1-4
5-8
9-12
13-16
17-20
21-24
25-28
29-32
33-36
37-40
41-44
voluntary EtOH consumption is induced. In rats subjected to this procedure, DNA-
microarray analysis reveales long term differential gene expression of limited groups
of genes in cingulate cortex and amygdala. Among regulated genes are both systems
previously implicated in alcoholism, e.g. several glutamatergic genes and monoamine
oxidase, as well as interesting novel candidates, such as the cannabinoid CB1
receptor, several kinases in the mitogen-activated protein (MAP) kinase pathway, and
subunits of Na+/K+-ATPase. Our findings illustrate that this strategy has an ability to
identify targets which are not only correlative but may also be causally related to the
alcoholic phenotype: both acamprosate, a partial agonist at glutamatergic NMDA-
receptors, and a CB1 antagonist suppress alcohol drinking in subjects with a history of
dependence, but not in regular laboratory rats.
A final level of analysis which is currently being developed is to apply modern
bioinformatics to identify systems whose differential expression correlates with
relevant behavioral phenotypes across several models. The application of this strategy
promises to strengthen the probability for identifying candidates which are causally
related to the phenotype, and therefore provide the most attractive targets for future
drug developments efforts.
DOPAMINE NEURO-TRANSMISSION A POTENTIAL
TREATMENT TARGET FOR ALCOHOL ADDICTION?
understanding its actions on dopamine (DA) neurotransmission in the meso-
accumbens reward pathway. It is now well established that behaviorally relevant
doses of ethanol activate this system. Evidence supporting a role of this effect in the
acute reinforcing actions of ethanol comes from findings that self-administration of
ethanol increases DA release in the nucleus accumbens (NAcc) in a dose-dependent
manner, that this effect is enhanced in alcohol preferring P rats, and that ethanol-
maintained reinforcement is modified by pharmacological agents that interact with
meso-accumbens DA transmission. Moreover, whereas ethanol acutely activates this
system, withdrawal from chronic ethanol leads to substantial deficits in DA function
that, are in part, reversible by renewed ethanol self-administration. These findings
have given rise to the hypothesis that meso-accumbens DA hypofunction after chronic
ethanol use is an important factor in the maintenance of alcohol addiction by
promoting ethanol intake to compensate for its deceased efficacy on DA release, and
by motivating resumption of drinking during withdrawal to reverse DA deficits.
Consistent with the animal literature, several clinical and laboratory studies in humans
suggest that DA antagonists reduce the euphorigenic and stimulant actions of ethanol,
depression. These findings confirm a role of DA in different aspects of ethanol’s
addictive and suggest that direct or indirect manipulation of DA transmission may be
of therapeutic benefit.
has been implicated in mediating behavior that brings subjects into contact with a
reinforcer. A role of DA in this “incentive-motivational” aspect of ethanol’s actions
may have important implications for understanding the mechanisms regulating the
initiation of ethanol-seeking and, by extension, ethanol craving and relapse.
Considering the chronic relapsing nature of alcoholism, it was of interest to elucidate
the role of DA in ethanol-seeking behavior associated with the conditioned incentive
effects of alcohol-associated environmental stimuli, and to determine whether this
neurochemical system is a potential treatment target for the prevention of relapse.
associated context increases extracellular DA levels in the NAcc of Wistar rats and
whether this effect is sensitive to manipulation of the animals’ motivational status. In
addition, the effects of DA D1 and D2 receptor antagonists on the initiation and
maintenance of drug-seeking behavior induced by ethanol-related contextual stimuli
were examined. Finally, microdialysis and pharmacological manipulations were
employed to study the role of meso-accumbens DA in the anti-relapse actions of
opiate antagonists.
environment reliably increased DA release in the NAcc, and this effect was enhanced
in rats subjected to ethanol deprivation prior to testing. In rats, presented with ethanol-
predictive discriminative stimuli, administration of D1 and D2 receptor antagonists
dose-dependently increased the latency to initiate responding and reduced the number
of responses at a previously active, ethanol-paired lever. In a second set of
experiments, the opiate antagonist, naltrexone (NTX) was found to block increases in
accumbal DA release induced by ethanol, but not DA release induced by an ethanol-
associated environment. Nonetheless, NTX reversed ethanol-seeking behavior in the
latter group of rats. Subsequent experiments using discrete intracerebral injection of
the naloxone derivative, methylnaloxonium, have identified the ventral pallidum (i.e.,
the major site for neural output from the NAcc) as the site of action responsible for
the attenuation of conditioned ethanol-seeking behavior by opiate antagonists.
stimuli by DA antagonists extends prior evidence on a role of DA transmission in
ethanol reinforcement to a role of this transmitter in conditioned drug-seeking
responses and, by inference, craving and relapse associated with exposure to alcohol
cues. Moreover, the increase in accumbal DA release produced by these stimuli
implicates the meso-accumbens system in the mediationof their motivating effects.
Although not fully conclusive, the results also suggest that opiate antagonists may act
to intercept the effects of the accumbal dopaminergic activation produced by alcohol
cues at the level of the ventral pallidum. Overall, the findings confirm a role of meso-
accumbens DA transmission in different aspects of the addictive cycle associated with
alcoholism and implicate brain DA as an important potential treatment target.
Moreover, as suggested by the results, accessing DA function indirectly via other
and, possibly, superior pharmacotherapeutic approach.
alcoholism, schizophrenia, Parkinson's disease, Tourette syndrome, tardive dyskine-
sia, Huntington's disease, and attention deficit hyperactivity disorder. With respect to
alcoholism quantitative trait locus experiments have identified a preference locus in
the middle of chromosome 9 in the mouse, where dopamine D2 gene (DRD2) is lo-
calized and the gene that codes for the 5-HT
1B-receptor (Crabbe et al. 1999).
Others tested in a large family-based sample whether the DRD2 locus is associated
with alcohol dependence. Neither the transmission-disequilibrium-test nor the
affected-family-based-controls'-test provided any evidence of linkage or association
between the DRD2 locus and alcohol dependence (Edenberg et al. 1998). DRD2
knock-out-mice consumed less ethanol in a free-choice-paradigm than wild type mice
(Phillips et al. 1998). In place-conditioning experiments knock-out-mice did not
prefer ethanol instead of water (Cunningham et al. 2000). Futhermore, the ethanol-
induced reduction of locomotor activity was suspended in knock-out-mice (Phillips et
al. 1998). A reduction of preference has also been demonstrated for opiates in the
place-preference paradigm (Maldonado et al. 1997).
dissocial" alcoholics (Hetata et al. 1994). SPECT investigation demonstrated a redu-
ced number of dopamine transporters (DAT) in the striatum of "non-dissocial"
alcoholics in contrast to dissocial ones. The density of the latter group was slightly
higher than that of healthy controls (Tiihonen et al. 1995).
Increases in DRD2 receptors (52%) in the nucleus accumbens in rats was accom-
plished by vector administration of the respective gene. The overexpression of DAD2
receptors was associated with a marked reduction in alcohol preference (43%) and
alcohol intake (64%) of ethanol preferring and non-preferring rats (preference 16%,
intake 75%, Thanos et al. 2001). All these findings suggest an important contribution
of dopaminergic neurones to some aspects of alcoholism.
genes including dopamine D1, D2, D3, D4, D5 receptors, tyroxine hydroxylase, mo-
noamine oxidase, and dopamine transporter. The dopamine D2 receptor was of spe-
cial interest because of the evidence of its important role presented above, the pos-
sibility of genetic analysis and of the assessment of the activity of dopamine D2 re-
ceptors at various timepoints during the course of the disease, using the apomorphine-
induced growth hormone response. The neuroendocrine testing was performed
routinely during intoxication at the time of admission to an inpatient alcohol treatment
later during a rehabilitation programme for abstinence. Two-factor analysis of
variance (ANOVA) revealed a significant change of GH response over time between
intoxication and postintoxication (P < 0.001) and between abstainers and relapses (P =
0.032). Standardized canonical discriminant coefficient was highest for reduced GH
response compared with other relapse predictors in the model used. These and other
findings initiated a study to examine the hypothesis that reduced dopamine function
and/or diminished ability of dopamine function to adapt to the non-intoxicated state in
the rehabilitation programme is an important cause for relapse. Therefore, we treated
alcoholic patients with the dopamine D2 receptor agonist Lisuride using a randomized
double-blind placebo-controlled design.
THEIR HUMAN COROLLARIES
Wales, UK
important functions in the central nervous system, including mood. It is because of
the frequent incidence of mood disturbances in alcohol-dependent patients that
investigators have been preoccupied for over four decades now in studying the
relationship between alcohol consumption and the metabolism of serotonin and its
precursor amino acid tryptophan (Trp). It is only since the mid 1980’s that, because
it has become apparent that serotonin may also control the desire to drink alcohol,
emphasis in alcohol-serotonin research has shifted from mood to alcohol-
consummatory behaviour; a shift that seems to parallel broadly the development of
basic research on serotonin receptor physiology in relation to appetite control, and
clinical research on serotonin in the context of impulse control.
that of its Trp precursor, because the brain level of the latter is the most important
single metabolic determinant of the rate of serotonin synthesis. This is because the
rate-limiting enzyme of this synthesis, Trp hydroxylase, exists unsaturated with its
Trp substrate. Consequently, central serotonin synthesis is dependent on peripheral
factors controlling Trp availability to the brain. These factors include, at the primary
level of control, activity of hepatic Trp pyrrolase, the quantitatively most important
enzyme of Trp degradation, and, at the secondary, but more immediate, level, Trp
binding to albumin and extent of competition with Trp for entry into the brain from at
least 5 other amino acids (the competing amino acids or CAA), namely Val, Leu, Ile,
Phe and Tyr. In human studies, the most accurate predictor of brain Trp, and hence,
5-HT, changes is therefore the circulating [Trp]/[CAA] ratio.