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Individual
Differences in Alcohol-Induced Aggression
A Nonhuman-Primate Model
J.
DEE HIGLEY, PH.D., is a research psychologist at the National Institute
on Alcohol Abuse and Alcoholism, Bethesda, Maryland.
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Some
people are more likely than others to become aggressive after consuming alcohol.
Researchers studying alcohol use and aggression hope to identify individual differences
in behavior and biochemistry that exist among subjects who become aggressive following
alcohol consumption. Research with nonhuman primates has shown that individual
differences in brain chemistry predict impulsivity, aggression, and alcohol-induced
aggression. These differences appear to be associated with early rearing experiences
and remain stable throughout the individuals life. KEY WORDS: AOD (alcohol or other drug) dependence; Cloningers typology; aggressive behavior; AODR (AOD
related) violence; impulsive behavior; animal model; serotonin; brain function;
cerebrospinal fluid; hydroxyindoleacetic acid; child
rearing; predictive factor
Research
has demonstrated a consistent relationship between alcohol use and violent behavior.
Both perpetrators and victims of violent crimes are likely to have consumed
alcohol prior to certain aggressive acts, such as rape, assault, domestic violence,
and murder (Collins and Messerschmidt 1993; Arseneault et
al.2000; Cunradi et al. 1999; Scott et al. 1999).
For example, in one study of domestic violence, prior alcohol consumption was
likely in cases of physical violence but not in cases of verbal aggression,
and prior alcohol consumption by both partners was more likely in episodes of
severe violence (Leonard and Quigley 1999). Moreover, high alcohol consumption
by couples was predictive of future acts of violence by the male partner (Quigley
and Leonard 2000). Although not all alcoholics
are violent, alcoholics are more likely than nonalcoholics
to have a history of violent behavior (Swanson 1993), and alcohol abuse is a
major risk factor in spousal violence and homicide (Soyka
1999).
There
appears to be a growing consensus that alcohol consumption is related to violent
behavior and aggression. In an extensive review of violence related injuries,
Cherpitel (1997) reported that compared with other
injured emergency room patients admitted at the same time, people with violence
related injuries entering an emergency room were more likely to have a positive
blood alcohol concentration (BAC), to report drinking prior to the injury, and
to report more frequent heavy drinking and alcohol related problems. In addition,
recent comprehensive meta analyses analyzing a high number of studies from different
laboratories have concluded that alcohol increases aggression under certain
conditions (Bushman 1997; Ito et al. 1996), especially in certain individuals
(Zhang et al. 1997).
This
article examines the differences in brain chemistry among individuals that influence
whether alcohol increases aggression. A nonhuman primate model is described
that has been developed specifically to study these differences and the influence
of environment and rearing on brain chemistry and alcohol-induced aggression.
Individual
Differences in Alcohols Effect on Aggression
Although
it is widely believed that aggression and alcohol use are strongly related,
most people who consume alcohol do so without acting aggressively. Predicting
which individuals are likely to exhibit aggression following alcohol consumption
is an important and intriguing research problem. Perhaps the lack of focus on
the individual is one of the reasons why demonstrating a direct causal relationship
between alcohol consumption and aggression has, at times, yielded mixed results
(see reviews in Brain 1986; Lipsey et al. 1997). Some researchers have suggested that
demonstrating a clear relationship between alcohol intake and aggression is
difficult, because alcohol consumption increases aggressiveness in some individuals,
but decreases it in others (Dougherty et al. 1996; Lipsey et al. 1997; van Erp and
Miczek 1997; Winslow et al. 1988; Winslow and Miczek 1985; Zhang et al. 1997). Such mixed findings may be
related to researchers lack of focus on differences among individuals.
For example, research indicates a stronger relationship between alcohol consumption
and aggression in subjects with certain traits, including antisocial personality
(Moeller et al. 1998), alcohol dependency (Arseneault
et al. 2000), impaired cognitive functions (Welte
and Wieczorek 1998), previous aggressive episodes
(Leonard and Quigley 1999), and low levels of the brain chemical serotonin in
the central nervous system (CNS) (Dougherty et al. 1999; Hoaken
and Pihl 2000; Pihl et al.
1995; Virkkunen et al. 1995).
Animal
Models and Individual Differences
Studying
alcohol-induced aggression in humans has several limitations (see side bar).
One solution to these problems has been to use animal models. Studies with animal
models have helped delineate how alcohol affects aggression and the mechanisms
that induce these changes. For example, using a rodent model, Miczek
and colleagues (1993) showed that alcohols effect on aggression is dose
dependent, increasing aggression at low dosages, but decreasing it at higher
dosages. This study showed that these effects are not universal, but that wide
differences exist between individuals in the effects of alcohol on aggression.
The authors found that the same dose of alcohol increased aggression in some
subjects, decreased aggression in other subjects, and had no effect on some
other subjects. Alcohols effect on aggression was found to be a stable,
traitlike response (i.e., the effect was consistent
for a given individual, like gregariousness is a personality trait that is stable
between situations and across time). Whether this difference is present in higher
animals, such as primates, is the focus of this article.
Difficulties
in Studying Alcohol-Induced Aggression in Humans
Studies
investigating the effects of alcohol on aggression in humans have typically
used an experimental approach in which a person consumes alcohol and is then
provoked or asked to compete with another person. Aggression is measured when
the person is given an opportunity to shock or verbally threaten a competitor.
Under such conditions, many studies have found that aggression is more likely
to occur after alcohol consumption (e.g., see Taylor 1993). These studies have
outlined a number of possible reasons why alcohol consumption increases the
probability of aggression, and a few studies have focused on individual differences
and the variables that induce some people to become aggressive (Gustafson 1991a,
1991b).
Predicting
which individuals will become violent after consuming alcohol in real world
settings remains elusive, however. This may be attributable partly to the tenuous
relationship between alcohol-induced aggression in the laboratory and real world
alcohol-induced violence. In addition, researchers ethically can not induce
true violence in the laboratory. Such research in humans also poses problems,
because difficulties arise in measuring underlying etiological mechanisms, such
as variations in the activity of key chemicals in the brain and inherent biochemical
differences that exist among people.
--J.
Dee Higley
References
GUSTAFSON,
R. Aggressive and nonaggressive behavior as a function of alcohol intoxication
and frustration in women. Alcoholism: Clinical and Experimental Research
15:886-892, 1991a.
GUSTAFSON,
R. Male physical aggression as a function of alcohol, frustration, and subjective
mood. International Journal of the Addictions 26:255-266, 1991b.
TAYLOR,
S.P. Experimental investigation of alcohol-induced aggression in humans.
Alcohol Health & Research World 17:108-112, 1993.
A
Nonhuman-Primate Model
Our
laboratory has recently used a nonhuman-primate model to investigate individual
differences in the effects of alcohol on aggression. Because non-human primates
are genetically our closest relatives, findings from these animals are more
likely to have relevance to the human condition than findings from other animals.
We chose rhesus macaques for our studies because of their close genetic similarity
to humans and because they have the most well characterized CNS of the nonhuman
primates. As a consequence of their genetic similarity to humans, rhesus macaques
also display similar neurodevelopment and functional neuroanatomy
and have many neurobiological features that are similar, if not identical, to
human neurobiology (Azmitia and Gannon 1986; Berger et al. 1991; Uylings and van Eden 1990). Rhesus macaques have a similar
CNS to humans and, perhaps as a result of this sophisticated CNS, have developed
a complex social system. Like that of humans, this social system is based on
specific rules for relationships and social behaviors. Moreover, rhesus macaques
develop long lasting social bonds that may endure their life span. For individuals
to live in such societies, they must learn to control their impulses--that is,
display proper social behavior at appropriate times, in applicable settings,
and modify their behavior depending on the situation and partner with whom they
are interacting.
In
modeling psychopathology, non-human primates offer numerous advantages. Their
rearing histories can be controlled systematically and manipulated in a manner
not possible in humans, thus allowing researchers to test hypotheses concerning
the role of early experiences. Experimental procedures that are not practical
in humans are possible in nonhuman primates. For example, researchers often
assess the activity of brain chemicals (i.e., neurotransmitters) by taking samples
of the fluid that bathes the brain and spinal cord (i.e., cerebrospinal fluid
[CSF]). Repeated CSF samples can be readily obtained in a highly controlled
fashion to assess subjects longitudinally. An added advantage of using nonhuman
primates, such as rhesus macaques, is that the develop
mental process is compressed; they mature four to five times more rapidly than
do humans. Thus, developmental outcomes can be studied prospectively in a fraction
of the time it takes to complete a comparable human prospective developmental
study. Nonhuman primates are ideal for studying many aspects of human alcohol
psychopathology. Nevertheless, some features of human alcohol-related psychopathology
exist that non human primates do not model as well as they do some other features.
For example, measuring the role of alcohol expectancies on aggression in the
non verbal primate would be difficult.
Serotonin
and Impulsivity, Drinking, and Violence
Some
clues are emerging that may help identify individuals prone to violence when
drinking alcohol and reveal the underlying mechanisms involved in this relationship.
Not all alcoholics are aggressive. Cloninger (1987, 1988) has proposed that two subtypes of alcoholism
exist, type I and type II. Type I alcoholics are believed to consume alcohol
primarily to reduce anxiety, whereas alcohol use for type II alcoholics appears
to be part of an overall behavior pattern of impulsive, antisocial behavior.
Type II alcoholism is, therefore, characterized by impaired impulse control,
antisocial traits, difficulties in social relationships, and physically aggressive
behaviors (Cloninger 1986, 1987, 1988). Indeed, Bergman
and Brismar (1994) concluded that type II alcoholism
is determined by a genetic predisposition to both alcoholism and violence.
A
principal neurobiological feature of type II alcoholism is a CNS serotonin deficit
(Fils-Aime et al. 1996; Javors et al. 2000; Swann et al. 1999; Virkkunen
et al. 1994a, 1994b). Both animal and human studies suggest that
reduced serotonin functioning is related to impaired impulse control (Higley et al. 1996b, 1996c; Linnoila et al. 1983; Mehlman et
al. 1994; Soubrie 1986). Therefore, Cloninger and other researchers have suggested that serotonin
function is related to loss of control over drinking among type II alcoholics
(Cloninger 1986, 1987; Linnoila
et al. 1994).
Research
also indicates that alcoholics who have reduced levels of serotonin in the brain
are prone to violent behavior (Virkkunen et al. 1995, 1994b), which may be a product
of impaired impulse control. Scott and colleagues (1999), for example, found
that perpetrators and victims of assault are more likely to score high in impulsivity
and that alcohol further heightens the likelihood of violence among such people.
Type II alcoholics, sons of alcoholic fathers (Giancola
et al. 1993; Limson et al. 1991; Schulsinger
et al. 1986; Sher et al. 1991) and, in some studies,
daughters of alcoholic fathers (Sher et al. 1991)
have scored high on measures of impulsivity and aggression (Tomori
1994). In a series of studies, Virkkunen and colleagues
(1995, 1994a, 1994b) found that alcoholic men were particularly
prone to violence if they had low concentrations of the serotonin metabolite
5-hydroxyindoleacetic acid (5-HIAA). After reviewing such findings, Linnoila and colleagues (1994) concluded that excessive alcohol
intake and violence in type II alcoholics may both originate from dysfunctional
impulse control, which in turn results from impaired serotonin functioning.
A
Nonhuman-Primate Model for Type II Alcoholism
Nonhuman
primates provide a potentially relevant animal model to test the assumptions
of Cloningers model, which postulates that high
levels of violent behavior in alcoholics are associated with impaired serotonin
functioning. Like humans, each individual monkey exhibits quantifiable personality
traits, and like humans, appropriate early rearing patterns are crucial for
normative development. When an alcohol solution is palatable, most nonhuman
primates, like humans, will freely consume alcohol. Most subjects consume alcohol
at modest levels, but about 20 percent of the subjects will consume alcohol
at high levels that produce both visible signs of intoxication and blood alcohol
levels above 0.10 percent. During the past decade, we have investigated individual
differences in alcohol consumption in nonhuman primates by studying CNS and
temperamental influences on excessive alcohol consumption. In this effort, we
have focused on the relationships between neurophysiology, impulsivity, aggression,
and alcohol consumption.
Paralleling
studies in humans, research with nonhuman primates has shown that low CSF 5-HIAA
concentrations are associated with type II like behaviors, including behaviors
characteristic of impaired impulse control (Higley
and Bennett 1999). For example, nonhuman primates with low CSF 5-HIAA concentrations
exhibit spontaneous, long leaps at dangerous heights and are repeatedly captured
in baited traps (Higley et al.
1996b, 1996c; Mehlman et al. 1994). Low CSF 5-HIAA concentrations
in nonhuman primates also are correlated with increased rates of wounding, unprovoked
and unrestrained violence, and inappropriate aggression (Higley et al. 1996a, 1996b, 1996c, 1992a;
Mehlman et al. 1995, 1994; Westergard et al. 1999).
Research
findings suggest that low CSF 5-HIAA concentrations are not correlated with
high rates of overall levels of aggression, but only are correlated with high
levels of spontaneous, impulsive aggression, which tends to escalate to physically
damaging conflicts (Higley et al. 1996c). This
association indicates that the high rates of violent aggression shown by these
monkeys probably result from impaired impulse control. Further more, escalated
aggression in subjects with low CSF 5-HIAA concentrations is strongly correlated
with measures of impulsivity (Higley et al. 1996b).
In addition, alcohol consumption is binge like and excessive in subjects with
low CSF 5-HIAA concentrations (Higley et al. 1996e).
Research
using nonhuman primates has been particularly useful, because it has delineated
possible underlying mechanisms that produce impaired serotonin functioning.
Long term studies of non human primates in which researchers have repeatedly
sampled CSF from the same subjects have shown that individual differences in
CSF 5-HIAA concentrations remain stable over time (Higley
et al. 1992b, 1993;
Kraemer et al. 1989). Furthermore, even under conditions when the settings
and situations change, individual differences remain stable. For example, when
CSF 5-HIAA is sampled while the subjects live alone in single cages, and then
again after they are placed into new social groups, individual differences in
CSF 5-HIAA concentrations are positively correlated (Higley
et al. 1996a). Furthermore, when 14 CSF samples were obtained over a
1-year period from the same adult female subjects, individual differences in
the 5-HIAA levels remained consistent over the time period (i.e., the levels
had high interindividual stability) (Higley
et al. 1996a).
This
consistent high level of interindividual stability
is not limited to the laboratory setting, where environmental changes are closely
controlled and experiences are relatively homogeneous. In their natural environment,
adolescent male macaques migrate from their birth groups to join new social
groups (Higley et al. 1994). This is a period of high
social stress, because the young males must form new relationships and face
social challenges in which trauma and premature mortality are relatively frequent
(Higley et al. 1994). Despite these rather dramatic
environmental changes, interindividual differences
in CSF 5-HIAA concentrations during the year preceding migration to a new social
group are positively correlated with interindividual
differences in CSF 5-HIAA concentrations following migration. Such interindividual differences also appear to stabilize beginning
early in life. CSF 5-HIAA concentrations were stable when samples were taken
from monkeys 14, 30, 60, 90, 120, and 150 days after birth (Shannon et al. 1995).
These early differences remain stable, with mean concentrations of CSF 5-HIAA
taken in late infancy (i.e., at age 6 months) predicting concentrations 1 year
later in middle childhood (Higley et al. 1992b)
and into adulthood (Higley et al. 1996d, 1996e).
Such findings suggest that as a potential risk factor, low CSF 5-HIAA concentrations
are present early in life and endure over time and across situations.
Influence
of the Early Environment on CNS Development
The
relationships between serotonin and behavior problems may begin early in life.
In one study, pubertal children of alcoholics who exhibited low concentrations
of serotonin in their blood received high ratings for behavioral disinhibition
and aggression (Twitchell et al. 1998, 2000). Similarly, children with high
ratings on measures of aggression and social deviancy and low ratings on competent
social behaviors displayed relatively low CSF 5-HIAA concentrations (Kruesi et al. 1990). Early events may adversely affect the
serotonin systems.
Animal
studies have shown that appropriate environmental input during developmental
periods is essential for the normal development of the CNS (Black et al. 1989;
Greenough 1987). Primate societies are explicitly
structured to assure that infants receive such input. When the primate order
diverged into Old and New World species, New World species evolved a new system
of parental care not typically seen in Old World species. Among most Old World
monkey societies, newborns initially develop their social skills within the
protective and watchful tutelage of their biological mothers. Mothers are especially
important social agents through which infant and juvenile monkeys develop the capacity to properly
inhibit and express emotions, including aggression (Bernstein and Ehardt 1986; Harlow 1969; Harlow and Harlow 1965; Higley and Suomi 1986, 1989).
In
research settings, instances in which peers are the primary teachers of young
monkeys (peer only rearing) have been widely used to study development in monkeys.
The subjects are removed from their mothers at birth and reared without adults
but with constant access to other age matched infants. Peer only reared monkeys
exhibit many deficits in impulse control. For example, as adolescents, when
alcohol is freely available, they are prone to excessive alcohol consumption
(Higley et al. 1991a), and during competitive
interactions, minor episodes of aggression are more likely to escalate to severe
aggression (Higley et al. 1994).
Interaction
between young monkeys and adults not only affects the acquisition and development
of behavior, but also plays a crucial role in the organization and proper development
of the CNS. For example, a number of studies using nonhuman primates have shown
that early experiences affect serotonin functioning during infancy and childhood
(Higley et al. 1992b, 1993, 1996e; Kraemer
et al. 1989). These studies have shown that adult influence, particularly maternal
input, is critical to the development of the CNS serotonin system. In the absence
of adult influence, the development of serotonin functioning is impaired. When
CSF 5-HIAA was obtained from peer only reared and mother reared monkeys 14,
30, 60, 90, 120, and 150 days after birth, parentally neglected, peer reared
subjects exhibited lower CSF 5-HIAA concentrations than did mother reared subjects
(Shannon et al. 1995). One study with a limited sample size suggested that the
effect of early rearing experiences on CSF 5-HIAA may disappear by adolescence
(Higley et al. 1991b). However, in a study in which
peer only reared and mother reared subjects were studied from infancy into adulthood,
the peer only reared subjects exhibited lower CSF 5-HIAA concentrations than
did the mother reared subjects in both infancy and adulthood (Higley
et al. 1996e).
Although
conclusions may be some what preliminary, recent studies indicate that early
adverse experiences may affect human as well as nonhuman primate CNS serotonin
functioning. Boys reared in adverse environments, such as with parents who are
absent or who show harsh parenting practices, show lower levels of a molecule
that binds with serotonin and mediates its activity (i.e., a serotonic
receptor) compared with boys reared in better family settings (Pine et al. 1996).
In a recent study of adults who had grown up in and were currently living in
poverty, researchers used a serotonin acting drug to stimulate the release of
the hormone prolactin and found that these adults
released less prolactin than did people reared in
better environments (Matthews et al. 2000). Therefore, some evidence indicates
that as with nonhuman primates, being brought up in a less favor able environment
may adversely affect CNS serotonin functioning in humans.
Alcohol
and Aggression in Nonhuman Primates
Some
studies of nonhuman primates have shown that alcohol increases the probability
of aggression in some individuals (Winslow and Miczek 1988). Evidence shows that alcohol is more likely to
increase aggression in subjects with impaired CNS serotonin functioning. For
example, we found that CSF 5-HIAA concentrations were negatively correlated
with high ratings for lifetime aggressiveness (Doudet
et al. 1995) -- that is, animals with low CSF 5-HIAA concentrations were more
likely to act aggressively throughout life. Moreover, whereas nonhuman primates
with low CSF 5-HIAA concentrations are typically more likely than others to
consume alcohol in excess and exhibit severe aggression, the administration
of sertraline, a compound that interferes with serotonins
activity (i.e., a serotonin reuptake inhibitor), reverses these aberrant behaviors
by reducing both alcohol consumption and aggression (Higley et al. 1998). Similarly, administration of the serotonin
precursor tryptophan blocks self aggression in primates
prone to self abuse (Weld et al. 1999).
Nevertheless,
although low CSF 5-HIAA concentrations are correlated with both excessive alcohol
consumption and impulsive, violent behavior (e.g., see Higley
et al. 1996c, 1996d, 1996e; Mehlman
et al. 1994), no long term studies have been conducted on the relationships
between serotonin, a life history of violent behavior, and alcohol-induced aggression.
Based on the above studies, we posited that low CSF 5-HIAA concentrations would
correlate with high lifetime rates of violent behavior and that a lifetime pattern
of violent behavior prior to alcohol exposure would predict aggressive behavior
under the influence of alcohol. Such a finding would indicate that individuals
who act aggressively under the influence of alcohol have a life long pattern
of aggression, and that in these individuals, alcohol probably increases the
likelihood of acting aggressively.
To
test this theory, monkeys were given alcohol intravenously to produce modest
levels of intoxication (i.e., a blood alcohol concentration of about 0.25 percent).
Then each animal was placed into a separate room, and researchers scored each
monkeys incidents of aggressive behavior toward a provoker. To obtain
these scores, an investigator entered the room, stood in the opposite corner
from the monkey, maintained eye contact, and directed an open mouth threat face
at the monkey every 30 seconds for 5 minutes, a procedure shown to elicit mild
aggression from macaques (Kalin and Shelton 1989). To test the relationship between
lifetime rates of aggression and aggression during intoxication, two researchers
who had extensive experience observing rhesus monkey behavior independently
rated the animals for aggressiveness using the monkeys medical treatment
records. These ratings were based on the frequency of removal from the home
cage for perpetrating violent behavior or receiving veterinary care for aggression
and the frequency and severity of wounds resulting from aggressive encounters.
Animals
rated as having a greater lifetime history of severe physical aggression were
more likely than others to exhibit higher rates of aggression while intoxicated.
Day-to-day home cage competitive aggression--which is used to defend status,
tends to be con-trolled and restrained, and generally does not result in injury--was
not correlated with aggression during intoxication. A life history of severe
traumatic, but not restrained, competitive aggression was also predictive of
aggression when the animals were intoxicated. Studies investigating humans also
show that alcohol is most likely to increase aggression in people already disposed
to violent behavior (Zhang et al. 1997).
Both
animal and human studies show that rates of aggression during intoxication are
stable within individuals (Miczek et al. 1992; Zhang
et al. 1997). Similarly, Jaffe and colleagues (1988) found that men who exhibit
aggressive behavior when intoxicated are more likely to have had high levels
of aggression as children. Our findings suggest that high rates of aggression
during intoxication are an extension of a life long pattern of impulsive, violent
aggression, rather than a special form of aggression. This finding is similar
to what has been found among men and nonhuman primates with low CSF 5-HIAA concentrations.
These studies show that impulsive, severe aggression, but not controlled or
competitive aggression, is correlated with diminished serotonin functioning
(Coccaro 1989; Higley et al. 1996b; Linnoila
et al. 1983). It is noteworthy that in a study of men selected at random from
the general population, reducing circulating levels of the serotonin precursor
tryptophan augmented rates of alcohol-induced aggression,
particularly under conditions of provocation (Pihl
et al. 1995).
Conclusions
and Future Directions
As
in humans, primates with low CNS serotonergic activity
exhibit behaviors indicative of impaired impulse control and unrestrained aggression.
The studies reviewed here suggest that impaired serotonin functioning may increase
the risk for aggression following alcohol consumption. Possibly, a common neurobiological
mechanism, such as low serotonin production and turnover, underlies both excessive
alcohol consumption and impulsive aggressive behavior. The reviewed studies
also show that interindividual differences in the CNS serotonin turnover
rate exhibit traitlike qualities and are stable across
time and settings, with day-to-day individual differences in CSF 5-HIAA concentrations,
for example, showing positive correlations. Such findings suggest that to the
extent that type II psychopathology is mediated by an impaired CNS serotonin
system, subjects with low CSF 5-HIAA concentrations may have a long term risk
for type II psychopathology and alcohol mediated violence that can be detected
early in life. Maternal and paternal genetic influences play major roles in
producing low CNS serotonin functioning beginning early in life. These genetic
influences on serotonin functioning are exacerbated by early rearing experiences,
particularly parental deprivation, thus affecting the risk for type II alcohol
psychopathology.
Whereas
impulsivity is thought to underlie the aggressive tendencies in serotonin-deficient,
type II alcoholics, little is known about other cognitions that are associated
with serotonin deficits. It would not be surprising to find that alcohol affects
other cognitive skills that are involved in controlling aggression. Studies
are under way to assess the extent to which cognitive deficits in nonhuman primates
with low CSF 5-HIAA concentrations are limited to measures of impulsivity or
result in a larger overall pattern of cognitive deficits. Moreover, temperaments
that accompany subjects with low CSF 5-HIAA concentrations may play a role in
the emotional instability that often is seen in humans with low CSF 5-HIAA concentrations.
Finally, serotonin has received much attention in this area of research. Clearly,
other neurotransmitters are involved in regulating aggression and alcohol consumption.
Subsequent studies are under way to assess their roles together with serotonin
in controlling aggression mediated by alcohol.
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