1-4
5-8
9-12
13-16
17-20
21-24
25-28
29-32
33-36
37-40
41-44
between such status in alcohol-dependent subjects in the absence of alcohol
consumption (i.e. during medium– or long-term abstinence) from the pharmacological
effects induced by acute and chronic alcohol consumption and subsequently during
the acute withdrawal phase.
shown to exert major effects on serotonin and Trp metabolism and disposition in man
and experimental animals. In animals, liver Trp pyrrolase activity is enhanced by
acute, but inhibited after chronic, ethanol administration, then enhanced during
withdrawal. These changes lead to alterations (in the opposite directions) in brain
serotonin synthesis and turnover mediated by corresponding changes in circulating
Trp availability to the brain. A brain serotonin deficiency is present in the alcohol-
preferring C57BL/6J mouse strain and many alcohol-preferring rat lines. In this
mouse strain, the liver Trp pyrrolase enhancement causes the serotonin deficiency.
Trp pyrrolase. This may explain alcohol-induced depression, aggression and loss of
control in susceptible individuals. Chronic alcohol intake in dependent subjects may
be associated with liver Trp pyrrolase inhibition and a consequent enhancement of
brain serotonin function, whereas subsequent withdrawal may induce the opposite
effects. Relapse into drinking is associated with a return of the liver Trp pyrrolase
inhibition, an effect that should lead to elevation of brain serotonin levels. It is
therefore possible to suggest that some abstinent alcoholics may have a central
serotonin deficiency, which they correct by liver Trp pyrrolase inhibition through
drinking. There may be a role for the excitotoxic Trp metabolite quinolinate, produced
through the Trp pyrrolase-dependent activation of the hepatic kynurenine pathway, in
the behavioural disturbances of the alcohol-withdrawal syndrome.
expressed by a lower [Trp]/[CAA] ratio than in controls) in 1-day abstinent subjects is
associated with the presence of depressive and aggressive tendencies only in early-
onset alcoholism, it has been show that this decreased availability occurs irrespective
of the presence of depression or aggression, and also in the absence of typing.
Recently, we found that a positive family history of alcoholism is not associated with
a decrease in Trp availability to the brain, thus suggesting that a potential serotonin
deficiency in alcoholism is unlikely to be related to family history of alcoholism. A
central serotonin deficiency, however, has been demonstrated in a nonhuman primate
model of alcoholism, characterized by a low CSF [5-HIAA], and exhibiting
behaviours characteristic of Type II alcoholism, especially deficits in impulse control,
e.g. spontaneous risky and reinforcing behaviours, impaired social competence, social
alienation and unrestrained and violent aggression. However, this primate model is
not primarily a genetic one, unlike the Type 2 human model, with a high genetic
loading. It is of interest that evidence linking antisocial alcoholism to the serotonin
5HT1B receptor gene and of impulsive aggression to a mutation in the gene encoding
for monoamine oxidase type A (the form of MAO responsible for serotonin
degradation) have been reported. Serotonin function has also been examined in
subjects at high risk for alcohol dependence. With CSF [5-HIAA] measurements,
impairment was demonstrated, whereas in serotonin receptor binding studies, the
results have been controversial. It is therefore possible that the presence of a
with special characteristics.
to establish more accurately the serotonin and Trp status during alcohol dependence
and the subsequent acute withdrawal phase. Studies in longer-term abstinence are
also needed to establish this status in relation to predisposition to dependence and to
the associated psychological and behavioural disturbances, which may also be
important determinants of the dependence mechanism through negative
reinforcement. Establishing the serotonin status in relation to personality
characteristics and alcoholism typologies will also make an important contribution
towards identifying the biopsychosocial determinants of dependence, biological
(including genetic) vulnerability factors, and patient characteristics, which should lead
to more effective screening and detection of subjects at risk of becoming dependent
on alcohol, targeting patients for specific pharmacological interventions and
improving the practice of detoxification.
TREATMENT OF ALCOHOL DEPENDENCE
USA
5-HT) selective pharmacotherapy in the treatment of alcohol dependence and will
provide both historical and current perspectives on its use. The last 20 years of
research has shown us that 5-HT neurotransmission is related to alcohol dependence.
Both theoretical and empirical research has supported the idea that alcohol
dependence is a recurrent disorder and that biological vulnerabilities contribute to the
pathogenesis of alcohol dependence. Pre-clinical studies have consistently
demonstrated that there is a relationship between 5-HT function and alcohol
consumption. However, the clinical studies have been inconsistent in their
conclusions. Furthermore, there is growing evidence that distinct alcoholic subtypes,
who may be differentiated by the type or complexity of their 5-HT dysfunction, are
differentially responsive to 5-HT pharmacotherapy with respect to drinking-related
outcomes. This may explain the modest and variable 5-HT pharmacotherapeutic
effects that have previously been reported in the earlier studies that included large,
heterogeneous subject groups. However, results following from this new line of
inquiry, while relatively optimistic, have not been straightforward, calling for further
investigations into this area of research.
Mental Health (CIMH), University of Heidelberg, Mannheim
mediation of acute and chronic alcohol effects. In a long-term model of alcohol self-
administration with repeated deprivation phases we could demonstrate enhanced
glutamatergic activity following voluntary alcohol intake. In addition the glutamate
release inhibitor lamotrigine abolished the alcohol deprivation effect (ADE) in our rat
model. In order to study the involvement of different glutamate receptors in mediating
relapse drinking we administered low affinity non-competitive NMDA receptor
antagonists (memantine and MRZ 2/579) and a AMPA receptor antagonist (GYKI
52466) to rats which had voluntary access to alcohol for more than one year with
repeated deprivation phases. Memantine and MRZ 2/579 abolished the ADE
demonstrating the importance of NMDA receptors in relapse behaviour. It should be
noted, however, that the selective NMDAR-2B antagonist ifenprodil was without
effect on the ADE despite the fact that alcohol sensitivity is partially mediated by this
subunit. In contrast to NMDA receptors AMPA receptors seem not to be involved in
relapse behaviour since GYKI 52466 did not interfere with the alcohol deprivation
effect. The latter result could be confirmed by AMPA receptor knockout mice which
showed no alteration in drinking behaviour when compared to wildtype mice.
SPECIAL REFERENCE TO DEPENDENCE-
PRODUCING DRUGS
17176 Stockholm, Sweden
and AMPA/kainate or as G-protein- coupled metabotropic glutamate receptors. Each
subclass of glutamate receptors are composed from various combinations of glutamate
receptor subtypes and accumulated evidence suggests that this may at least partially
explain the fact that currently available NMDA and AMPA glutamate receptor
antagonists differ in their relative affinity for various receptor subtypes and thereby
also in their potency to selectively modulate dopaminergic neurotransmission in the
brain. Some recent observations concerning the effects of different categories of
stimulant drugs in the nucleus accumbens of rat brain will be presented and discussed.
According to a classic working hypothesis it is suggested that a blockade of NMDA
receptors will inhibit the acquisition of a learned response or chronic drug effects (e.g.
tolerance) whereas a blockade of AMPA receptors will antagonize the expression of
such events. This theory is based upon the assumption that chronic exposure to at
least CNS stimulant drugs will cause long-term changes of glutamate brain
mechanisms, and consequently their putative role as modulators of dopamine
neurotransmission, in selective brains areas. Several newly developed techniques can
be used for the detection of e.g. drug-produced alteration in the production of
glutamate sybtype receptor genes and their corresponding protein. Some preliminary
findings of how such techniques will be integrated into our ongoing work with
various dependence-producing drugs, like nicotine and ethanol, will be presented.
– HUMAN STUDIES
Addiction Medicine, J 5, D-68159 Mannheim, Germany, Andreas Heinz, Dept. of Psychiatry,
Humboldt-University, Charité, D-10098 Berlin, Germany
provided insights into its mechanisms of action. Clinically the compound was
evaluated in about twenty randomized placebo-controlled trials in Europe, Australia
and the US. The overwhelming majority of these studies showed a significant effect in
terms of the prevention of relapses and the amount of alcohol consumed compared to
the placebo control group. The latest study was done in the US without showing an
advantage of acamprosate. The reasons will be discussed. Based on the overall
evidence the FDA examined this compound for approval in the US. Their arguments
as well as the final decision will also be discussed.
attempt is currently being undertaken in a large study (PROJECT PREDICT) which is
funded by the German Government. Bsed on animal work we hypothesize a reward
craving which can be distinguished from relief craving. While the former is supposed
to better respond to acamprosate, the latter should rather be improved by naltrexone.
The rationale of this project will also be outlined.