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).