Download review neurochemical markers of alcoholism vulnerability in humans

Alcohol & Alcoholism Vol. 37, No. 6, pp. 522–533, 2002
REVIEW
NEUROCHEMICAL MARKERS OF ALCOHOLISM VULNERABILITY IN HUMANS
JOELLE E. RATSMA*, ODIN VAN DER STELT1 and W. BOUDEWIJN GUNNING
Academic Center for Child and Adolescent Psychiatry, University of Amsterdam, P. O. Box 12474, 1100 AL Amsterdam, The Netherlands and
1
Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
(Received 22 March 2002; accepted 10 May 2002)
Abstract — This review considers several neurochemical characteristics or trait markers that may be related to a genetic vulnerability
to alcoholism. These potential neurochemical markers of alcoholism vulnerability include indices of activity of five neurotransmitter
systems, namely γ-aminobutyric acid, serotonin, dopamine, noradrenaline and β-endorphin. This review evaluates whether potential
abnormalities in these neurochemical indices, as assessed in alcoholics and in the children of alcoholics, meet three criteria for
the identification of a vulnerability marker of alcoholism: (1) heritable; (2) associated with alcoholism in the general population; (3) state
independent. It is concluded that, at present, indices of increased baseline activity of the serotonin transporter in platelets and of
increased responsiveness of the pituitary β-endorphin system may fulfil each of these three criteria. Additional research efforts should
be devoted to the evaluation of trait marker properties of neurochemical indices in individuals at high risk for alcoholism.
INTRODUCTION
obscure the relation between a marker and a clinical
syndrome. Family studies are required to determine whether
the trait marker co-segregates with alcoholism within families,
since all members of a family are part of the same population.
However, there is as yet little information on the cosegregation of neurochemical markers with alcoholism in
affected families.
This review evaluates whether abnormalities in certain
neurochemical indices, as assessed in alcoholics and in COA,
meet the three above-mentioned criteria for the identification
of a trait marker of alcoholism. Thus, the issue is addressed
whether a certain neurochemical abnormality is associated
with alcoholism, or with a given subtype of alcoholism, in the
general population. To clarify this issue, studies are reviewed
in which measures of neurochemical activity are compared
between alcoholics and unrelated non-alcoholic controls. In
addition, to evaluate whether a certain neurochemical abnormality is heritable, this review focuses on twin and adoption
studies to find out whether the abnormality is mediated largely
by genetic, as opposed to environmental, factors. Finally, to
evaluate whether the neurochemical abnormality is state independent, that is, not reflecting the current state of alcoholism
but present throughout an individual’s lifetime, studies are
reviewed in which the neurochemical measure of interest is
compared between individuals at high risk for alcoholism and
low-risk controls. As opposed to this high-risk research,
studies of (abstinent) alcoholics cannot distinguish between
state and trait markers of alcoholism. Even after many years of
abstinence from alcohol, the prolonged abuse of alcohol may
have had long-term neurotoxic effects, potentially affecting
neurochemical trait markers in abstinent alcoholics.
This review will focus on indices of neurochemical
markers. These are indices of changes in neurotransmitter
systems that are studied as trait markers in alcoholism, in
accordance with the three above-mentioned criteria. The state
effect of alcohol on changes in neurotransmission has been
widely studied within neurotransmitter systems. It has, for
example, been the main approach adopted in studies of the
N-methyl-D-aspartate receptor of the glutamatergic system.
Alcoholism is generally assumed to be a multifactorial
disease, in which polygenic influences and environmental
influences interact (Goldman, 1995). This conceptualization
of alcoholism has been inferred from adoption studies
(Goodwin et al., 1973; Bohman et al., 1981; Cadoret et al.,
1985; Cloninger et al., 1985) and twin studies (Romanov
et al., 1991; Kendler et al., 1994, 1997; Reed et al., 1996; Treu
et al., 1996; Heath et al., 1997). The question arises as to what
is inherited in alcoholism? Over the past two decades, research
on so-called phenotypic trait or vulnerability markers of
alcoholism has attempted to shed light on this basic issue. This
research has focused on various behavioural, electrophysiological, and neurochemical characteristics that may be related
to alcoholism vulnerability (Begleiter and Porjesz, 1988;
Farren and Tipton, 1999; Schuckit, 1999; Van der Stelt, 1999).
This review evaluates whether abnormalities in certain
neurochemical indices, as assessed in alcoholics and in the
children of alcoholics (COA), may serve as neurochemical
markers of alcoholism vulnerability.
A trait or vulnerability marker may be defined as a
‘heritable trait, associated with a causative pathophysiological
factor in an inherited disease’ (Gershon and Goldin, 1986). As
opposed to a diagnostic marker, a vulnerability or pathophysiological marker is not required to have high sensitivity or high
specificity to a certain clinical disorder (Nurnberger, 1992).
While sensitivity and specificity are not critical criteria, it has
been proposed that a certain behavioural or biological trait
should meet at least three basic criteria in order to be considered as a trait marker (Goldin et al., 1986): (1) heritable;
(2) associated with the disease in the general population; (3) state
independent. The reason for these requirements is to prevent
false-positive or false-negative conclusions about the validity
of a certain characteristic as a trait marker due to certain
conditions, particularly population stratification, which may
*Author to whom correspondence should be addressed.
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© 2002 Medical Council on Alcohol
NEUROCHEMICAL MARKERS OF ALCOHOLISM VULNERABILITY
However, this review focuses on indices of changes within
five neurotransmitter systems that may have a trait effect on
alcoholism. This includes the following neurotransmitters:
(1) γ-aminobutyric acid (GABA) (Frye and Breese, 1982;
Koob et al., 1986); (2) 5-hydroxytryptamine (serotonin;
importantly, the impaired functioning of CNS serotonin may
result in diminished impulse control, a neurobiological feature
of type II alcoholism) (Linnoila et al., 1983; Cloninger, 1987);
(3) dopamine (Gessa et al., 1985; Imperato and Di Chiara,
1986; Wise and Bozarth, 1987); (4) noradrenaline (Cloninger,
1994); (5) β-endorphin. This last topic is the subject of two
contradictory hypotheses. The endorphin compensation or deficiency hypothesis states that alcohol use compensates for a
predisposed or acquired deficiency of endorphinergic receptor
activity (Blum, 1983; Volpicelli et al., 1985; Erickson, 1990),
whereas the opioid surfeit hypothesis states that alcohol use is
increased by a surfeit of opioidergic receptor activity, rather
than a deficit (Reid and Hunter, 1984; Hubbell et al., 1986;
Reid et al., 1991). Both hypotheses are equally applicable
to other neurotransmitter systems. G-proteins and adenylyl
cyclase (or any other secondary messenger systems) have not
been included in this review as they are not neurotransmitters.
GENERAL PRINCIPLES AND OBSERVATIONS FROM
ANIMAL STUDIES
This review focuses on central and peripheral indices
of activity of the five neurotransmitter systems, GABA,
serotonin, dopamine, noradrenaline and β-endorphin. On the
basis of findings mainly from animal research, each of these
neurotransmitter systems has been implicated in the aetiology
and pathophysiology of alcoholism. The requisite theoretical
background was provided by animal studies carried out in the
1950s, which reported that changes in neurotransmission in rat
brains led to addiction-related behaviour. Olds and Milner
(1954) found that intracranial stimulation of the hypothalamus
and associated structures can act to reinforce operant
conditioning. Brain stimulation itself activated systems that
were normally activated by a reinforcing stimulus, such as
feeding or drinking (Deutsch and Howarth, 1963). Brain selfstimulation (using electrodes placed in the vicinity of
dopaminergic neurons) was accompanied by locomotor
activation and positive reinforcement (Routtenberg, 1978).
Similarly, it has been hypothesized that euphoria and drugseeking behaviour (whether induced by alcohol or other
commonly abused substances) arise from activation of the
mesolimbic dopaminergic reward pathways of the brain
(Gessa et al., 1985; Imperato and Di Chiara, 1986; Wise and
Rompre, 1989). Endogenous opioids were also reported to be
involved in reward processes during brain self-stimulation
(Schaefer, 1988). The intracerebroventricular self-administration
of β-endorphin in rats has demonstrated that this substance
acts as an endogenous positive reinforcer of behaviour. Thus,
it might intrinsically control behaviour such as the selfadministration of addictive drugs (Van Ree et al., 1979). In
addition, the opioid antagonist naltrexone blocks the release
of dopamine at the level of the nucleus accumbens, which
follows alcohol administration (Benjamin et al., 1993).
However, the results of animal and human studies suggest
that the effects of alcohol consumption are not restricted to
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dopamine and endogenous opioids. Alcohol consumption may
also affect several other brain neurotransmitters, including
noradrenaline (Ahlenius et al., 1973; Brown and Amit, 1982),
serotonin (McBride et al., 1988; Murphy et al., 1988) and
GABA (Hwang et al., 1990; McBride et al., 1990). As alcohol
seems to activate most neurotransmitter pathways, the question arises whether vulnerability to alcoholism is associated
with a pre-existing deficit within neurotransmitter pathways.
TYPES OF HUMAN STUDIES
Human research on neurochemical vulnerability markers
of alcoholism mainly consists of those at baseline, studies
assessing neurochemical indices following a pharmacological
challenge, and post-mortem studies. Baseline studies attempt
to identify individual variations in the trait marker, in the
absence of any interference from alcohol. Challenge studies
often attempt to identify individual variations of the trait
marker after alcohol intake, while some studies use challenge
drugs other than alcohol (acting on one or more of the five
neurotransmitter systems under review). This is because any
individual variation in sensitivity to the effects of alcohol
(or other challenge drugs) might be associated with a variation
in the risk of alcoholism (Schuckit et al., 1983; Schuckit and
Smith, 1996). Generally, post-mortem studies simply reveal
that alcohol has a toxic effect on neurotransmitter systems.
The reported results do not usually draw a distinction between
the trait and the state effects of alcohol. Baseline and challenge studies are not only performed in alcoholics, but also in
high-risk individuals, such as COA. COA represent a unique,
high-risk group in studies of the state independence of the
trait marker. This is because they have a heightened risk of
alcoholism, and because the youngest groups do not generally
consume alcohol on a regular basis (Eskay and Linnoila, 1991;
Hill et al., 1991; Sher et al., 1991). This review includes
neurochemical-trait-marker studies that investigated changes
in the levels of neurotransmitters (or their metabolites) in
cerebrospinal fluid (CSF) or plasma, and changes in the
number, activity and affinity of receptors in the brain. Also
included in this review are studies performed on the brain
either directly or indirectly (by means of peripheral assessments). There is still some doubt concerning the degree of
correspondence between the latter measurements and
neurotransmitter activity in the central regions. However, there
are problems associated with making some of the abovementioned measurements in neurobiological studies on humans.
For example, it may be ethically problematic to subject one
particular group of high-risk individuals — the young COA —
to invasive or extensive examinations. This is because such
examinations include investigations of the CSF, alcohol
challenge tests, and various brain-imaging techniques that use
radioactive substances. Neurobiological research in high-risk
groups, on the other hand, can be carried out with the aid of
peripheral blood samples, using platelets for example (Ratsma
et al., 1999).
In this review, results from challenge studies, baseline
studies, and post-mortem studies of alcoholics and their
children are evaluated to determine whether certain neurochemical abnormalities meet the three criteria outlined above
for the identification of a vulnerability marker of alcoholism.
J. E. RATSMA et al.
524
γ-AMINOBUTYRIC ACID
Pharmacological properties
GABA acts on the GABAA receptor, which is a transmittergated chloride channel. GABAA receptors are composed of
three subunits: α, β, and γ. Fourteen variants have been identified to date, six α variants, three β variants, three γ variants
and two δ variants. Alcohol and benzodiazepines act on
the γ subunit of the GABAA receptor (Suzdak et al., 1986),
whereas GABA acts on the α subunit. Changes in the subunit
expression of GABAA receptors are reflected in the pharmacological properties of the receptors (Levitan et al., 1988). By
contrast, GABAB receptor is a G-protein-coupled receptor
without a benzodiazepine binding site.
Research findings
In the post-mortem frontal cortex, expression of mRNA
for the GABAA receptor’s α1 and β3 subunits is higher in
alcoholics than in controls (Lewohl et al., 1997; Mitsuyama
et al., 1998). These findings are consistent with the results of
two post-mortem studies, in which non-cirrhotic alcoholics
were found to have more GABA receptors in their cerebral
cortex and superior frontal gyrus than the control subjects
(Tran et al., 1981; Dodd et al., 1992). Brain imaging studies
using single-photon emission computed tomography (SPECT)
(Abi-Dargham et al., 1998; Lingford-Hughes et al., 1998)
have found that, in alcoholics and type II alcoholics, the
benzodiazepine receptor distribution volume in the anterior
cingulate, the prefrontal, frontal, parietal and temporal cortices and in the cerebellum was reduced, relative to controls.
Similarly, challenge studies using positron emission tomography (PET) revealed the existence of a blunted glucose
utilization response to lorazepam in alcoholics (in the basal
ganglia and thalamus) and in COA (in the cerebellum),
relative to controls (Volkow et al., 1993, 1995). These SPECT
and PET findings indicate abnormalities in brain GABA–
benzodiazepine receptor reactivity in alcoholics and individuals at high risk for alcoholism. Finally, in alcoholics in the
early phase of abstinence and those who had been abstinent
for 1–2 years, a challenge with γ-hydroxybutyric acid (a GABA
agonist) showed a blunted growth-hormone (GH) response,
relative to controls (Vescovi and Coiro, 1995, 1997). This also
may represent reduced GABA neurotransmitter reactivity.
In apparent contrast to these findings of blunted, postchallenge GABA responses in alcoholics and COA, one study
has reported that GABA plasma levels of COA increased
much more in response to alcohol than was the case in
controls (Moss et al., 1990). Another study, however, found no
significant difference in the GABA plasma levels between
COA and controls following a diazepam challenge (Cowley
et al., 1996).
A twin study (Berrettini et al., 1982) showed that the interindividual differences in baseline plasma level of GABA are
heritable. Abstinent adult male alcoholics were found to have
a lower baseline plasma GABA level than non-alcoholics
(Coffman and Petty, 1985; Petty et al., 1993). In COA, one
study showed similarly that COA had lower baseline plasma
levels of GABA than controls (Moss et al., 1990), but another
study found no significant group difference (Cowley et al.,
1996). The young adult COA in the latter study were selected
for having no history of alcohol or drug abuse at ages 18–25
years. This may mean that they were at reduced risk of an
early onset of alcoholism, which, in turn, may have biased the
sample.
In conclusion, a lower baseline plasma level of GABA
seems to fulfil two criteria for the identification of a vulnerability marker of alcoholism. Inter-individual differences
in measures of baseline plasma level of GABA appear to be
heritable and alcoholics show reduced levels of GABA in their
plasma (see Tables 1 and 2). It remains to be determined,
however, whether a lower baseline plasma level of GABA in
alcoholics represents a state marker or a trait marker that can
also be detected in individuals at high risk for alcoholism.
Similarly, measures of decreased GABA receptor responsiveness appear to fulfil two trait marker criteria. Decreased
GABA receptor responsiveness seems to characterize both
alcoholics and their children. It remains to be clarified whether
this characteristic is genetically mediated, though.
5-HYDROXYTRYPTAMINE
Pharmacological properties
5-Hydroxytryptamine (5-HT, serotonin) acts on 15 known
subtypes of 5-HT receptors, which fall into four structural and
functional ‘families’ of receptors. Three types (5-HT1, 5-HT2
and 5-HT4) are coupled to G-proteins, whereas the 5-HT3
receptor acts as a 5-HT-gated ion channel. Although the genes
of three other types (5-HT5, 5-HT6 and 5-HT7) have been
cloned, their physiological functions are as yet unknown. The
5-HT transporter is located in the serotonergic axon terminals,
where it terminates 5-HT action in the synapse, and in platelet
membranes, where it takes up 5-HT from the blood (Blakely
et al., 1991). The synthesis of serotonin is influenced by the
amount of the precursor tryptophan in the brain. In order to
gain entry to the brain, tryptophan has to compete with other
amino acids. The extent to which tryptophan in the blood
circulation is available to the brain may be decreased in alcoholics with a positive family history (see review by Badawy,
1999). The concentration of 5-hydroxyindol-3-yl-acetic acid
(5-HIAA; the major metabolite of serotonin) in CSF seems to
reflect central serotonergic activity (Banki and Molnar, 1981).
Research findings
Post-mortem studies of brain tissue from alcoholics have
revealed reduced 5-HT transporter binding in the hippocampus (Gross-Isseroff and Biegon, 1988; Chen et al., 1991).
Similarly, binding was found to be reduced in the 5-HT1A
receptors of alcohol consumers relative to those of subjects
who did not (Dillon et al., 1991).
Following a challenge with a mixed serotonin partial
agonist, m-chlorophenylpiperazine (mCPP), the adrenocorticotropic hormone response and the serotonergic activation in
the basal ganglia circuits (involving orbital and prefrontal
cortices) were found to be lower in alcoholics, than in nonalcoholics (Krystal et al., 1994; George et al., 1997; Hommer
et al., 1997). These findings were reflected by a decrease in
the brain’s utilization of glucose, as shown by PET. This
suggests that 5-HT2C receptors in alcoholics exhibit reduced
sensitivity. Other studies reported challenges in which GH,
prolactin and cortisol exhibited blunted responses to
fenfluramine (releasing serotonin as an indirect agonist),
NEUROCHEMICAL MARKERS OF ALCOHOLISM VULNERABILITY
525
Table 1. Trait marker criteria for neurochemical baseline activities and responses to challenges
Neurochemical
markers
GABA-ergic activity
Baseline (plasma GABA)
Challenge
(receptor reactivity)
Serotonergic activity
Baseline
(5-HT transporter activity)
Challenge
(receptor reactivity)
Dopaminergic activity
Baseline
(plasma or CSF HVA)
Challenge
(receptor activity)
Noradrenergic activity
Baseline
(CSF noradrenaline)
Challenge
(receptor reactivity)
β-Endorphinergic activity
Baseline
(plasma or CSF β-endorphin)
Challenge
(pituitary reactivity)
Presence in alcoholics
(compared with controls)
Heritable
State independent
(presence in high-risk groups,
compared with controls)
Yes
—
Decreased
Decreased
Inconsistent
Decreased
Yes
Increased
—
Increased
(long abstinence)
Decreased
—
Inconsistent
Inconsistent
—
Decreased
(long abstinence)
—
—
Decreased
—
—
Decreased
—
—
Decreased
Yes
Increased
Decreased
(receptor density)
Increased
Increased
(one study)
GABA, γ-aminobutyric acid; 5-HT, serotonin or 5-hydroxytryptamine; CSF, cerebrospinal fluid; HVA, homovanillic acid.
Table 2. γ-Aminobutyric acid (GABA) studies
GABA post-mortem studies
Alcoholics vs controls:
Increased expression of GABAA
receptors in frontal cortex (Lewohl
et al., 1997; Mitsuyama et al., 1998)
Alcoholics vs controls:
Increased number of GABA
receptors; frontal and cerebral
cortex studies (Tran et al., 1981;
Dodd et al., 1992)
GABA challenge studies
Alcoholics vs controls:
Decreased glucose utilization
response to agonist lorazepam
in basal ganglia, thalamus
(Volkow et al., 1993)
Alcoholics vs controls:
Decreased growth hormone
response to agonist GHB
(Vescovi and Coiro, 1995,
1997)
COA vs controls:
Decreased glucose utilization
response to agonist lorazepam in
cerebellum (Volkow et al., 1995)
COA vs controls:
Increased plasma GABA levels
after alcohol (Moss et al., 1990)
COA vs controls:
Indifferent plasma GABA
levels after agonist diazepam
(Cowley et al., 1996)
GABA baseline studies
Alcoholics vs controls:
Decreased benzodiazepine
receptor density in the cortex
(Lingford-Hughes et al., 1998)
Alcoholics type II vs controls:
Decreased benzodiazepine
receptor density in the cortex
and cerebellum (Abi-Dargham
et al., 1998)
Alcoholics vs controls:
Decreased GABA plasma
levels (Coffman and Petty,
1985; Petty et al., 1993)
COA vs controls:
Decreased plasma GABA
levels (Moss et al., 1990)
COA vs controls:
Indifferent plasma GABA
levels (Cowley et al., 1996)
GHB, γ-hydroxybutyric acid; COA, children of alcoholics.
mCPP and sumatriptan (a 5-HT1D receptor agonist). The
subjects in question were active alcoholics and abstaining
alcoholics who had not used alcohol for 1–2 years (Balldin
et al., 1994; Krystal et al., 1996; Vescovi and Coiro, 1997).
Conversely, an elevated cortisol response was reported after a
challenge with fenfluramine in a high-risk group of attentiondeficit hyperactivity disorder (ADHD) boys, versus ADHD
boys with a low risk of alcoholism; the assessed degree of risk
was based on the presence or absence of parental alcoholism
(Schulz et al., 1998).
The results of a study using SPECT showed a reduction in
brain-stem serotonin transporters in alcoholics (after 3–5 weeks
of abstinence) relative to controls (Heinz et al., 1998). A
decrease in alcoholism-related serotonin transport was associated with a decrease in the 5-HT content of platelets in
alcoholics (Banki, 1978). It also corresponded to a decrease
526
J. E. RATSMA et al.
(relative to controls) in the uptake of [3H]5-HT by platelets in
alcoholics undergoing a 2-week period of detoxification (Kent
et al., 1985). A twin study found that 5-HT uptake in blood platelets is moderated by genetic factors (Meltzer and Arora, 1988).
Alcoholics who had abstained from alcohol for periods of
1 month to 22 years (and their children) were found to have a
higher [3H]5-HT platelet uptake than controls (Ernouf et al.,
1993). This is contrary to the findings in active alcoholics and
in those who had only recently started practising abstinence. In
addition, male COA were found to have a higher Vmax (capacity)
of platelet serotonin uptake than controls (Rausch et al., 1991).
As a result, it was suggested that an increase (rather than a
decrease) in platelet serotonin transport was a trait marker for
alcoholism (Ernouf et al., 1993). It is important to note that earlyonset alcoholics exhibit higher platelet-serotonin-transporter
activity than late-onset alcoholics (Javors et al., 2000).
With regard to 5-HIAA, the levels of this metabolite in CSF
taken from abstinent alcoholics of both sexes were shown to
be lower than in controls (Ballenger et al., 1979; Banki, 1981;
Borg et al., 1985). Alcoholic impulsive offenders had lower
CSF 5-HIAA levels than alcoholic non-impulsive offenders,
whereas the controls had intermediate levels (Virkkunen
et al., 1994). Early-onset alcoholics had lower 5-HIAA levels
than late-onset alcoholics (Fils-Aime et al., 1996). This was
consistent with studies demonstrating low precursor serotonin
availability in early-onset alcoholism (Buydens-Branchey
et al., 1989). CSF 5-HIAA concentrations might be a staterelated phenomenon, since essential dietary fatty acids could
cause changes in CSF 5-HIAA concentrations (Hibbeln et al.,
1998). However, an animal study of CSF 5-HIAA levels in
monkeys revealed a high degree of intra-individual stability
(Raleigh et al., 1992). The above-mentioned CSF 5-HIAA
studies, which were only performed in alcoholics, were consistent with the hypothesis that decreased CSF 5-HIAA levels
represent a central serotonergic deficit in a subgroup of earlyonset male alcoholics (Linnoila et al., 1983).
In conclusion, the inter-individual differences in baseline
serotonin transporter activity in platelets seem to be heritable.
There are also indications that baseline serotonin transporter
activity is elevated in COA and in alcoholics who have been
abstinent for a protracted period of time. The measurement of
increased baseline serotonin transporter activity in platelets
would therefore appear to fulfil three of the criteria for trait
markers for alcoholism. Challenge studies of serotonin receptor
responsiveness have shown (albeit inconsistently) a decreased
5-HT response in alcoholics. There is also one report of an
elevated response in COA, thus one criterion may have been
met (Tables 1 and 3).
Table 3. Serotonin studies
Serotonin post-mortem studies
Alcoholics vs controls:
Decreased binding 5-HT transporter
(Gross-Isseroff and Biegon, 1988;
Chen et al., 1991)
Alcohol consumers vs controls:
Decreased binding 5-HT1A receptor
(Dillon et al., 1991)
Serotonin challenge studies
Alcoholics vs controls:
Decreased glucose utilization in
basal ganglia circuits and ACTH
response to partial 5-HT agonist
mCPP (Hommer et al., 1997)
Alcoholics vs controls:
Decreased ACTH response to
mCPP (Krystal et al., 1994;
George et al., 1997)
Alcoholics vs controls:
Decreased prolactin and cortisol
response to serotonin (Balldin
et al., 1994; Krystal et al., 1996),
Alcoholics vs controls:
Decreased growth hormone
response to 5-HT1D receptor
agonist sumatriptan (Vescovi
and Coiro, 1997)
COA with ADHD vs controls with
ADHD:
Increased cortisol response to
5-HT agonist fenfluramine
(Schultz et al., 1998)
Serotonin baseline studies
Alcoholics vs controls:
Decreased brainstem serotonin
transporters (SPECT) (Heinz et al.,
1998)
Alcoholics vs controls:
Decreased platelet serotonin uptake
and content (Banki, 1978; Kent
et al., 1985)
Alcoholics vs controls:
Increased platelet serotonin uptake
(Ernouf et al., 1993)
(long-term abstinence)
COA vs controls:
Increased platelet serotonin uptake
(Rausch et al., 1991;
Ernouf et al., 1993)
Early-onset vs Late-onset
alcoholics:
Increased platelet serotonin uptake
(Javors et al., 2000)
Alcoholics vs controls:
Decreased CSF 5-HIAA level
(Ballenger et al., 1979; Banki, 1981;
Borg et al., 1985)
Early-onset vs late-onset
alcoholics:
Decreased CSF 5-HIAA level
(Fils-Aime et al., 1996)
Impulsive vs non-impulsive
alcoholics:
Decreased CSF 5-HIAA
levels (Virkkunen et al., 1994)
5-HT, serotonin or 5-hydroxytryptamine; ACTH, adrenocorticotropic hormone; mCPP, m-chlorophenylpiperazine; SPECT, single-photon emission
computed tomography; COA, children of alcoholics; ADHD, attention-deficit hyperactivity disorder; CSF, cerebrospinal fluid; 5-HIAA,
5-hydroxyindol-3-yl-acetic acid.
NEUROCHEMICAL MARKERS OF ALCOHOLISM VULNERABILITY
DOPAMINE
Pharmacological properties
Dopamine acts on at least five dopamine receptors, which
are divided into two major groups: (1) the D1-like receptors
(D1 and D5); (2) the D2-like receptors (D2, D3 and D4). All
dopamine receptors are G-protein-coupled receptors, the
D1 receptor stimulates adenylyl cyclase activity, whereas the
D2 receptor inhibits adenylyl cyclase activity. Homovanillic
acid (HVA) is the major metabolite of dopamine.
Research findings
In one challenge study, male alcoholics who had been abstinent for a period of 7 years exhibited reduced postsynapticdopamine-receptor sensitivity relative to controls. This was
expressed as a reduced maximum GH response to the agonist
apomorphine (Balldin et al., 1992). This report was consistent
with the reduction in GH response (relative to controls) seen
in alcoholics who had been abstaining from alcohol for periods
ranging from 8 days to 6 months (Dettling et al., 1995). However, an earlier study showed that, after a withdrawal period of
4–7 days, alcoholics exhibited an elevated GH response to
dopamine infusion, whereas their GH responses to apomorphine were similar to those of controls (Annunziato et al.,
1983; Balldin et al., 1985). The dopamine receptor involved in
GH secretion was thought to be a D2-type receptor, whereas
D1 receptors are believed to be involved in prolactin secretion
(Fabbrini et al., 1988). The reduction in postsynapticdopamine-D2-receptor sensitivity in alcoholics who had been
abstaining from alcohol for ≥8 days might be a trait marker for
alcoholism. This may be consistent with the dopaminergic
hypothesis of alcoholism (Eckardt et al., 1998; Koob et al.,
1998; Ikemoto and Panksepp, 1999). It may also account for
the fact that, prior to detoxification, active alcoholics exhibit
a reduced prolactin response to the antagonist haldol. This
response reverted to control values 13 days after detoxification
(Markianos et al., 2000).
Baseline studies of HVA found that alcoholics had lower
levels of this metabolite in their plasma than did control
subjects (Fulton et al., 1995). However, the HVA levels found
527
in the CSF of alcoholics and in the plasma of male COA were
similar to those found in controls (Roy et al., 1990; Limson
et al., 1991; Howard et al., 1996; George et al., 1999; Petrakis
et al., 1999). Early-onset alcoholics were found to have lower
levels of HVA in their CSF than late-onset alcoholics (FilsAime et al., 1996). These results were contradicted by other
studies, however, which found increased CSF HVA levels in
early-onset alcoholics relative to late-onset alcoholics (George
et al., 1999; Petrakis et al., 1999).
In conclusion, these inconsistent baseline studies show
that the changes in dopaminergic neurotransmission that are
associated with alcoholism do not appear to fulfil either of the
reviewed criteria for a trait marker of alcoholism. The challenge studies in alcoholics who had been abstaining for a
protracted period of time showed a decreased dopamine receptor
response that seems to fulfil one of the criteria for a trait
marker, namely that it is present in alcoholics (Tables 1 and 4).
NORADRENALINE
Pharmacological properties
Noradrenaline acts on various adrenergic receptors (two
α receptors and two β receptors), all of which are G-protein
coupled. The α1 adrenergic receptor is linked to the mobilization
of intracellular calcium by phospholipase C, whereas the α2
adrenergic receptor inhibits adenylyl cyclase. The β1 and β2
adrenergic receptors stimulate adenylyl cyclase. A major metabolite of noradrenaline is 3-methoxy-4-hydroxyphenylglycol.
Research findings
Reduced numbers of melanin-containing noradrenergic
neurons were found in the post-mortem locus coeruleus of
alcoholics, which indicates a lower level of noradrenergic
neurotransmission (Arango et al., 1994). This was inconsistent
with the findings of Baker et al., (1994), however, which
showed no differences post-mortem. In a baseline study,
CSF and plasma were continuously sampled in controls and
in alcoholics who had been abstaining for 38–124 days
(Geracioti et al., 1994). The results showed that CSF
Table 4. Dopamine studies
Dopamine challenge studies
Alcoholics vs controls:
Decreased GH response to apomorphine
(Balldin et al., 1992; Dettling et al., 1995)
(long-term abstinence)
Alcoholics vs controls:
Increased GH response to dopamine infusion
(Annuziato et al., 1983) (short-term abstinence)
Alcoholics vs controls:
Indifferent GH response to apomorphine
(Balldin et al., 1985) (short-term abstinence)
Alcoholics vs controls:
Decreased prolactin response to haldol during
alcohol intake, indifferent response after
detoxification (Markianos et al., 2000)
Dopamine baseline studies
Alcoholics vs controls:
Indifferent CSF HVA levels (Roy et al., 1990; Limson et al.,
1991; George et al., 1999; Petrakis et al., 1999)
Alcoholics vs controls:
Decreased HVA plasma levels (Fulton et al., 1995)
COA vs controls:
Indifferent HVA plasma levels (Howard et al., 1996)
Early-onset vs late-onset alcoholics:
Decreased CSF HVA levels
(Fils-Aime et al., 1996)
Early-onset vs late-onset alcoholics:
Increased CSF HVA levels
(George et al., 1999; Petrakis et al., 1999)
GH, growth hormone; HVA, homovanillic acid; CSF, cerebrospinal fluid; COA, children of alcoholics.
J. E. RATSMA et al.
528
noradrenaline was lower in alcoholics than in controls, which
was consistent with the findings of Arango et al. (1994).
Although there were no differences in terms of the noradrenaline
levels in plasma (Geracioti et al., 1994), alcoholics were found
to have a lower basal level relative to controls (Ehrenreich
et al., 1997).
The same study reported that, following a challenge with
human CRF or a stress test, the noradrenaline response was
unaffected (Ehrenreich et al., 1997). In addition, alcoholics
were found to have a blunted GH response to clonidine (an
α2 adrenergic receptor agonist) in comparison to controls. The
effect was found shortly after detoxification and also after
6 months of abstinence (Glue et al., 1989; Berggren et al.,
2000). Similarly, in comparison to controls, alcoholics were
found to have an enhanced cortisol response to yohimbine
(an α2 adrenergic receptor antagonist). This reflects the downregulation of postsynaptic noradrenergic receptors that is
observed in alcoholics (Krystal et al., 1996).
In conclusion, both the basal studies of decreased noradrenaline levels in CSF (but not in plasma) and the challenge
studies of receptor responsiveness showed that a decrease in
noradrenergic neurotransmission seems to fulfil one criterion
for a trait marker, that it should be present in alcoholics
(Tables 1 and 5).
β-ENDORPHIN
Pharmacological properties
Opioids act on three major classes of opiate receptors:
µ, δ and κ. These G-protein-coupled receptors, which inhibit
adenylyl cyclase, are distributed throughout the CNS. The
distribution of β-endorphin, however, is somewhat restricted.
It is primarily confined to neurons in the hypothalamus, which
send projections to the periaqueductal grey region and to
noradrenergic nuclei in the brain stem.
Research findings
Baseline studies in humans have shown that, in individuals
at risk of alcoholism, the basal activity level of the endogenous
opioid system might be lower than in individuals with a low
risk of alcoholism (Volpicelli et al., 1990). Such a finding
would be consistent with the opioid-deficiency hypothesis.
This was supported by the fact that the β-endorphin levels in
the plasma and CSF of alcoholics were lower than those found
in controls (Genazzani et al., 1982; Aguirre et al., 1990). It
was reported in one study that alcohol may have an equally
strong effect on the central levels of β-endorphin as it does on
peripheral levels (Peterson et al., 1996). A lower dose of
naloxone completely blocked any reduction in synaptic opioid
content and/or opioid receptor density in high-risk individuals.
This indicates that endogenous hypothalamic opioid activity
levels in these individuals are lower than those in low-risk
subjects (Wand et al., 1998). Using a placebo, it was found
that cortisol levels in high-risk subjects were higher than
in low-risk subjects. This indicates that there is probably no
increase in opioid receptor affinity, as this would result in
more inhibitory tone, and lower cortisol levels.
With regard to challenge studies, the opioid antagonist
naloxone produced higher cortisol and β-endorphin responses
in alcoholics than in controls. It also caused alcoholics
to reduce their consumption of ethanol (Kemper et al., 1990;
O’Malley et al., 1992; Volpicelli et al., 1992). The ingestion
of a moderate dose of ethanol induced a dose-dependent
increase in plasma β-endorphin levels in high-risk subjects,
but not in low-risk subjects. Although these elevated levels
were not produced by the peripheral adrenal cortisol system,
the more central pituitary β-endorphin system showed an
increased sensitivity to ethanol. This might mediate ethanol’s
reinforcing effects in high-risk subjects (Gianoulakis et al.,
1989, 1996). These baseline and challenge studies are consistent with the opioid-deficiency hypothesis. In a twin study,
the inter-individual difference in β-endorphin response to
alcohol was found to be heritable (Froehlich et al., 2000).
In conclusion, the measurement of decreased β-endorphin
baseline activity appears to fulfil two of the reviewed criteria
for a trait marker of alcoholism. These are lower β-endorphin
levels in alcoholics and decreased opioid receptor density
in COA. However, the measurement of increased β-endorphin
responsiveness seems to fulfil three such criteria in that it is
heritable, it is present in alcoholics and it is state independent
(present in COA). (Tables 1 and 6).
Table 5. Noradrenaline studies
Noradrenaline post-mortem studies
Alcoholics vs controls:
Decreased number of noradrenergic
neurons in locus ceruleus
(Arango et al., 1994)
Alcoholics vs controls:
Indifferent number of noradrenergic
neurons in locus ceruleus (Baker
et al., 1994)
Noradrenaline challenge studies
Alcoholics vs controls:
Indifferent response of
noradrenaline in plasma after
CRF or a stress test (Geraciotti et al.,
1994; Ehrenreich et al., 1997)
Alcoholics vs controls:
Increased cortisol response to
antagonist yohimbine (Krystal
et al., 1996)
Alcoholics vs controls:
Decreased growth hormone
response to agonist clonidine
(Glue et al., 1989; Berggren
et al., 2000)
CSF, cerebrospinal fluid; CRF, corticotropin-releasing factor.
Noradrenaline baseline studies
Alcoholics vs controls:
Decreased levels of noradrenaline
in CSF (Geraciotti et al., 1994)
Alcoholics vs controls:
Indifferent levels of noradrenaline
in plasma (Geraciotti et al., 1994)
Alcoholics vs controls:
Decreased levels of noradrenaline
in plasma (Ehrenreich et al., 1997)
NEUROCHEMICAL MARKERS OF ALCOHOLISM VULNERABILITY
529
Table 6. β-Endorphin studies
β-Endorphin challenge studies
Alcoholics vs controls:
Increased cortisol response to naloxone
(Kemper et al., 1990)
Alcoholics vs controls:
Increased β-endorphin response to naloxone
(O’Malley et al., 1992)
Alcoholics vs controls:
Decreased alcohol consumption with naloxone
(Volpicelli et al., 1992)
COA vs controls:
Increased β-endorphin response to alcohol
(Gianoulakis et al., 1989, 1996)
β-Endorphin baseline studies
Alcoholics vs controls:
Decreased basal level of β-endorphin in plasma
(Aguirre et al., 1990)
Alcoholics vs controls:
Decreased basal level of β-endorphin in CSF
(Genazzani et al., 1982)
COA vs controls:
Decreased opioid receptor density
(Wand et al., 1998)
CSF, cerebrospinal fluid; COA, children of alcoholics.
GENERAL CONCLUSIONS AND COMMENTS
The present report reviewed five neurotransmitters: GABA,
serotonin, dopamine, noradrenaline and β-endorphin (see
Table 1). Two possible neurochemical markers seemed to fulfil the three reviewed criteria of a trait marker of alcoholism.
The first possible marker is the measurement of increased
baseline activity of the serotonin transporter in platelets. This
is heritable, and is present in both long-term abstinent
alcoholics and in COA. The second possible marker is the
measurement of increased responsiveness of the pituitary
β-endorphin system to challenges. This is heritable, and is
present in both alcoholics and COA. Both possible neurochemical markers have yet to be assessed in family cosegregation studies to determine whether the marker
segregates with alcoholism within families, to prevent falsepositive conclusions.
It can be concluded from the GABA challenge studies in
alcoholics and in COA that the measurement of decreased
responsiveness in GABA neurotransmission fulfils two of
the reviewed criteria for a trait marker: it is present in both
alcoholics and in COA. Further studies on the question of
heritability are needed. Another possible trait marker is the
measurement of reduced baseline GABA levels in plasma. Its
properties must be further studied in COA, to assess the state
independence of these effects.
Studies on serotonin activity in alcoholics and COA have
shown that increases in serotonin transporter activity can be
masked by the recent consumption of alcohol, which may lead
to a decrease in serotonin transporter activity in active and
newly abstinent alcoholics. This may also hold true for the use
of challenge studies to determine the presence of a decreased
postsynaptic-serotonin-receptor response in alcoholics, versus
an elevated response in COA. The serotonin post-mortem
studies that have been reviewed also showed decreased
binding to the serotonin transporter and receptor. This may
be consistent with a masking effect produced by alcohol
(Menninger et al., 1998).
Although the challenge and baseline studies of dopamine
activity in alcoholics produced contradictory results,
decreased receptor reactivity was found in alcoholics who had
been abstaining for a protracted period of time. The measurement of dopamine levels in plasma poses certain problems;
however the use of neuro-imaging techniques (which measure
central dopaminergic functions) holds considerable promise
for the future.
Indices of changes in the noradrenaline system all
corresponded to a fall in noradrenaline baseline levels, and to
a reduction in postsynaptic-α2-adrenergic-receptor reactivity.
There may be reduced activity in the noradrenaline system, of
which the assessment might represent a trait marker for alcoholism. However, further studies are required on the presence
of these possible markers in COA, and on their heritability.
The reduced baseline level of β-endorphin in alcoholics,
together with reduced opioid receptor density in COA and
an elevated β-endorphin response to alcohol and naloxone
in alcoholics and COA, might be consistent with the opioiddeficiency hypothesis. The finding that inter-individual differences in challenged β-endorphin levels are heritable suggests
that the measurement of increased responsiveness of the
β-endorphin system may be a trait marker for alcoholism.
In the course of producing this review, no familial cosegregation studies were found on possible neurochemical
trait markers and alcoholism. Such studies would have been
of use in addressing the issue of possible false-positive conclusions. However, many familial and population-based linkage
studies have been carried out into candidate, neurochemistryrelated, alcoholism genes. The Collaborative Study of the
Genetics of Alcoholism (COGA) has performed linkage
analyses in a large number of families with severe alcoholism.
The COGA is a multicentre study for the detection and characterization of genes that influence susceptibility to alcohol
dependence and related phenotypes. Data from COGA have
been used to study the linkage of vulnerability for alcoholism
on regions of chromosomes 1, 2 and 7 (Reich et al., 1998).
Neurogenetic candidate genes on chromosomes 4 and 11 have
been reported in a genome-wide scan for genetic linkage
to alcohol dependence in a South-western American Indian
Tribe (Long et al., 1998). The regions in question are those
near the β1 GABA receptor gene on chromosome 4, and near
the tyrosine hydroxylase and dopamine D4 receptor genes on
chromosome 11.
Genome-wide screenings must be followed by investigations
in alcoholics and COA, to determine whether the candidate
gene has a real causal relationship with the development of
alcoholism over time. As pointed out in the review by Rutter
(1994), it is essential that the component of a multidimensional phenotype of alcoholism be accurately defined
J. E. RATSMA et al.
530
and that it be strongly homogeneous in genetic terms. This
indicates that further research is needed on the aetiological
heterogeneity, mode of transmission and incomplete penetrance
of the genes involved in alcoholism (Devor et al., 1994).
In conclusion, this review presents three main items. First,
two possible neurochemical markers fulfil three criteria of a
trait marker for alcoholism. The markers in question are the
measurements of increased baseline activity of the serotonin
transporter in platelets and increased responsiveness of
the pituitary β-endorphin system to challenges. Secondly, a
description of changes in GABA, dopamine and noradrenaline
neurotransmitter systems is presented. As yet, however, these
do not fulfil all three reviewed criteria for a trait marker of
alcoholism. Thirdly, we would like to emphasize that the use
of high-risk groups is essential (a view supported by the many
inconsistent studies in COA). Such an approach facilitates
investigations into the state independence of a trait marker.
This is due to the marked influence of alcohol on neurotransmitter systems, which results in state-dependent changes after
alcohol use. It also makes it possible to determine (preferably
by the use of longitudinal data) whether an index of a change
within a neurotransmitter system has a causal relationship
with the development of alcoholism. If so, this would mean
that it could serve as a trait marker. Trait markers for
alcoholism which do not yet fulfil all of the criteria may do so
in the future, once they have been more extensively studied.
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