TECHNOLOGIES FOR UNDERSTANDING AND PREVENTING SUBSTANCE ABUSE AND ADDICTION
US Government Office of Technology Assessment
October 18, 1994
CHAPTER 3 BIOLOGY AND PHARMACOLOGY
Substance abuse and addiction are complex phenomena that defy
simple explanation or description. A tangled interaction of
factors contribute to an individual's seeking out, use, and
perhaps subsequent abuse of drugs. Since more individuals
experiment with drugs than eventually develop substance abuse
problems, great interest persists in understanding what
differentiates these groups. Factors that can play a role in drug
abuse susceptibility include a person's psychological makeup
(e.g., self-esteem, propensity to take risks, impulsivity,
depression), biological response to drugs, environmental
situation (e.g., peer groups, family organization, socioeconomic
status), and the availability of drugs. The exact combination of
elements that lead to substance abuse varies among individuals.
Underlying all substance use, abuse and addiction are the
actions and effects that drugs of abuse exert. For a complete
understanding of drug abuse and addiction one must address how
drugs affect the brain, why certain drugs have the potential for
being abused, and what, if any, biological differences exist
among individuals in their susceptibility to abuse drugs. While
many other factors ultimately contribute to an individual's
drug-taking behavior, understanding the biological components is
crucial in understanding substance abuse, addiction, and
dependency.
Two biological factors contribute to substance use, abuse,
and addiction: the effects drugs of abuse exert on a person; and
the biological status of the individual taking drugs. The former
relates to the acute mechanisms of action of drugs in the brain
and the long-term effects that occur after chronic exposure. The
latter pertains to an individual's biological constitution, most
importantly the presence of inherited characteristics that affect
that person's response to a drug.
The biological mechanisms of substance abuse are complex and
interactive. A previously published background paper by the
Office of Technology Assessment (OTA) entitled Biological
Components of Substance Abuse and Addiction thoroughly discusses
the basic concepts, neuropharmacology, and genetics of drug
abuse. This chapter is a synopsis of the background paper.
DRUG ACTION
Acute Actions
Drugs of abuse alter the brain's normal balance and level of
biochemical activity (see box 3-1). In order to have these
affects, a drug must first reach the brain. This is accomplished
by the drug diffusing from the circulatory system into the brain.
The routes of administration, methods by which a drug enters the
bloodstream, affect how quickly a drug penetrates the brain. The
chemical structure of a drug plays an important role in the
ability of a drug to cross from the circulatory system into the
brain. The four main routes of administration for drugs of abuse
are oral, nasal, intravenous, and inhalation. With oral
ingestion, the drug must be absorbed by the stomach or gut which
results in a delay before effects become apparent. When the nasal
route of administration is used, effects are usually felt within
3 minutes, as the capillary rich mucous membranes of the nose
rapidly absorb substances into the bloodstream. Intravenous
administration usually produces effects in 1/2 to 2 minutes and
is slowed only by the detour back through the lungs that venous
blood must take to reach the brain. Lastly, the inhalation method
bypasses the venous system completely because the drug is
absorbed into the pulmonary circulation which goes directly from
the lungs to the heart and then to the brain. As a result,
effects are felt within 5 to 10 seconds, making inhalation the
fastest route of administration. The route of administration can
determine the drug's potency and the efficacy the drug will have
on affecting brain activity, thereby contributing to the abuse
potential of the drug.
Distinct from other psychoactive agents, drugs of abuse, in
part, affect those areas of the brain that mediate feelings of
pleasure and reward (see box 3-2). Evidence is accumulating that
positive sensations experienced during these activities are
mediated by the brain reward system. Studies have shown that
direct stimulation of the areas of the brain involved in the
reward system, in the absence of any goal-seeking behavior,
produces extreme pleasure that has strong reinforcing properties
in its own right (48,60). Animals with electrodes implanted in
these areas in such a way that electrical impulses produce a
pleasurable sensation will repeatedly press a bar, or do any
other required task, to receive electrical stimulation. The fact
that animals will forego food and drink or will willingly
experience a painful stimulus to receive stimulation of the
reward system attests to the powerful reinforcing characteristics
of the reward system. Most drugs of abuse, either directly or
indirectly, are presumed to affect the brain reward system.
Inducing activity in the brain reward system gives drugs of
abuse positive reinforcing actions that support their continued
use and abuse. Drug reinforcement is defined as increasing the
behavior that led to the taking of the drug. Put more simply,
individuals who use drugs experience some effect, such as
pleasure, detachment, or relief from distress which initially
establishes and then maintains drug self-administration. The
consequence of taking the drug enhances the probability that it
will continue to be used for some real or perceived effect and,
hence, tends to lead to continued compulsive self-administration.
In fact, the ability of a drug to support self-administration in
experimental animals is a measure of the drug's strength as a
reinforcer.
While growing evidence suggests that the brain reward system
plays a role in the reinforcing properties of most drugs of
abuse, the precise mechanisms involved are complex, vary among
substances, and have yet to be completely described (41,42,43).
For example, while some drugs of abuse directly affect the
chemical release of dopamine (see box 3-3), the interactions of
other neurotransmitters such as gamma amino butyric acid (GABA),
opioid peptides, and serotonin may also be important.
Chronic Actions
Chronic, long-term exposure to drugs of abuse can cause
changes in the brain that may take weeks, months, and possibly
years, to reverse once drug use has stopped.
Most drugs of abuse have complex actions in the brain and
other parts of the body resulting in a variety of behavioral
effects. In general, tolerance develops to many of the effects of
drugs of abuse and a withdrawal syndrome occurs on cessation
after prolonged use. However, the details of these phenomena vary
from drug to drug, and the specific details of the biological
mechanisms that underlie these phenomena are not completely
understood. Recent advances in neuroscience research have begun
to unravel how neuroadaptive responses manifest themselves for
various drugs of abuse.
Tolerance to a drug develops when, following a prolonged
period of use, more of the drug is required to produce a given
effect (33,38). This response occurs with many types of drugs. It
is a common, but unnecessary, characteristic of drug abuse (see
box 3-4). For example, while tolerance develops to some of the
effects of cocaine and amphetamines, sensitization can also occur
to some of their other effects. Also, while it is unclear from
available data whether tolerance develops to cocaine's
reinforcing effects, the notion is supported by some experimental
evidence and anecdotal reports from cocaine users that the drug's
euphoric action diminishes with repeated use. In a recent study,
it has been shown that acute tolerance to dopamine response is
induced by binge patterns of cocaine administration in male rats
(51). Tolerance develops to most of the effects, including the
reinforcing properties, of opiates, barbiturates, and alcohol.
Sensitization, the opposite of tolerance, occurs when the
effects of a given dose of a drug increase after repeated, but
intermittent, administration. Sensitization to a drug's effects
can play a significant role in supporting drug- taking behavior.
Dependence is a type of neuroadaptation to drug exposure.
With prolonged use of a drug, cells in the brain adapt to its
presence such that the drug is required to maintain normal cell
function. On abrupt withdrawal of the drug, the cell behaves
abnormally and a withdrawal syndrome ensues. Generally, the
withdrawal syndrome is characterized by a series of signs and
symptoms that are opposite to those of the drug's acute effects.
For example, withdrawal of sedative drugs produce excitation and
irritability. Conversely, withdrawal of stimulants produces
profound depression.
The magnitude of the withdrawal syndrome varies from drug to
drug. Although the severity varies, withdrawal is associated with
the cessation of use of most drugs of abuse. Opiates, cocaine,
amphetamines, barbiturates, alcohol, and benzodiazepines produce
pronounced and sometimes severe withdrawal symptoms
(20,24,56,68,74) while those for nicotine and caffeine are less
intense (1,31). A mild withdrawal episode is associated with
discontinued cannabis use, while none is associated with lysergic
acid diethylamide (LSD) use (12,63). No matter the severity of
the physical withdrawal syndrome, its existence can create a
craving or desire for the drug and dependence can play a very
strong role in recurrent patterns of relapse and maintaining
drug-seeking behavior to forestall withdrawal.
At one time, withdrawal was believed to peak within several
hours after drug-taking was discontinued and then dissipate;
similarly, common knowledge held that tolerance to most drugs was
thought to dissipate gradually with time, as the brain readapted
to the drug's disappearance. Substantial evidence now indicates
that persistent, residual neuroadaptations are present, which can
last for months or possibly years, and may or may not be
associated with the pathways that mediate physical dependence
(33,44,45,77). An important component of this phenomena may be
the learning which takes place during drug-taking behavior.
Moreover, with repeated cycles of abstinence and reinitiation of
drug use, the time required to elicit drug dependence grows
shorter and shorter. Evidence also indicates that the
administration of naloxone, a drug that blocks the actions of
opiates, may elicit a withdrawal syndrome in individuals who have
abstained from use for extended periods of time. These data
indicate the existence of long-lasting, drug- induced
neuroadaptive changes that persist for as yet undefined periods
of time. Although information explaining this effect is lacking,
these changes may help account for the relapses that sometimes
occur in long-term abstinent, drug-dependent individuals.
Abuse Liability
The Comprehensive Drug Abuse Prevention and Control Act
(Public Law 91-513) and the Psychotropic Substances Act of 1978
(Public Law 95-633) gives exclusive authority to the Secretary of
the Department of Health and Human Services to determine the
abuse liability of substances and to make recommendations
concerning substance regulation and other drug policy decisions.
Although the Secretary receives advice from the Drug Enforcement
Administration (DEA), the Food and Drug Administration (FDA), and
various other regulatory agencies, these laws explicitly state
that the National Institute on Drug Abuse (NIDA) must provide to
the Secretary information relevant to the abuse potential of
suspected drugs of abuse and all facts key to an assessment of
their abuse potential. On the basis of this information from
NIDA, and input from FDA and DEA, the Secretary makes a judgment
as to the dependence potential of new drugs. NIDA supports a
variety of activities in commercial and private laboratories
around the country to provide this information.
A drug's abuse liability is measured by the likelihood that
its use will result in drug addiction. Many factors ultimately
play a role in an individual's drug-taking behavior;
nevertheless, the abuse potential of a drug is related to its
intrinsic rewarding properties and/or the presumed neuroadaptive
motivational effects that result from its prolonged use. Drugs
can be tested and screened for their abuse liability in animals.
Four criteria can be evaluated to classify a drug as having
significant abuse potential:
o pharmacological equivalence to known drugs of abuse,
o demonstration of reinforcing effects,
o tolerance, and
o physical dependence.
The capacity to produce reinforcing effects is essential to
any drug with significant abuse potential, whereas tolerance and
physical dependence often occur but are not absolutely required
to make such a determination.
Testing new pharmaceuticals for their abuse potential is an
important step in new drug development. Many major pharmaceutical
firms today emphasize the development of new and safer drugs for
pain reduction and in the development of psychoactive compounds
for treatment of brain disorders. In particular, scientific
strides in understanding the brain, neurological disease,
psychiatric disturbances, and aging are fueling research into
treatment of brain disorders. As psychoactive compounds become
available, they must be screened for abuse potential. The abuse
liability assessment of new products is not simply at the
discretions of the manufacturer. Various federal regulatory laws
mandate such testing and federal regulatory agencies are charged
with seeing that testing is carried out. The College on Problems
of Drug Dependence (CPDD), and, specifically, its Drug Evaluation
Committee (DEC), provides the majority of abuse liability testing
information to NIDA.
Animal models are generally used to screen for the abuse
potential of new drugs in earlier stages of drug development or
to evaluate abuse potential in drugs that cannot be readily
studied in humans (2). Laboratory methods for abuse potential
evaluation in humans are also well developed and is an area of
active research (21). However, factors such as the heterogeneity
of drug-using populations, the use of multiple drugs, and the
other biological, social, and environmental factors involved in
human drug use make human studies complex.
In terms of the validity of animal models as a means of
studying human drug addiction, an excellent correlation exists
between predicting the abuse liability of specific classes of
drugs in animals and humans (34). However, it is recognized that
animal models are imperfect and, in fact, there are examples of
drugs that proved to have significant abuse potential in humans,
whereas the preclinical testing in animals revealed relatively
minimal abuse potential (9,33,38). The ultimate answer to the
issue of whether a drug has significant abuse potential is
long-term experience with the drug once it has become available,
either legally or illegally. Nevertheless, animal models serve as
the only practical means of initially screening drugs for abuse
liability and have proven to be the most effective means of
detecting whether there is likely to be a problem in humans.
Self-Administration
The predominant feature of all drugs with significant
addiction-producing properties is that they are self-
administered. In fact, self-administration of a drug to the point
when the behavior becomes detrimental to the individual is the
primary criterion for classifying a drug as having significant
abuse potential for addiction. In addition to
self-administration, another contributing factor to abuse
liability is the notion of craving (9,33,38). Although craving is
a difficult term to quantify, once a drug is voluntarily or
involuntarily withdrawn, the increased desire to take the drug
can play a role in the relapse to substance abuse. As previously
mentioned, the reinforcing properties of the drug may shift the
pattern of administration established during the initial, early
phase of drug?addiction. Specifically, the drug may have
initially been self-administered for its pleasurable effects but
may eventually be self-administered to relieve the discomfort
associated with withdrawal.
Animals can be readily trained to self-administer drugs in a
variety of settings (9). Animal models of self- administration
provide a powerful tool that can give a good indication of the
abuse liability of new or unknown drugs. These models also permit
examination of the behavioral, physiological, and biological
factors leading to sustained self-administration.
Drug Discrimination
Another tool in the assessment of abuse liability of drugs is
drug discrimination, which refers to the perception of the
effects of drugs (3,9). Specifically, animals or humans trained
to discriminate a drug from a placebo show a remarkable ability
to discriminate it from other drugs with different properties.
These procedures also permit a determination of whether the
subject considers the drug to be the pharmacological equivalent
of another drug. Pharmacological equivalence refers to the fact
that drugs of particular classes, such as opiates, stimulants,
and depressants cause a series of affects on the brain and other
organs which collectively constitute their pharmacological
profile. Drug discrimination provides a useful measure in animals
to assess the subjective effects of drugs in humans.
Dependence and Tolerance
Physical dependence and tolerance to drugs of abuse can
readily be induced in animals by chronic administration of these
drugs (37,38). Following abrupt cessation of these drugs, a
withdrawal syndrome will often develop and, if given the
opportunity, self-administration rates will be increased.
Furthermore, since the understanding of the biological changes
which take place during the development of physical dependence
and tolerance are poorly understood in humans, with the possible
exception of opiate dependency (45), animal models offer a unique
opportunity to carry out experiments designed to address these
issues.
GENETIC FACTORS
Why does one person abuse or become dependent on drugs while
another, exposed to a similar environment and experiences, does
not? To date, the majority of biomedical research has focused on
the role, if any, that genetics plays in individual
susceptibility to substance abuse and dependence. There is
growing interest, however, in researching other factors that
effect a person's biological status. For example, nutrition,
biological development, in utero experiences, early exposure to
environmental lead, head injuries, and other environmental
components, can modify individual neurophysiology. Thus, while
this section features genetics, there are many other factors that
can influence individual biological susceptibility to the effects
of a drug.
Progress in understanding the genetics of various conditions
and diseases has brought with it a realization that substance
abuse and addiction probably involve a genetic component. That
is, hereditary biological differences among individuals may make
some more or less susceptible to drug dependency than others.
However, a genetic component alone is undoubtedly insufficient to
precipitate substance abuse and addiction. Unlike disorders such
as Huntington's disease and cystic fibrosis that result from the
presence of alterations in a single gene, any genetic component
of substance abuse is likely to involve multiple genes that
control various aspects of the biological response to drugs,
individual temperament, and the propensity to engage in
risk-taking behaviors, or physiological predisposition to become
an abuser. In addition, the involvement of many behavioral and
environmental factors indicates that any genetic component acts
in consort with other nongenetic risk factors to contribute to
the development of substance abuse and addiction. Thus, the
presence or absence of a genetic factor neither ensures drug
addiction nor precludes it. Two questions arise when considering
a genetic component to substance abuse and addiction. Do
inherited factors exist? If so, what are they? To date, most of
the work done in this field is related to alcoholism; much less
is known about the genetics of other drugs of abuse.
Do Inherited Factors Exist?
Results from family, twin, and adoption studies as well as
extensive research on animal models indicate that there are
heritable influences on patterns of alcohol use. Animal studies
using selective breeding techniques have established that alcohol
preference, the reinforcing actions of alcohol, alcohol
tolerance, and alcohol physical dependence can be affected by
genetic factors. Although fewer studies have examined the genetic
component of vulnerability to the addictive properties of other
drugs of abuse, evidence from animal studies confirms the role of
a genetic influence on the use and abuse of drugs other than
alcohol. To study nonalcoholic drug abuse in humans has been
difficult because of substantially lower population prevalence
and marked changes in availability and, hence, exposure to these
substances. Investigation in this area is further hampered by the
complexity of subjects' drug use--most drug abusers have used
(and had problems from using) multiple substances. This has led
researchers either to concentrate on one class of drug or to
treat all illicit drug use as equivalent. The tendency to lump
all illicit drugs into one category makes results difficult to
interpret or compare.
Family Studies: Alcoholism
References to a familial tendency or hereditary
"taint" of alcoholism date back to classical times
(23). Family studies have repeatedly confirmed that the risk of
alcoholism is higher among first-degree relatives (i.e., parents,
siblings, children) of alcoholics as compared with the general
population (54). Moreover, while family studies can establish
that a disorder (or liability to a disorder) is transmitted, in
general they fail to distinguish between biological and
environmental transmission. This issue, however, can be evaluated
in large family studies by analyzing multiple classes of
relatives with differing degrees of genetic relatedness.
Results of numerous family studies indicate that alcoholism
segregates within families, with male first-degree relatives of
alcoholics having a higher incidence (ranging from 27 to 54
percent) than female first-degree relatives (6 to 17 percent) as
compared to first-degree relatives of nonalcoholics (20 percent
of males, 4 percent of females) (26,66,76). In fitting models of
inheritance to family data, researchers concluded that observed
patterns of inheritance were consistent with the hypothesis that
familial factors predisposing to alcoholism were the same in men
and women, but that nonfamilial environmental factors exerted
more influence in the development of alcoholism in women (14).
However, a review of drug abuse research on women presented
several comparative studies of men and women showing that
alcoholism among some women appeared more highly correlated with
a family history of alcohol problems. Compared to alcoholic men
in various studies, alcoholic women had a greater likelihood of
having an alcoholic father and/or parents, as well as alcoholic
siblings (47). Additionally, while perhaps not genetically
influenced, familial alcoholics (those with at least one relative
with alcoholism) appear to have earlier onset, more antisocial
symptoms, more social complications of alcohol use, and worse
treatment outcome than nonfamilial alcoholics (22,62,70).
Familial is not identical to genetic, and in the case of
alcoholism, the familial patterns of inheritance are not
consistent with those of a purely genetic condition (36,79). In
addition, researchers suggest that the transmissibility of
alcoholism has increased over time (65). Thus, any genetic
factors promoting the development of alcoholism are significantly
moderated by nongenetic influences.
Family Studies: Other Drugs
Although fewer family studies have been conducted on the
genetic transmission of liability to other drugs of abuse,
researchers suggest that, as in the case of alcohol, addiction to
other psychoactive substances appears to run in families.
One study found evidence of drug use running in families,
based on family history obtained from individuals admitted for
substance abuse treatment (53). However, this study combined use
of all illicit drugs into one category and relied on self-reports
by the subject on his or her drug use as well as that of family
members. A large family interview of opiate addicts found that
the relatives of opiate users had elevated rates of drug
addiction as compared with the controls (67). In addition, an
association was found between opiate use and the presence of
antisocial personality disorder (ASPD). Further analysis of these
data revealed that the incidence of both drug abuse and ASPD was
higher among the siblings of the opiate subjects than among their
parents (49,50).
A familial association between opiate addiction and
alcoholism has been noted in some studies (46). However, another
family history study found that while both opiate addiction and
alcoholism clustered within families, co- occurrence of the
disorders within families occurred only as frequently as expected
by chance, thus supporting the hypothesis of independent
transmission (29).
Little has been done to test hypotheses regarding familial
transmission of liability to addiction to specific substances
other than opiates or alcohol. One study examining treated drug
abusers and their relatives found that alcoholism was equally
common among relatives of individuals who preferentially abused
opiates, cocaine, or sedative-hypnotics (27 percent, 31 percent,
and 24 percent of male relatives, respectively), whereas
relatives of sedative-hypnotic users were subject to diagnoses of
other substance abuses (2 percent of male relatives, versus 11
percent of male relatives of opiate abusers and 16 percent of
male relatives of cocaine abusers) (55).
Twin and Adoption Studies
Twin and adoption studies provide information to distinguish
between biological and cultural transmission. Twin studies
observe siblings raised in the same environment, but compare how
often identical twins, who are genetically identical, and
fraternal twins, who have the genetic similarity of nontwin
siblings are concordant for a trait. A high concordance rate for
a trait among identical twins versus fraternal twins usually
indicates a genetic component for the trait. Adoption studies, by
contrast, compare the presence of a trait among biological versus
adoptive family members or other control groups. In this way
individuals sharing the same environment but having different
genetic heritages, or vice versa, can be compared.
Evidence from twin studies suggests genetic influences on
drinking patterns as well as alcohol-related problems. Results
from twin studies demonstrate genetic influences on measures of
alcohol consumption such as abstention, average alcohol intake,
and heavy alcohol use (28,39,61). Twin studies also indicate an
inherited risk for smoking (16).
When evaluating the development of alcoholism, twin studies
have generally supported the existence of genetic influences over
the disorder's development. One early study found a higher
concordance rate for alcohol abuse between identical twins (54
percent) than in fraternal twins (28 percent) (35), while two
other studies did not find such a relationship (25,61). A 1991
study examined male and female identical twin pairs, and male and
female fraternal twin pairs, with one member of the pair meeting
the criteria for alcohol abuse or dependence (64). Researchers
found that identical male twins differed from fraternal male
twins in the frequencies of both alcohol abuse and dependence as
well as other substance abuse and/or dependence. On the other
hand, female identical and fraternal twins were equally likely to
abuse alcohol and/or become dependent on other substances, but
identical female twins were more likely to become alcohol
dependent. Another study of 356 twin pairs also found higher
identical than fraternal rates of concordance for problems
related to alcohol and drug use as well as conduct disorder (52).
The same study also noted that among men, heritability played a
greater role in the early rather than late onset of alcohol
problems, whereas no such effect was seen among women. However, a
study of 1,030 female twin pairs found evidence for substantial
heritability of liability to alcoholism, ranging from 50 to 60
percent (40).
Thus, twin studies provide general agreement that genetic
factors influence certain aspects of drinking. Most twin studies
also show genetic influence over pathological drinking, including
the diagnosis of alcoholism, which appears (like many other
psychiatric disorders) to be moderately heritable. Whether
genetic factors operate comparably in men and women, and whether
severity of alcoholism influences twin concordance is less clear.
How psychiatric comorbidity may affect heritability of alcoholism
also remains to be clarified.
Adoption studies have supported the role of heritable factors
in risk for alcoholism (6,11,71). The results from a series of
studies conducted in Denmark during the 1970s are typical.
Researchers studied male adoptees, later comparing them with
nonadopted brothers; female adoptees, later comparing them with
nonadopted daughters of alcoholics, comparisons were also made
with matched control adoptees. Sons of alcoholic and nonalcoholic
parents who were put up for adoption were compared for the
development of alcoholism. Sons of alcoholic parents were found
to be four times as likely as sons of nonalcoholic parents to
have developed alcoholism; evidence also suggested that the
alcoholism in these cases was more severe. The groups differed
little on other variables, including prevalence of other
psychiatric illness or "heavy drinking." Being raised
by an alcoholic biological parent did not further increase the
likelihood of developing alcoholism; that is, rates of alcoholism
did not differ between the adopted-away children and their
nonadopted brothers. In contrast, a study of daughters of
alcoholics revealed no elevated risk of alcoholism (23).
Another analysis examined factors promoting drug abuse as
well as alcoholism (10). In this study, all classes of illicit
drug use were categorized into a single category of drug abuse.
Most of the 40 adopted drug abusers examined had coexisting ASPD
and alcoholism; the presence of ASPD correlated highly with drug
abuse. Among those without ASPD, a biological background of
alcoholism (i.e., alcoholism in a biological parent) was
associated with drug abuse. Also, turmoil in the adoptive family
(divorce or psychiatric disturbance) was associated with
increased odds for drug abuse in the adoptee.
Finally, results from other adoption studies suggest two
forms of alcohol abuse (7,13). The two forms were originally
classified by C.R. Cloninger as "milieu-limited" or
type 1 alcohol abuse and "male-limited" or type 2
alcohol abuse (15). Type 1 alcohol abuse is characterized by
moderate alcohol problems and minimal criminal behavior in the
parents, and is generally mild, but occasionally severe,
depending on presence of a provocative environment. Type 2 is
associated with severe alcohol abuse and criminality in the
biological fathers. In the adoptees, it is associated with
recurrent problems and appears to be unaffected by postnatal
environment.
While the appropriateness of the biological and environmental
parameters used in the Cloninger study have been challenged, the
discriminating characteristics used to classify individuals as
type 1 or 2 alcohol abusers have not been--until recently. A new
study of familial and nonfamilial male alcoholics has
investigated the type 1 and 2 classifications by analyzing the
importance of age differences and cohort distributions (19). The
researchers showed that among the male alcoholics, there was not
a clear distinction between familial and nonfamilial based
alcohol abuse problems and type 1 or 2 characteristics, as
reported in previous studies. Additionally, another recent
publication discusses the absence of paternal sociopathy in the
etiology of severe alcoholism, and the possibility of a type 3
alcoholism (30). This type of research raises obvious questions
as to the validity of the discriminating characteristics
originally outlined by Cloninger and currently used in the
classification of individual alcohol abusers.
In summary, adoption studies of alcoholism clearly indicate
the role of biological, presumably genetic, factors in the
genesis of alcoholism. They do not exclude, however, a possible
role for nongenetic, environmental factors as well. Moreover,
researchers have suggested more than one kind of biological
background may be conducive to alcoholism. In particular, one
pattern of inheritance suggests a relationship between parental
antisocial behavior and alcoholism in the next generation. Thus,
adoption studies, like other designs, suggest that even at the
genetic level, alcoholism is not a homogeneous construct.
What Is Inherited?
While study results indicate a probable genetic component to
alcoholism and probably other drug abuse, they lack information
about what exactly is inherited. For example, do individuals with
a family history of drug abuse have an increased susceptibility
or sensitivity to the effects of drugs with reinforcing
properties? If a susceptibility exists, what are its underlying
biological mechanisms? To understand what might be inherited,
both individuals who have a substance abuse problem and animals
models of substance abuse are studied. Various types of
information can be derived from these studies. As with family,
twin, and adoption studies, much more information is available
about alcoholism as compared with other drugs of abuse.
First, it may be possible to identify specific inherited risk
markers for alcoholism and other substance abuse. A risk marker
is a biological trait or characteristic associated with a given
condition. Thus, if an individual is found to have an identified
marker for substance abuse, he or she is at risk for developing a
drug dependency. To date, no biological characteristic has been
clearly identified as being a risk marker for either alcoholism
or substance abuse, although evidence suggests some possible
candidates. The identification of a valid and reliable risk
marker could provide important information about the fundamental
mechanisms underlying substance abuse and addiction and would be
an invaluable aid in diagnosis and treatment.
Second, inherited differences in biochemical, physiological,
and anatomical processes related to differences in drug responses
might be identified and studied. Animal models of substance abuse
allow thorough biological assays to be carried out. Animal
genetic models of substance abuse consist of strains of animals
(usually rodents) that have been selectively bred to either
exhibit a preference for taking or refusing a drug, or to differ
in some way in their behavioral or physiological response to a
drug. In the case of alcohol, studies suggest that low doses of
alcohol are more stimulating and produce a stronger positive
reward in rats bred to have a high preference for alcohol as
compared with normal rats. Experimental data indicate that this
may be due to inherited differences in the dopamine, GABA, and
serotonin systems (27,32, 57,73). These differences represent
inherited traits related to drug taking behavior, and these
animals can be examined to determine what biological mechanisms
are involved in the expression of these traits.
Third, the genetic technique of linkage analysis can narrow
the area on a chromosome where a gene may be located. It can lead
to the identification of the gene itself which in turn can
improve the understanding of the molecular events that underlie
the expression of the gene. There have been few genetic linkage
studies related to substance abuse since few specific biological
traits associated with drug dependency have been identified. Some
studies in humans have been carried out related to alcoholism but
the findings of these studies are contradictory and inconclusive.
Several studies have reported an association between
alcoholism and a gene that regulates the number of a type of
dopamine receptor in the brain; other studies have found no such
link (4,5,8,18,58). The reason for this discrepancy is unclear.
One study revealed a relationship between the presence of the
gene not only in alcoholics, but in other disorders such as
autism, attention deficit hyperactivity disorder, and Tourette's
syndrome (17). Thus, the presence of this particular gene, while
not uniquely specific for alcoholism, may cause an alteration in
the brain's dopamine system that somehow exacerbates or
contributes to alcohol abuse.
Few studies have examined possible inherited biological
mechanisms associated with the abuse of other drugs. For example,
strains of rats and mice that differ in their sensitivity to the
reinforcing effects of cocaine and in their cocaine-seeking
behavior have been observed to also have differences in the
actual number of dopamine-containing neurons and receptors in
certain brain areas. Also, a comparison of one strain of rat that
self-administers drugs of abuse at higher rates than another
strain, found that the higher self-administering strain exhibited
differences in the intracellular mechanisms that control activity
in some of the neurons in the brain reward system (see box 3-2)
as compared with the low self-administering strain. Additional
studies exploring the role of genes in drug response are needed
to more fully understand the full range of biological factors
associated with drug abuse. The recent development of new and
more sensitive techniques to analyze brain activity and processes
will facilitate these studies.
ROLE OF LEARNING
The learning that occurs during drug-taking activities is an
important force in the continued use and craving of drugs
(59,72). Drugs of abuse often produce feelings of intense
pleasure in the user. In addition, such drugs produce changes in
numerous organ systems (e.g., cardiovascular, digestive,
endocrine). Both the behavioral and physiological effects of a
drug occur in the context of the individual's drug-seeking and
drug-using environment. As a result, environmental cues are
present before and during an individual's drug use that are
consistently associated with a drug's behavioral and
physiological effects. With repetition the cues become
conditioned stimuli, that on presentation, even in the absence of
the drug, evoke automatic changes in organ systems and sensations
that the individual reports as drug craving. This is analogous to
Pavlov's classical conditioning experiments in which dogs
salivated at the cue of a bell following repeated pairing of food
presentation with a ringing bell. Evidence for this effect is
seen in numerous studies showing that animals seek out places
associated with reinforcing drugs and that the physiological
effects of drugs can be classically conditioned in both animals
and humans (72).
Conditioning also occurs in relation to the withdrawal
effects of drugs (75). It was observed that opiate addicts who
were drug free for months and thus should not have had any signs
of opiate withdrawal, developed withdrawal symptoms (e.g.,
yawning, sniffling, tearing of the eyes) when talking about drugs
in group therapy sessions. This phenomenon, termed conditioned
withdrawal, results from environmental stimuli acquiring the
ability, through classical conditioning, to elicit signs and
symptoms of pharmacological withdrawal. Conditioned withdrawal
can also play a role in relapse to drug use in abstinent
individuals. The emergence of withdrawal symptoms as a result of
exposure to conditioned cues can motivate an individual to seek
out and use drugs.
These associations are difficult to reverse. In theory,
repeated presentation of the environmental cues, without the drug
should extinguish the conditioned association. Animal studies
indicate that stopping the conditioned response is difficult to
achieve and does not erase the original learning. These types of
studies examining drug conditioning have found that various
aspects of extinguished responses can either be reinstated with a
single pairing of the drug and environmental cue, can be
reinstated with a single dose of drug in the absence of the
environmental cue, or canspontaneously recover (72).
Thus, exposure to environmental cues associated with drug use
in the past can act as a stimulus for voluntary drug- seeking
behavior. If the individual succeeds in finding and taking the
drug, the chain of behaviors is further reinforced by the
drug-induced, rewarding feelings and the effects of the drug on
other organ systems (59). The effects of the environmental
stimuli can be similar to the priming effects of a dose of the
drug.
The complexity of human responses to drugs of abuse, coupled
with the number of drugs that are abused, complicates
understanding of the role of biology in drug use and abuse.
Nevertheless, scientists know the site of action of many drugs in
the brain, and sophisticated new devices are expected to improve
that understanding. A genetic component to drug use and abuse is
likely, but it has not been fully characterized.
SUMMARY
Underlying all alcohol and drug problems are the actions and
effects that drugs of abuse exert. It is important to understand
how drugs work in the brain, why certain drugs have the potential
for being abused, and what, if any, biological differences exist
among individuals in their susceptibility to abuse drugs.
Two biological factors contribute to substance abuse and
addiction: the effects drugs of abuse exert on the individual,
and the biological status of the individual taking drugs. The
effects the drugs exert can be either acute or chronic and will
vary depending on the drug and its route of administration. Most
drugs of abuse influence the brain's reward system. The
pleasurable sensations that drug use can produce reinforce
drug-seeking and -taking behaviors. These actions differ with
different drugs: and, thus, some substances have greater
potential for abuse and addiction than others.
Prolonged or chronic use of a substance or substances can
produce both biological and behavioral changes (some long-
lasting). Biological changes can include sensitization and/or
tolerance and, if use is discontinued, withdrawal. The behavioral
changes from continued drug use are directly related to these
biological changes. An individual's drug- craving, -seeking, and
-taking behaviors are amplified through the neuroadaptive changes
in the brain reward system that occur with chronic
administration.
Environmental cues also play a large role in drug-seeking and
-taking behavior. On encountering certain environmental stimuli
(i.e., specific locations, smells, tastes), drug- craving and
drug withdrawal symptoms have been reported by former drug users
who have been drug-free for months, even years.
Through family, twin, and adoption studies, most researchers
agree that genetic factors play some part in the heritability of
alcohol problems and, although less clear, other drug problems.
No conclusive evidence has been found to explain precisely what
is inherited or the overall importance of this inherited
material. It has been hypothesized that there are probably
numerous genes (as opposed to one) that interact in complex ways,
and whose expressions are affected by a myriad of environmental
factors. Thus, the presence or absence of a genetic factor
neither ensures nor protects against drug dependency.
BOX 3-1: Neuropharmacology
Neurons are the cells that process information in the brain.
Neurotransmitters are chemicals released by neurons to
communicate with other neurons. When a neuron is activated it
releases a neurotransmitter into the gap between two neurons (see
figure 3-1). The molecules of the neurotransmitter move across
the gap and attach to proteins, called receptors, in the outer
wall of an adjacent cell. Once the receptor is activated, the
neurotransmitter is removed from the gap, either by reabsorption
into the neuron that released it or by being broken down
chemically.
For each neurotransmitter in the brain, there are specific
receptors to which it can attach. Receptors and receptor subtypes
can activate a variety of membrane and cellular mechanisms. In
this way, one chemical can have diverse effects in different
areas of the brain. Many chemicals have been identified as
neurotransmitters. Some particularly relevant to the reported
pleasurable sensations associated with drug abuse include
dopamine, norepinephrine, serotonin, opioids and other
neuropeptides, gamma amino butyric acid (GABA), and glutamate.
A neuron can have thousands of receptors for many different
neurotransmitters. Some neurotransmitters activate neurons
(excitatory neurotransmitters), while others decrease neuron
activity (inhibitory neurotransmitters). Some receptors are
biochemically coupled: the activation of one modulates the
function of the other, either increasing or decreasing its
activity. A neuron can also have receptors for the chemical it
releases. In this way, neurons can regulate their release of a
particular neurotransmitter. Thus, these so-called autoreceptors
act as a feedback mechanism. The activity of a neuron will be
determined by the cumulative activity of all its various
receptors.
Drugs that work in the brain, including drugs of abuse, alter
normal neuropharmacological activity through a variety of
different mechanisms. They can affect the production, release, or
reuptake of a chemical, they can mimic or block the action of a
chemical at a receptor, or they can interfere with or enhance the
activity of a membrane or cellular mechanism associated with a
receptor. Prolonged drug use has the potential to alter each of
these processes.
SOURCE: Office of Technology Assessment, 1994.
BOX 3-2: The Brain Reward System
Eating, drinking, sexual, and maternal behaviors are
activities essential for the survival of the individual and the
species. Natural selection, in order to ensure that these
behaviors occur, has imbued them with powerful rewarding
properties. The brain reward system evolved to process these
natural reinforcers.
The reward system is made up of various brain structures. A
key part of this system for drug reward appears to be the
mesocorticolimbic pathway (MCLP). The MCLP is composed of the
axons of neuronal cell bodies in the middle part of the brain
(i.e., ventral tegmental area) projecting to areas in the front
part of the brain (i.e., the nucleus accumbens, a nucleus in the
limbic system, a network of brain structures associated with
control of emotion, perception, motivation, gratification, and
memory; medial prefrontal cortex, part of the front of the brain
involved with higher ordered thinking) (see figure 3-2). Ventral
tegmental neurons release the neurotransmitter dopamine to
regulate the activity of the cells in the nucleus accumbens and
the medial prefrontal cortex. Other parts of the reward system
include the nucleus accumbens and its connections with other
limbic structures, and other regions in the front part of the
brain (i.e., substantia innominata-ventral palladium). The
nucleus accumbens also sends signals back to the ventral
tegmental area. Finally, other neuronal pathways containing
different neurotransmitters regulate the activity of the
mesocorticolimbic dopamine system and may also be involved in
mediating the rewarding properties of drugs of abuse.
SOURCE: Koob, G.F., "Drugs of Abuse: Anatomy,
Pharmacology, and Function of Reward Pathways," Trends in
Pharmacological Sciences 13:177-184, 1992; Koob, G.F.,
"Neural Mechanisms of Drug Reinforcement," P.W. Kalivas
and H.H. Samson (eds.), The Neurobiology of Drug and Alcohol
Addiction, Annals of the American Academy of Sciences
654:171-191, 1992.
BOX 3-3: How Drugs of Abuse Affect the Chemical Release of
Dopamine
The rewarding properties of stimulant drugs such as cocaine
and amphetamines are due directly to the effects of the chemical
dopamine. Opiates, on the other hand, indirectly stimulate
dopamine by activating other chemical pathways, which in turn
increase dopamine activity. Similarly, alcohol, barbiturates, and
benzodiazepines likely have an indirect action which increases
dopamine activity. All of these drugs have reinforcing
properties. Phencyclidine (PCP) is also a strong reinforcer but
its relationship, if any, to activity in the dopamine pathway has
yet to be established. Other drugs are either weak reinforcers or
have not been shown to support self-administration in animal
experiments. Nicotine stimulates dopamine neurons; however, its
effect is modest when compared with cocaine or amphetamine.
Likewise, caffeine is a weak reinforcer, but the precise
mechanisms of its reinforcement are unclear. Finally, cannabis
and lysergic acid diethylamide (LSD) also produce positive
effects that clearly support their use.
SOURCE: Office of Technology Assessment, 1994.
BOX 3-4: The Two Types of Tolerance
The two types of tolerance are: dispositional
(pharmacokinetic) and pharmacodynamic. Dispositional tolerance
develops when the amount of drug reaching active sites in the
brain is reduced in some way. Generally, this arises from an
increased breakdown of the drug or a change in its distribution
in the rest of the body. Thus, more drug must be taken to achieve
the same blood levels or concentrations at the active sites in
the brain.
Pharmacodynamic tolerance represents a reduced response of
the brain to the same level of drug. It develops during the
continued and sustained presence of the drug. It may be that the
mechanism of adaptation may differ from drug to drug and depend
on the original mechanism of action of a given drug. The net
effect is that more drug is required to overcome this new
neuronal adaptation to produce an equivalent pharmacologic
effect.
Although dispositional tolerance represents a component of
tolerance to some drugs (e.g., alcohol, barbiturates), in most
cases much or all of the tolerance which develops to drugs with
significant abuse potential can be attributed to pharmacodynamic
tolerance. Tolerance can contribute to drug- taking behavior by
requiring that an individual take larger and larger doses of a
drug to achieve a desired effect.
SOURCES: Jaffe, J.H., "Drug Addiction and Drug
Abuse," The Pharmacological Basis of Therapeutics, A.G.
Gilman, T.W. Rall, A.S. Nies, and P. Taylor (eds.), (New York:
Pergammon Press, 1990). Kalant, H., "The Nature of
Addiction: An Analysis of the Problem," Molecular and
Cellular Aspects of the Drug Addictions, A. Goldstein, (ed).,
(New York, NY: Springer Verlag, 1989). _