UvA-DARE (Digital Academic Repository) Biological ... · 1 1 Neurochemicallmarkerso falcoholis mvulnerability innhuman s ABSTRACT T Thissrevie wconsider spossibl eneurochemica ltrai

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Biological vulnerability to alcoholism in children of alcoholics

Ratsma, J.E.

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Citation for published version (APA):Ratsma, J. E. (2001). Biological vulnerability to alcoholism in children of alcoholics

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1 1

Neurochemicall markers of alcoholism vulnerability

inn humans

ABSTRACT T

Thiss review considers possible neurochemical trait markers that may be related to

alcoholismm vulnerability. Potential trait markers for alcoholism of neurochemical

originn have been studied in alcoholics and in the children of alcoholics. Indices of

changess within five neurotransmitter systems, GABA, serotonin, dopamine,

norepinephrinee and ^-endorphin have been implicated as important factors in

alcoholism,, and have been studied as trait markers for this condition. This review

investigatess whether possible neurochemical markers meet three criteria, to be: (1)

heritable;; (2) present in alcoholics but not in unrelated non-alcoholics; (3) state

independent,, as determined from studies of the children of alcoholics. Two

neurochemicall markers seemed to fulfi l the three trait-marker criteria studied: (a)

thee measurement of increased baseline activity of the serotonin transporter in

platelets;; and (b) the measurement of increased responsiveness of the pituitary p*-

endorphinn system to challenges. Regarding neurochemical vulnerability for

alcoholism,, argumentss are presented to underline the necessity of studying trait

markerr properties in individuals at risk for alcoholism.

ss chapter was submitted as: Ratsma, J.E., Van der Stelt, O., Gunning, W. B.

Neurochemicall markers of alcoholism vulnerability in humans.

14 4

INTRODUCTION N

Alcoholismm is a multifactorial disease, in which polygenic influences and

environmentall influences interact (Goldman, 1995). This has been

demonstratedd by adoption studies (Goodwin et al., 1973; Bohman et al.,

1981;; Cloninger et al., 1985; Cadoret et al., 1985) and by twin studies

(Heathh et al., 1997; Kendler et al., 1994; 1997; Reed et al., 1996; Romanov

ett al., 1991, Treu et al., 1996). The question arises as to what is inherited in

alcoholism?? The research on trait markers may contribute to knowledge

aboutt genetic risk factors for alcoholism. The search for trait markers has

focusedd on behavioural, psychophysiological, or neurochemical trait

markerss for alcoholism (Begleiter and Porjesz, 1988; Farren and Tipton,

1999;; Reich et al., 1999; Schuckitt, 1999; Van der Stelt, 1999). This review

investigatess whether the possible neurochemical trait markers that were

previouslyy reported represent trait effects, rather than state effects following

thee onset of alcoholism. Thus, in addition to the use of trait marker studies

inn alcoholics, neurochemical trait marker studies in the children of

alcoholicss (COAs) are reviewed.

AA trait marker is a pathophysiological marker that has the potential

too increase our understanding of the aetiology of the clinical condition in

question.. For example, how an inherited pathophysiological abnormality

mayy lead to alcoholism within an individual. Unlike a diagnostic marker, a

traitt marker need not necessarily have high sensitivity and specificity for the

clinicall condition itself (Begleiter and Porjesz, 1988; Nurnberger, 1992).

Traitt markers for alcoholism are characteristics with two main features, to

bee reliable and valid. To be reliable, the trait marker needs to be identifiable,

15 5

easilyy measured, and have a good within-subject and between-subject

reliabilityy (Farren and Tipton, 1999; Froehlich et al., 2000). The features

concerningg the validity of trait markers are studied in this review. Firstly,

theyy are heritable. Twin studies or adoption studies demonstrate that

variationss in the trait marker are largely based on genetic factors as opposed

too environmental factors. Secondly, they are more prevalent in alcoholics

thann in unrelated non alcoholics. Thirdly, they are state independent This

meanss that, rather than reflecting the current state of alcoholism, they are

presentt throughout an individual's lifetime (something that can be assessed

inn high-risk groups). The marker should also be co-segregated with

alcoholismm within families, as demonstrated by sib pair analyses, or other

geneticc analyses of pedigree data (Begleiter & Porjesz, 1988). This wil l

preventt false positive conclusions based on population stratification.

Althoughh the state independence of the trait marker can be investigated in

long-termm abstinent alcoholics, this procedure does not discriminate

accuratelyy between state markers and trait markers. The effects of long-term

dailyy alcohol use may have affected the activity of neurochemical trait

markerss in alcoholics. The trait marker's mode of genetic transmission can

bee assessed either by a genetic analysis of pedigree data (using a genome-

widee screen) or by a linkage analysis of candidate genes within families.

Thee issue of transmission is not addressed in the present review.

Thiss review wil l focus on neurochemical risk markers. These are

indicess of changes in neurotransmitter systems that are studied as trait

markerss in alcoholism, in accordance with the three above-mentioned

criteria.. The state effect of alcohol on changes in neurotransmission has

16 6

beenn widely studied within neurotransmitter systems. It has, for example,

beenn the main approach adopted in studies of the NMD A receptor of the

glutamatergicc system. However, this review focuses on indices of changes

withinn five neurotransmitter systems that may have a trait effect on

alcoholism.. This includes the following neurotransmitters: (1) y-

aminobutyricc acid (GABA) (Frye and Breese, 1982; Koob et al., 1986); (2)

5-hydroxytryptaminee (serotonin; importantly, the impaired functioning of

CNSS serotonin may result in diminishedd impulse control, a neurobiological

featuree of type II alcoholism) (Cloninger, 1987; Linnoila et al., 1983); (3)

dopaminee (Gessa et al., 1985; Imperato and Di Chiara, 1986; Wise and

Bozarth,, 1987); (4) norepinephrine (Cloninger, 1994); (5) p-endorphin. This

lastlast topic is the subject of two contradictory hypotheses. The endorphin

compensationn or deficiency hypothesis states that alcohol use compensates

forr a predisposed or acquired deficiency of endorphinergic receptor activity

(Blum,, 1983; Erickson, 1990; Volpicelli et al, 1985). Whereas the opioid

surfeitt hypothesis states that alcohol use is increased by a surfeit of

opioidergicc receptor activity, rather than a deficit (Reid and Hunter, 1984;

Hubbelll et al., 1986; Reid et al., 1991). Both hypotheses are equally

applicablee to other neurotransmitter systems. G-proteins and adenylyl

cyclasee (or any other secondary messenger systems) have not been included

inn this review as they are not neurotransmitters.

Thee requisite theoretical background was provided by animal

studiess carried out in the 1950s, which reported that changes in

neurotransmissionn in rat brains led to addiction-related behaviour. Olds and

Milnerr (1954) found that intracranial stimulation of the hypothalamus and

17 7

associatedd structures can act to reinforce operant conditioning. Brain

stimulationn itself activated systems that were normally activated by a

reinforcingg stimulus, like feeding or drinking (Deutsch and Howarth, 1963).

Brainn self-stimulation (using electrodes placed in the vicinity of

dopaminergicc neurones) was accompanied by locomotor activation and

positivee reinforcement (Routenberg, 1978). Similarly, it has been

hypothesizedd that euphoria and drug-seeking behaviour (whether induced by

alcoholl or other commonly abused substances) arise from activation of the

mesolimbicc dopaminergic reward pathways of the brain (Gessa et al., 1985;

Imperatoo and Di Chiara, 1986; Wise and Rompre, 1989). Endogenous

opioidss are also reported to be involved in reward processes during brain

self-stimulationn (Schaefer, 1988). The intracerebroventricular self-

administrationn of ^-endorphin in rats has demonstrated that this substance

actss as an endogenous positive reinforcer of behaviour. Thus it might

intrinsicallyy control behaviour like the self-administration of addictive drugs

(Vann Ree et al., 1979). In addition, the opioid antagonist naltrexone blocks

thee release of dopamine at the level of the nucleus accumbens, which

followss alcohol administration (Benjamin et al., 1993). However, the results

off animal and human studies suggest that the effects of alcohol consumption

aree not restricted to dopamine and endogenous opioids. Alcohol

consumptionn may also affect several other brain neurotransmitters,

includingg norepinephrine (Ahlenius et al., 1973; Brown and Amit, 1982),

serotoninn (McBride et al., 1988; Murphy et al., 1988) and GABA (Hwang et

al.,, 1990; McBride et al., 1990).

18 8

Alcoholism-relatedd behaviour patterns are defined in terms of the

subtypess of alcoholics, like types 1 or 2 (with a clinical-theoretical basis)

(Cloninger,, 1987) or types A or B (with an empirical basis) (Babor et al.,

1992).. These types represent a specific clustering of phenotypes with a

distinctt aetiology of alcoholism. There may be areas in which different

typologiess overlap one another. For example, type 2 and type B are both

relatedd to the early onset of alcoholism, the presence of externalising

psychopathologyy in childhood, multiple drug abuse and aggressive

behaviourr (Cloninger, 1987; Babor et al., 1992). Phenotypic components

couldd be assessed by measuring neurophysiological parameters, such as the

P33 event-related potential (Van der Stelt, 1999). It has been shown, for

example,, that alcoholics generate a smaller P3 than non-alcoholics (Cohen

ett al., 1995; Pfefferbaum et al., 1991; Porjesz et al., 1998). The same applies

too the children of alcoholics, relative to control children (Begleiter et al.,

1984;; Hill et al., 1995; Porjesz et al., 1998; Van der Stelt et al., 1998). The

P33 phenotypic event-related potential has also been associated with an

increasee in personality-dimension externalising behaviour (Bauer and

Hesselbrock,, 1999; Carlson et al., 1999; Van der Stelt et al., 1998).

Thee methods used to investigate human neurobiological

vulnerabilityy to alcoholism include baseline studies, challenge studies and a

varietyy of post-mortem studies. Baseline studies identify individual

variationss in the trait marker, in the absence of any interference from

alcohol.. The aim is to investigate the state independence of the trait marker

inn question. Challenge studies often attempt to identify individual variations

off the trait marker after alcohol intake, while some studies use challenge

19 9

drugss other than alcohol (acting on one or more of the five neurotransmitter

systemss under review). This is because any individual variation in

sensitivityy to the effects of alcohol (or other challenge drugs) might be

associatedd with a variation in the risk of alcoholism (Schuckit et al., 1983;

Schuckitt and Smith, 1996). Generally, post-mortem studies simply reveal

thatt alcohol has a toxic effect on neurotransmitter systems. The reported

resultss do not usually draw a distinction between the trait and the state

effectss of alcohol. Baseline and challenge studies are not only performed in

alcoholics,, but also in high-risk individuals, such as the children of

alcoholicss (COA). The children of alcoholics represent a unique, high-risk

groupp in studies of the state independence of the trait marker. This is

becausee they have a heightened risk of alcoholism, and because the

youngestt groups do not generally consume alcohol on a regular basis (Eskay

andd Linnoila , 1991; Hil l et al., 1991; Sher et al., 1991). This review includes

neurochemical-trait-markerr studies that investigated changes in the levels of

neurotransmitterss (or their metabolites) in cerebrospinal fluid (CSF) or

plasma,, and changes in the number, activity and affinit y of receptors in the

brain.. Also included in this review are studies performed on the brain either

directlyy or indirectly (by means of peripheral assessments). There is still

somee doubt concerning the degree of correspondence between the latter

measurementss and neurotransmitter activity in the central regions. However,

theree are problems associated with making some of the above-mentioned

measurementss in neurobiological studies on humans. For example, it would

bee ethically indefensible to subject one particular group of high-risk

individual ss - the young children of alcoholic patents - to invasive or

20 0

extensivee examinations. This is because such examinations include

investigationss of the CSF, alcohol challenge tests, and various brain-

imagingg techniques that use radioactive substances. Neurobiotogical

researchh in high-risk groups, on the other hand, can be carried out with the

aidd of peripheral blood samples, using platelets for example (Ratsma et al.,

1999). .

Thee aim of this review is to evaluate three trait-marker criteria of

possiblee neurochemical trait markers by reporting challenge, baseline and

post-mortempost-mortem studies in alcoholics and their children.

GAMMA-AMINOBUTYRI CC ACID

PharmacologicalPharmacological properties

y-Aminobutyricc Acid (GABA) acts on the GABAA receptor, which is a

transmitter-gatedd chloride channel. GABAA receptors are composed of three

sub-units:: alpha, beta, and gamma. Fourteen sub-units have been identified

too date, six alpha variants, three beta variants, three gamma variants and two

deltaa variants. Alcohol and benzodiazepines act on the gamma sub-unit of

thee GABAA receptor (Suzdak et al., 1986), while GABA acts on the alpha

sub-unit.. Changes in the sub-unit expression of GABAA receptors are

reflectedd in the pharmacological properties of the receptors (Levitan et al.,

1988).. The GABA B receptor, is a G-protein-coupled receptor, without a

benzodiazepinee binding site.

21 1

ResearchResearch findings

Inn the post-mortem frontal cortex, expression of mRNA for the GABAA

receptor'ss oil and % sub-units was higher in alcoholics than in controls

(Lewohll et al., 1997) (Mitsuyama et al., 1998). These findings are consistent

withh the results of two post-mortem studies, in which noncirrhoti c

alcoholicss were found to have more GABA receptors in their cerebral cortex

andd superior frontal gyrus than the control subjects (Dodd et al., 1992) (Tran

ett al., 1981). Brain imaging studies have also been performed, using single-

photonn emission-computed tomography (SPECT) (Abi-Dargham et al.,

1998;; Lingford-Hughes et al., 1998). These studies found that, in alcoholics

andd type II alcoholics, the benzodiazepine receptor distributio n volume in

thee anterior cingulate, the prefrontal, frontal, parietal and temporal cortices

andd in the cerebellum was reduced relative to controls.

Somee challenge studies have used the technique of positron

emissionn tomography (PET). This revealed the existence of a blunted

glucosee utilization response to lorazepam in alcoholics (in the basal ganglia

andd thalamus) and in the children of alcoholics (in the cerebellum), relative

too controls. These findings indicate abnormalities in brain GABA-

benzodiazepinee receptor reactivity (Volkow et al., 1993; 1995). This might

bee consistent with previous SPECT studies in alcoholics, which revealed a

reductionn in benzodiazepine receptor volume. In alcoholics in the early

phasee of abstinence and those who had been abstinent for 1-2 years, a

challengee with gamma-hydroxybutyric acid (a GABA agonist) showed a

bluntedd growth-hormone (GH) response (relative to controls). This also

22 2

representss a loss of GABA neurotransmission (Vescovi and Coiro, 1995;

1997). .

Thee findings of blunted, post-challenge GABA responses in

alcoholicss and COA are not consistent with reported post-challenge plasma

GABAA levels in COA. GABA plasma levels of COA increased much more

inn response to alcohol than was the case in controls (Moss et al., 1990).

Neutrall results were also reported, where there was no difference between

thee GABA plasma levels in COA and in controls, following a diazepam

challengee (Cowley et al., 1996).

AA twin study (Berrettini et al., 1982) showed that the inter-

individuall difference in baseline plasma level of GABA is heritable.

Abstinent,, adult male alcoholics were found to have a lower baseline plasma

GABAA level than non alcoholics (Coffinan and Petty, 1985; Petty et al.,

1993).. Plasma GABA levels were also studied in the children of alcoholics.

Twoo studies of plasma GABA in male COA yielded conflicting results. One

studyy showed that COA had lower baseline plasma levels of GABA than

controlss (Moss et al.,1990) while the other found no such difference

(Cowleyy et al., 1996). The young adult COA in the latter study were highly

selectedd for having no history of alcohol or drug abuse at ages 18-25. This

mayy mean that they were at reduced risk of an early onset of alcoholism,

whichh in turn may have biased the sample.

Inn conclusion, baseline studies have indicated that the measurement

off GABA level in plasma seems to fulfi l two criteri a as a trait marker for

alcoholism.. Firstly , the inter-individua l difference is heritable and secondly,

alcoholicss have reduced levels of GABA in their plasma. Challenge studies

23 3

havee shown that the measurement of decreased GABA receptor

responsivenesss also appears to fulfi l two trait marker criteria. Firstly , it has

beenn reported in alcoholics and secondly, it has also been reported in COA

(Tablee land Table 2).

Tablee 1. Trait marker criteri a for neurochemical baseline activities and responsess to challenges

Neurochemicall markers

GABA-ergicc activity Baseline e (plasmaa GABA) Challenge e (receptorr reactivity) Serotonergicc activitv Baseline e (5HTT transporter activity) Challenge e (receptorr reactivity) Dopaminergicc activitv Baseline e (plasmaa or CSFHVA) Challenge e (receptorr activity) Noradrenergicc activitv Baseline e (CSFF norepinephrine) Challenge e (receptorr reactivity) p-Endorphinergic c activitv v Baseline e (plasmaa or CSF [J-endorphin) Challenge e (pituitaryy reactivity)

Heritable e

yes s

--

yes s

--

--

--

--

--

--

yes s

Presencee in alcoholics (comparedd with controls) )

decreased d

decreased d

increased d (longg abstinence) decreased d

inconsistent t

decreased d (longg abstinence)

decreased d

decreased d

decreased d

increased d

Statee independent (moree common in high-riskrisk groups)

inconsistent t

decreased d

increased d

increased d (onee study)

inconsistent t

--

--

--

decreased d (receptorr density) increased d

24 4

Tablee 2. GABA studies

GABB A Post-mortem studies s

GABAA Challenge studies GABAA Baseline studies

Alcoholicss vs. controls: : increasedd expression GABAAA receptors in frontall cortex (Lewohll et al., 1997; Mitsuyamaa et al., 1998) ) Alcoholicss vs. controls: : increasedd number of GABAA receptors frontall and cerebral cortexx studies (Dodd ett al., 1992; Tran et al.,, 1981)

Alcoholicss vs. controls: decreasedd glucose utilization responsee to agonist lorazepam inn basal ganglia, thalamus (Volkoww et a l, 1993)

Alcoholicss vs. controls: decreasedd growth hormone responsee to agonist GHB (Vescovii and Coiro, 1995; 1997) )

COAA vs. controls: decreasedd glucose utilization responsee to agonist lorazepam inn cerebellum(Volkow et al., 1995) ) COAA vs. controls: neutrall plasma GABA levels afterr alcohol (Moss et al.,1990) COAA vs. controls: neutrall plasma GABA levels afterr agonist diazepam (Cowley ett al., 1996)

Alcoholicss vs. controls: decreased d benzodiazepinee receptor densityy in the cortex (Lingford-Hughess et al., 1998) )

Alcoholicss type I I vs. controls: : decreased d benzodiazepinee receptor densityy in the cortex and cerebellumm (Abi-Darghamm et al., 1998)

Alcoholicss vs. controls: decreasedd GABA plasma levelss (Cofrman and Petty,, 1985; Petty etal., 1993) ) COAA vs. controls: decreasedd plasma GABA levelss (Moss et al.,1990) COAA vs. controls: neutrall plasma GABA levelss (Cowley et al., 1996)) _ _ „

25 5

5-HYDROXYTRYPTAMINE E


5-Hydroxytryptaminee (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-HTi, 5-HT2, and 5-HT4) are coupled to G-proteins,

whilee the 5-HT3 receptor acts as a 5-HT gated ion channel. Although the

geness of three other types (5-HT5, 5-HT& and 5-HT7) have been cloned,

theirr physiological functions are as yet unknown. The 5-HT transporter is

locatedd in the serotonergic axon terminals, where it terminates 5-HT action

inn the synapse, and in platelet membranes, where it takes up 5-HT from the

bloodd (Blakely et al., 1991). The synthesis of serotonin is influenced by the

amountt 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

whichh tryptophan in the blood circulation is available to the brain may be

decreasedd in alcoholics with a positive family history (see review by

Badawy,, 1999). The concentration of 5-Hydroxyindoleacetic acid (5-HIAA)

(thee major metabolite of serotonin) in cerebrospinal fluid (CSF) reflects

centrall serotonergic processes (Banki and Molnar, 1981).


Post-mortemm studies of brain tissue from alcoholics have revealed reduced

5-HTT transporter binding in the hippocampus (Gross-Isseroff and Biegon,

1988;; Chen et al., 1991). Similarly, binding was found to be reduced in the

5-HTT i A receptors of individuals who consumed alcohol relative to those of

subjectss who did not (Dillon et al., 1991).

26 6

Followingg a challenge with a mixed serotonin partial agonist, m-

chlorophenylpiperazinee (mCPP), the ACTH response and the activation in

thee basal ganglia circuits (involving orbital and prefrontal cortices) was

foundd to be lower in alcoholics than in non alcoholics (Krystal et al., 1994;

Georgee et al., 1997; Hommer et al, 1997). These findings were reflected by

aa decrease in the brain' s utilisation of glucose, as shown by PET. This

suggestss that 5-HT2C receptors in alcoholics exhibit reduced sensitivity.

Otherr studies reported challenges in which growth hormone, prolactin, and

Cortisoll exhibited blunted responses to fenfluramine (releasing serotonin as

ann indirect agonist), mCPP, and sumatriptan (a 5-HT1D receptor agonist).

Thee subjects in question were active alcoholics and abstaining alcoholics

whoo 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

wass reported after a challenge with fenfluramine in a high-risk group of

ADHDD (Attention-Deficit Hyperactivity Disorder) boys, versus ADHD boys

withh a low risk of alcoholism. The assessed degree of risk was based on the

presencee or absence of parental alcoholism (Schulz et al., 1998).

Thee results of a study using single photon emission computed

tomographyy (SPECT) showed a reduction in brain-stem serotonin

transporterss in alcoholics (after 3-5 weeks of abstinence) relative to controls

(Heinzz et al., 1998). A decrease in alcoholism-related serotonin transport

wass associated with a decrease in the 5-HT content of platelets in alcoholics

(Banki,, 1978). It also corresponded to a decrease (relative to controls) in the

uptakee of 3H-5HT by platelets in alcoholics undergoing a two-week period

27 7

off detoxification (Kent et al., 1985). A twin study found that 5-HT uptake in

bloodd platelets is moderated by genetic factors (Meltzer and Arora, 1988).

Alcoholicss who had abstained from alcohol for periods of 1 month

too 22 years (and their children) were found to have a higher 3H-5HT platelet

uptakee than controls (Ernouf et al., 1993). This is contrary to the findings in

activee 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).

Ass a result, it was suggested that an increase (rather than a decrease) in

platelett serotonin transport was a trait marker for alcoholism (Ernouf et al.,

1993).. It is important to note that early-onset alcoholics exhibit higher

platelet-serotonin-transporterr activity than late-onset alcoholics (Javors et

al.,, 2000).

Withh regard to 5-HIAA , the levels of this metabolite in CSF taken

fromfrom abstinent alcoholics of both sexes were lower than in controls

(Ballengerr et al., 1979; Banki, 1981; Borg et al., 1985). Alcoholic impulsive

offenderss had lower CSF 5-HIAA levels, than alcoholic non-impulsive

offenders,, while the controls had intermediate levels (Virkkune n et al.,

1994).. Early-onset alcoholics had lower 5-HIAA levels than late-onset

alcoholicss (Fils-Aime et al., 1996). This was consistent with studies

demonstratingg low precursor serotonin availability in early-onset alcoholism

(Buydens-Brancheyy et al., 1989). CSF 5-HIAA concentrations might be a

state-relatedd phenomenon, since essential dietary fatty acids could cause

changess in CSF 5-HIAA concentrations (Hibbeln et al., 1998). However, an

animall study of CSF 5-HIAA levels in monkeys revealed a high degree of

28 8

intra-individuall stability (Raleigh et al., 1992). The above-mentioned CSF

5-HIAAA studies, which were only performed in alcoholics, were consistent

withh the hypothesis that decreased CSF 5-HIAA levels represent a central

serotonergicc deficit in a subgroup of early-onset male alcoholics (Linnoila et

al,, 1983).

Inn conclusion, the inter-individual difference in baseline serotonin

transporterr activity in platelets seems to be heritable. There are also

indicationss that it is elevated in COA and in alcoholics who have been

abstinentt for a protracted period off time. The measurement of increased

baselinee serotonin transporter activity in platelets would therefore appear to

fulfi ll three of the criteria for trait markers for alcoholism. Challenge studies

off serotonin receptor responsiveness have shown (albeit inconsistently) a

decreasedd 5-HT response in alcoholics. There is also one report of an

elevatedd response in COA, thus one criterion may have been met (Table 1

andd Table 3).

29 9

Tablee 3. Serotonin studies

Serotoninn post-mortem studies s

Serotoninn challenge studies Serotoninn baseline studies

Alcoholicss vs. controls: decreasedd binding 5-HT transporterr (Gross-Isserofff and Biegon, 1988;; Chen etal., 1991) Alcoholl consumers vs. controls: : decreasedd binding 5-HTJAA receptor (Dillon et al.,, 1991).

Alcoholicss vs. controls: decreasedd glucose utilization in basall ganglia circuits and ACTH responsee to partial 5-HT agonist mCPPP (Hommer et al., 1997) Alcoholicss vs. controls: decreasedd ACTH response to mCPPP (Krystal et al., 1994; Georgee etal., 1997).

Alcoholicss vs. controls: decreasedd prolactine and Cortisol responsee to serotonin (Balldin et al.,, 1994; Krystal et al., 1996), Alcoholicss vs. controls: decreasedd growth hormone responsee to 5-HT ID receptor agonistt sumatriptan (Vescovi and Coiro,, 1997) COAA with ADHD vs. controls withh ADHD: increasedd Cortisol response to 5-HTT agonist fenfluramine (Schultz etal.,, 1998)

Alcoholicss vs. controls: decreasedd brainstem serotoninn transporters (SPECT)) (Heintz et al., 1998) ) Alcoholicss vs. controls: decreasedd platelet serotonin uptakee and content (Banki, 1978;; Kent et al., 1985)

Alcoholicss vs. controls: increasedd platelet serotonin uptakee (Ernouf et al., 1993) (long-termm abstinence) COAA vs. controls: increasedd platelet serotonin uptakee (Ernouf et al., 1993; Rauschetal.,, 1991)

Early-onsett vs. Late-onset alcoholics: : increasedd platelet serotonin uptakee (Javors et al., 2000)

Alcoholicss vs. Controls: decreasedd CSF 5-HIAA level (Ballengeretal.,, 1979; Banki,, 1981; Borg etal., 1985). . Early-onsett vs. Late-onset alcoholics: : decreasedd CSF 5-HIAA levell (Fils-Aime et al., 1996) Impulsivee vs. Non-impulsivee alcoholics: decreasedd CSF 5-HIAA levelss (Virkkunen et al., 1994) )

30 0

DOPAMINE E


Dopaminee acts on at least five dopamine receptors, which are divided into

twoo major groups: (1) the Dl-lik e receptors (Dl and D5) and (2) the D2-like

receptorss (D2, D3, and D4). All dopamine receptors are G-protein-coupled

receptors,, the Dl receptor stimulates adenylyl cyclase activity while the D2

receptorr inhibits adenylyl cyclase activity. Homovanillinic acid (HVA) is

thee major metabolite of dopamine.


Inn one challenge study, male alcoholics who had been abstinent for a period

77 years ( 6 years) exhibited reduced postsynaptic-dopamine-receptor

sensitivityy relative to controls. This was expressed as a reduced maximum

growthh hormone (GH) response to the agonist apomorphine (Balldin et al.,

1992).. This report was consistent with the reduction in GH-response

(relativee to controls) seen in alcoholics who had been abstaining from

alcoholl for periods ranging from 8 days to 6 months (Dettling et al., 1995).

However,, an earlier study showed that, after a withdrawal state of 4-7 days,

alcoholicss exhibited an elevated GH response to dopamine infusion,

whereass their GH responses to apomorphine were similar to those of

controlss (Annuziato et al., 1983; Balldin et al., 1985). The dopamine

receptorr involved in GH secretion was thought to be a D2-type receptor,

whilee Dl receptors are believed to be involved in prolactin secretion

(Fabbrinii et al., 1988). The reduction in postsynaptic-dopamine-D2-

receptor-sensitivityy in alcoholics who had been abstaining from alcohol for

31 1

att least 8 days might be a trait marker for alcoholism. This may be

consistentt with the dopaminergic hypothesis of alcoholism (Eckardt et al.,

1998;; Ikemoto et al., 1999; Koob et al., 1998). It may also account for the

factt that, prior to detoxification, active alcoholics exhibit a reduced prolactin

responsee to the antagonist haldol. This response reverted to control values

thirteenn days after detoxification (Markanios et al., 2000).

Baselinee studies of homovanillinic acid (HVA) , found mat

alcoholicss had lower levels of this metabolite in their plasma than did

controll subjects (Fulton et al., 1995). However, the HVA levels found in the

CSFF of alcoholics and in the plasma of male COA were similar to those

foundd in controls (Petrakis et al., 1999; George et al., 1999; Howard et al.,

1996;; Limson et al., 1991; Roy et al., 1990). Early-onset alcoholics were

foundd to have lower levels of HVA in their CSF than late-onset alcoholics

(Fils-Aimee et al., 1996). These results were contradicted by other studies,

however,, which found increased HVA CSF levels in early-onset alcoholics

relativee to late-onset alcoholics (George et al., 1999; Petrakis et al., 1999).

Inn conclusion, these inconsistent baseline studies show that the

changess in dopaminergic neurotransmission that are associated with

alcoholismm do not appear to fulfi l either of the reviewed criteri a for a trait

markerr for alcoholism. The challenge studies in alcoholics who had been

abstainingg for a protracted period of time showed a decreased dopamine

receptorr response that seems to fulfi l one of the criteri a for a trait marker,

namelyy that it is present in alcoholics (Tables 1 and 4).

32 2

Tablee 4. Dopamine studies

Dopaminee challenge studies

Alcoholicss vs. controls: decreasedd GH response to apomorphinee (Balldin et al., 1992)) (Dettlingetal., 1995) (long-term(long-term abstinence)

Dopaminee baseline studies s AlcoholicsAlcoholics vs. controls: neutrall HVA CSF levels (Petrakiss et al., 1999; Georgee etal., 1990; Limsonn et al-, 1991; Roy etal.,, 1990) Alcoholicss vs. controls: decreasedd HVA plasma levelss (Fulton et al., 1995)

COAA vs. controls: neutrall HVA plasma levelss (Howard et al., 1996) ) Early-onsett vs. late onset alcoholics: : decreasedd HVA CSF levelss (Fils-Aime et al., 1996) )

Early-onsett vs. late onset alcoholics: : increasedd HVA CSF levelss (George et al., 1999;; Petrakis etal.,

Alcoholicss vs. controls: increasedd GH response to dopaminee infusion (Annuziato et al.,, 1983) (short-term abstinence) Alcoholicss vs. controls: neutrall GH response to apomorphinee (Balldin et al., 1985)) (short-term abstinence) Alcoholicss vs. controls: decreasedd prolactine response to haldoll during alcohol intake, neutrall response after detoxificationn (Markianos et al., 2000) )

33 3

NOREPINEPHRINE E


Norepinephrinee acts on various adrenergic receptors (two a receptors and

twoo p receptors), all of which are G-protein coupled. The (Xi adrenergic

receptorr is linked to the mobilisation of intracellular calcium by

phospholipasee C, while the a2 adrenergic receptor inhibits adenylyl cyclase.

Thee pi and p2 adrenergic receptors stimulate adenylyl cyclase. A major

metabolitee of norepinephrine is 3-methoxy-4-hydroxyphenylglycol

(MHPG). .


Reducedd numbers of melanin-containing noradrenergic neurones were

foundd in the post-mortem locus ceruleus of alcoholics, which indicates a

lowerr level of noradrenergic neurotransmission (Arango et al., 1994). This

wass inconsistent with the findings of Baker et al., (1994), however, which

showedd no differences post-mortem. In a baseline study, cerebrospinal fluid

andd plasma were continuously sampled in controls and in alcoholics who

hadd been abstaining for 38-124 days (Geracioti et al., 1994). The results

showedd mat CSF norepinephrine was lower in alcoholics than in controls,

whichh was consistent with the findings of Arango et al., (1994). Although

theree were no differences in terms of the norepinephrine levels in plasma

(Geraciotii et al., 1994), alcoholics were found to have a lower basal level

relativee to controls (Ehrenreich et al., 1997).

Thee same study reported that, following a challenge with human

CRFCRF or a stress-test, the norepinephrine response was unaffected

34 4

(Ehrenreichh et al., 1997). In addition, alcoholics were found to have a

bluntedd growth hormone response to clonidine (an a2 adrenergic receptor

agonist)) in comparison to controls. The effect was found shortly after

detoxificationn and also after six months of abstinence (Glue et al., 1989;

Berggrenn et al., 2000). Similarly, in comparison to controls, alcoholics were

foundd to have an enhanced Cortisol response to yohimbine (an a2 adrenergic

receptorr antagonist). This reflects the down-regulation of postsynaptic

noradrenergicc receptors that is observed in alcoholics (Krystal et al., 1996).

Inn conclusion, both the basal studies of decreased norepinephrine

levelss in CSF (but not in plasma) and the challenge studies of receptor

responsivenesss showed that a decrease in noradrenergic neurotransmission

seemss to fulfi l one criterion for a trait marker, that it should be present in

alcoholicss (Table 1 and Table 5).

Tablee 5. Norepinephrine studies

Norepinephrinee post- Norepinephrine challenge Norepinephrine baseline mortemm studies studies studies Alcoholicss vs. controls: Alcoholics vs. controls: Alcoholics vs. controls: decreasedd number of neutral response of decreased levels of noradrenergicc neurones in norepinephrine in plasma after norepinephrine in CSF locuss ceruleus (Arango et CRF or a stress test (Geraciotti et (Geraciotti et al., 1994) al.,, 1994) al., 1994; Ehrenreich et al.,

1997) ) Alcoholicss vs. controls: Alcoholics vs. controls: Alcoholics vs. controls: neutrall number of increased Cortisol response to neutral levels of noradrenergicc neurones in antagonist yohimbine (Krystal et norepinephrine in plasma locuss ceruleus (Baker et al., 19%) (Geraciotti et al., 1994) al.,, 1994)

Alcoholicss vs. controls: Alcoholics vs. controls: decreasedd growth hormone decreased levels of responsee to agonist clonidine norepinephrine in plasma (Gluee et al., 1989; Berggren et (Ehrenreich et al., 1997) al.,, 2000)

35 5

BETA-ENDORPHIN N


Opioidss act on three major classes of opiate receptors: mu, delta and kappa.

Thesee G-protein-coupled receptors, which inhibit adenylyl cyclase, are

distributedd throughout the central nervous system. The distribution of p-

Endorphin,, however, is somewhat restricted. It is primarily confined to

neuroness in the hypothalamus which send projections to the periaqueductal

greyy region and to noradrenergic nuclei in the brain stem.


Baselinee studies in humans have shown that, in individuals at risk of

alcoholism,, the basal activity level of the endogenous opioid system might

bee 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 p-endorphin levels in the

plasmaa and cerebrospinal fluid of alcoholics were lower than those found in

controlss (Aguirre et al., 1990; Genazzani et al., 1982). It was reported in one

studyy that alcohol may have an equally strong effect on the central levels of

p-endorphinn as it does on the peripheral levels (Peterson et al., 1996). A

lowerr dose of naloxone completely blocked any reduction in synaptic opioid

contentt and/or opioid receptor density in high risk individuals. This

indicatess that endogenous hypothalamic opioid activity levels in these

individualss are lower than those in low-risk subjects (Wand et al., 1998).

Usingg a placebo, it was found that Cortisol levels in high-risk subjects were

higherr than in low-risk subjects. This indicates that there is probably no

36 6

increasee in opioid receptor affinity , as this would result in more inhibitor y

tone,, and lower Cortisol levels.

Withh regard to challenge studies, the opioid antagonist naloxone

producedd higher Cortisol and ^-endorphin responses in alcoholics than in

controls.. It also caused alcoholics to reduce their consumption of ethanol

(Kemperr et al., 1990; O'Malley et al., 1992; Volpicelli et al., 1992). The

ingestionn of a moderate dose of ethanol induced a dose-dependent increase

inn plasma ^-endorphin levels in high-risk subjects but not in low-risk

subjects.. Although these elevated levels were not produced by the peripheral

adrenall Cortisol system, the more central pituitar y p-endorphin system

showedd an increased sensitivity to ethanol. This might mediate ethanol's

reinforcingg effects in high-risk subjects (Gianoulakis et al., 1989; 1996).

Thesee baseline and challenge studies are consistent with the opioid-

deficiencyy hypothesis. In a twin study, the inter-individua l difference in p-

endorphinn response to alcohol was found to be heritable (Froehlich et al.,

2000). .

Inn conclusion, the measurement of decreased P-endorphin baseline

activityy appears to fulfi l two of the reviewed criteri a for a trait marker for

alcoholism.. These are lower P-endorphin levels in alcoholics and decreased

opioidd receptor density in COA. However, the measurement of increased p-

endorphinn responsiveness seems to fulfi l three such criteri a in that it is

heritable,, it is present in alcoholics and it is state independent (present in

COA).. (Table 1 and 6).

37 7

Tablee 6. ^-Endorphin studies

p-Endorphinn challenge studies Alcoholicss vs. controls: increasedd Cortisol response to naloxonee (Kemper et aL, 1990)

Alcoholicss vs. controls: increasedd ^-endorphin response to naloxonee (O'Malley et al., 1992)

Alcoholicss vs. controls: decreasedd alcohol consumption with naloxonee (Volpicelli et al., 1992) COAA vs. controls: increasedd ^-endorphin response to alcoholl (Gianoulakis et al., 1989; 1996) )

ft-Endorphinft-Endorphin baseline studies Alcoholicss vs. controls: decreasedd basal level of p-endorphinn in plasma (Aguirre ett al., 1990) Alcoholicss vs. controls: decreasedd basal level of fi-endorphinn in CSF (Genazzani etal.,, 1982) COAA vs. controls: decreasedd opioid receptor densityy (Wand et al., 1998)

38 8

CONCLUSIONS S

Thee present report reviewed five neurotransmitters: GABA, serotonin,

dopamine,, norepinephrine and ^-endorphin (see Table 1). Two

neurochemicall markers seemed to fulfi l the three reviewed criteria of a trait

markerr for alcoholism. The first possible marker is the measurement of

increasedd baseline activity of the serotonin transporter in platelets. This is

heritable,, and is presentt in both long-term abstinent alcoholics and in COA.

Thee second marker is the measurement of increased responsiveness of the

pituitaryy p-endorphin system to challenges. This is heritable, and is present

inn both alcoholics and COA. Both possible neurochemical markers have yet

too be assessed in family co-segregation studies to determine whether the

markerr segregates with alcoholism within families, to prevent false positive

conclusions. .

Itt can be concluded from the GABA challenge studies in alcoholics

andd in COA that the measurement of decreased responsiveness in GABA

neurotransmissionn fulfil s two of the reviewed criteria for a trait marker, it is

presentt in both alcoholics and in COA. Further studies on the question of

heritabilityy are needed. Another possible trait marker is the measurement of

reducedd baseline GABA levels in plasma. Its properties must be further

studiedd in the children of alcoholics, to assess the state independence of

thesee effects.

Studiess on serotonin activity in alcoholics and COA have shown

thatt increases in serotonin transporter activity can be masked by the recent

consumptionn of alcohol, which may lead to a decrease in serotonin

transporterr activity in active and newly abstinent alcoholics. This may also

39 9

holdd true for the use of challenge studies to determine the presence of a

decreasedd postsynaptic serotonin receptor response in alcoholics versus an

elevatedd response in COA. The serotonin post-mortem studies that have

beenn reviewed also showed decreased binding to the serotonin transporter

andd receptor. This may be consistent with a masking effect produced by

alcoholl (Menninger et al., 1998).

Althoughh the challenge and baseline studies of dopamine activity in

alcoholicss produced contradictory results, decreased receptor reactivity was

foundd in alcoholics who had been abstaining for a protracted period of time.

Thee measurement of dopamine levels in plasma poses certain problems,

howeverr the use of neuro-imaging techniques (which measure central

dopaminergicc functions) holds considerable promise for the future.

Indicess of changes in the norepinephrine system all corresponded to

aa fall in norepinephrine baseline levels, and to a reduction in postsynaptic-

a2-adrenergic-receptorr reactivity. There may be reduced activity in the

norepinephrinee system, of which the assessment might represent a trait

markerr for alcoholism. However, further studies are required on the

presencee of these possible markers in COA, and on their heritability .

Thee reduced baseline level of (J-endorphin in alcoholics, together

withh reduced opioid receptor density in COA and an elevated p-endorphin

responsee to alcohol and naloxone in alcoholics and COA, might be

consistentt with the opioid-deficiency hypothesis. The finding that inter-

individuall differences in challenged (̂ -endorphin levels are heritable

suggestss that the measurement of increased responsiveness of the f$-

endorphinn system may be a trait marker for alcoholism.

40 0

Inn the course of producing this review, no familial co-segregation

studiess were found on possible neurochemical trait markers and alcoholism.

Suchh studies would have been of use in addressing the issue of possible

false-positivee conclusions. However, many familial and population-based

linkagee studies have been carried out into candidate, neurochemistry-related,

alcoholismm genes. The Collaborative Study of the Genetics of Alcoholism

(COGA)) has performed linkage analyses in a large number of families with

severee alcoholism. The COGA is a multicentre study for the detection and

characterizationn of genes that influence susceptibility to alcohol dependence

andd related phenotypes. Data from COGA have been used to study the

linkagee of vulnerability for alcoholism on regions of chromosomes 1, 2 and

77 (Reich et al., 1998). Neurogenetic candidate genes on chromosomes 4 and

111 have been reported in a genome-wide scan for genetic linkage to alcohol

dependencee in a South-western American Indian Tribe (Long et al., 1998).

Thee regions in question are those near the pi GAB A receptor gene on

chromosomee 4, and near the tyrosine hydroxylase and dopamine D4

receptorr genes on chromosome 11.

Genome-widee screenings must be followed by investigations in

alcoholicss and CO A, to determine whether the candidate gene has a real

causall relationship with the development of alcoholism over time. As

pointedd out in the review by Rutter (1994), it is essential that the component

off a multidimensional phenotype of alcoholism be accurately defined and

thatt it be strongly homogeneous in genetic terms. This indicates that further

researchh is needed on the etiological heterogeneity, mode of transmission

41 1

andd incomplete penetrance of the genes involved in alcoholism (Devor et al.

1994). .

Inn conclusion, this review presents three main items. Firstly , two

possiblee neurochemical markers fulfi l three criteri a of a trait marker for

alcoholism.. The markers in question are the measurements of increased

baselinee activity of the serotonin transporter in platelets and increased

responsivenesss of the pituitar y p-endorphin system to challenges. Secondly,

aa description of changes in GABA, dopamine and norepinephrine

neurotransmitterr systems is presented. As yet, however, these do not fulfi l

alll three reviewed criteri a for a trait marker for alcoholism. Thirdly , we

wouldd like to emphasize that the use of high-risk groups is essential (a view

supportedd by the many inconsistent studies in CO A). Such an approach

facilitatess investigations into the state independence of a trait marker. This is

duee to the marked influence of alcohol on neurotransmitter systems, which

resultss in state dependent changes after alcohol use. It also makes it possible

too determine (preferably by the use of longitudinal data) whether an index of

aa change within a neurotransmitter system has a causal relationship with the

developmentt of alcoholism. If so, this would mean that it could serve as a

trai tt marker. Trait markers for alcoholism which do not yet fulfi l all of the

criteri aa may do so in the future, once they have been more extensively

studied. .

42 2

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