficit disorder among children,
and its frequent association with alcoholism, drug dependence and other
behavioral disorders, it may be that childhood attention-deficit disorder is a
predisposing cause to various disorders among adults. For example, there is a
significant correlation between attention-deficit hyperactivity disorder and
adult drug abuse (Gittleman, Mannuzza, Shenker and Bonagura 1985).
The Dopamine D2 Receptor
The A1 allele carries a behavioral risk factor that shows up not only in
substance addiction and attention-deficit disorder, 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 sample population of young
adolescents between 12 and 18 years old who were diagnosed as
pathologically violent" subjects (Blum Unpublished). A variant of
the dopamine transporter gene (VENT 10 repeat) was present in 100 percent of
the adolescents. Of these 70 percent had the so-called 10/10 form whereas 30
percent carried the 10/9 allelic form. Another study found that 59 percent of
Vietnam veterans with post-traumatic stress disorder also carried the A1
allele, compared to only 5 percent of veterans who were exposed to similar
stress but did not develop the disorder (Comings, Muhleman and Gysin 1996).
Why would carriers of the A1 allele be predisposed to the spectrum of disorders
associated with the reward deficiency syndrome? Individuals having the A1
allele have approximately 30 percent fewer D2 receptors than those with the A2
allele (Noble et al. 1991). Since the D2 receptor gene controls the
production of these receptors, the finding suggests that the A1 allele is
responsible for the reduction in receptors. In some way that we do not yet
understand, carrying the A1 allele reduces the expression of the D2 gene
compared to carrying the A2 allele. Perhaps a regulatory site for the D2
receptor gene is affected in A1 carriers.
Figure 11: Individuals who carry the A1 allele (top) of
the dopamine D2 receptor gene have a lower density of dopamine D2 receptors (green)
compared to individuals who carry the A2 allele (bottom) . The
authors propose that a decreased number of dopamine D2 receptors in the reward
pathways of the brain results in anger, anxiety and a craving for substances,
such as cocaine, alcohol or nicotine, that increase the release of the
neurotransmitter dopamine in the brain.
Fewer numbers of dopamine D2 receptors in the brains of A1
allele carriers may translate into lower levels of dopaminergic activity in
those parts of the brain involved in reward. A1 carriers may not be sufficiently
rewarded by stimuli that A2 carriers find satisfying. This may translate into
the persistent cravings or stimulus-seeking behavior of A1 carriers. Moreover,
because dopamine is known to reduce stress, individuals who carry the A1 allele
may have difficulty coping with the normal pressures of life. In response to
stress or cravings, A1 carriers may turn to other substances or activities that
release additional quantities of dopamine in an attempt to gain temporary
relief. Alcohol, cocaine, marijuana, nicotine and carbohydrates (like
chocolate) all cause the release of dopamine in the brain and bring about a
temporary relief of craving. These substances can be used singly, in
combination or to some extent interchangeably.
Although we believe that the gene for the D2 receptor plays a critical role in
reward deficiency syndrome, other genes (such as the dopamine transporter gene)
are undoubtedly involved in the different manifestations of the syndrome.
Scientists from Israel and the National Institute of Mental Health recently
showed that a genetic variation of the dopamine D4 receptor gene is associated
with people who are novelty (or sensation) seekers (Ebstein et al. 1996
and Benjamin et al. 1996). Both studies set out to test the hypothesis
advanced by Robert Cloninger of Washington University that novelty-seeking
behavior is modulated by the way brain cells process dopamine. Richard Ebstein
and his colleagues at the Herzog Memorial Hospital in Jerusalem found that
novelty seekers-who tended to be compulsive, exploratory, fickle, excitable,
quick-tempered and extravagant-were much more likely to have a longer version
of the receptor gene than individuals who were not novelty seekers. Subjects
with the shorter version of the gene scored lower on test of novelty seeking
and tended to be reflective, rigid, loyal, stoic, slow-tempered and frugal.
Jonathan Benjamin and his colleagues found similar results in their sample of
315 American subjects.
The work from the laboratories of Benjamin and Ebstein provide support of the
earlier work of Susan George and associates at the University of Toronto who
found a strong association between variants of the D4 gene and alcoholism and
nicotine dependence. The D2 receptor gene and the D4 receptor gene have fairly
similar nucleotide sequences and may have similar physiological functions. In
this respect, it is intriguing that investigators at the University of
California, Los Angeles found an association between the A1 allele and
individuals who were classified as " sensation seekers" and were
characterized by agitation, impulsivity, excitability and a " hot
(Compton et al. unpublished). All of these studies further
support a connection between the reward deficiency syndrome and the
In the United States 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 addicted to nicotine, 54 million people who are
at least 20 percent overweight, 3.5 million school-age children with
attention-deficit disorder or Tourette syndrome, and about 448,000 compulsive
gamblers. We believe that recognizing the role of dopamine and the D2 receptor
in the manifestation of these addictions and disorders is the first step toward
rational treatment for a devastating problem in our society.
There is reason to believe that a pharmacological approach could help people
with reward deficiency syndrome. It is tempting to speculate that the
pharmacological sensitivity of alcoholics to dopaminergic agonists
(bromocriptine, bupropion and n-propylnor-apomorphine) may be partly determined
by the individual's D2 genotoype. We predict that A1 carriers should be
pharmacologically more responsive to D2 agonists, especially in the treatment
of alcoholics or stimulant-dependent people. At least one study has already
shown that the direct microinjection of the D2 agonist n-propylnor-apomorphine
into the rat nucleus accumbens significantly suppresses the animal's symptoms after
the withdrawal of opiates (Harris and Aston-Jones, 1994).
Figure 12: Effectiveness of dopamine agonists (brown) in
the treatment of certain forms of alcoholism may depend on the individual's
genotype for the dopamine D2 receptor gene. The authors propose that alcoholics
who carry the A1 allele are more likely to respond positively to treatment with
a dopamine agonist (such as bromocriptine). However, if such individuals are
treated with a placebo (beige) they are more likely to relapse
into alcoholism. Alcoholics with the A2/A2 genotype do not respond to dopamine
agonists (or to a placebo) because their alcoholism is not associated with the
dopamine D2 receptor. The authors suggest that the use of dopamine agonists to
treat alcoholics with the A1 allele initiates a feedback system that produces
more dopamine receptors after a period of about six weeks.
A recent double-blind study demonstrates the utility of this
approach in human subjects (Lawford et al. 1995). The D2 agonist
bromocryptine or a placebo was administered to alcoholics who were carriers of
the A1 allele (A1/A1 and A1/A2 genotypes) or who only carried the A2 allele
(A2/A2). The greatest improvement in the reduction of craving and anxiety was
found among the A1 carriers who were treated with bromocryptine. The attrition
rate was highest among the A1 carriers who were treated with the placebo.
These findings provide an important rationale for DNA testing to detect genetic
variants for the D2 receptor or other dopamine-related genetic variants in the
tertiary treatment of alcoholism. Unlike certain other complex disorders, such
as Alzheimer's disease, the early identification and treatment of alcohol and
drug abuse can occasionally alter the devastating course of these addictions.
Consider the successes of self-help programs such as Alcoholics Anonymous and
Narcotics Anonymous, psychopharmacological adjunctive therapy, neuroregulation
or brain-wave training and electrophysiological stimulation. Identifying
individuals with the A1 allele offers the possibility of helping individuals
before alcoholism or substance abuse affect their lives. We foresee the
possibility for better treatment, new forms of prevention and the removal of
the social stigma attached not only to alcoholism but also to related
behaviors comprising the reward deficiency syndrome.
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