1-4
5-8
9-12
13-16
17-20
21-24
25-28
29-32
33-36
37-40
41-44
after a 15-day period of deprivation, suggesting that baclofen may have an anti-
relapse potential in alcoholics.
Finally, this laboratory investigated whether treatment with baclofen could affect
motivation to consume alcohol in sP rats. To this aim, sP rats were trained to press a
lever to orally self-administer 10% alcohol. Once lever-pressing behavior was
established, the effect of baclofen on the extinction responding for alcohol, defined as
the maximal number of lever responses reached by each rat in the absence of alcohol
reinforcement and used as an index of motivation, was determined. Treatment with
baclofen resulted in a dose-dependent suppression of extinction responding: indeed,
lever responses was reduced by 64, 88 and 98% in 1, 2 and 3 mg/kg baclofen-treated
rats, respectively, when compared to saline-dosed rats. These results suggest that the
reducing effect of baclofen on alcohol intake may be secondary to its ability to
suppress alcohol motivational capacities.
Taken together, these results suggest that the pharmacological stimulation of GABAB
receptors may reduce alcohol consumption and reinforcement in animal models of
alcoholism. Finally, together with the outcome of the first double-blind placebo-
controlled study in human alcoholics (G. Addolorato, this meeting), these results
suggest that baclofen may constitute a novel pharmacotherapy for alcohol
dependence.
ALCOHOL ADDICTION
C. Ancona, F. Lorenzini, R. Agabio, G.L. Gessa, G. Colombo, G.
Gasbarrini.
Università di Bologna; Dipartimento di Neuroscienze “B.B Brodie”, Università di Cagliari; Istituto
di Neurogenetica e Neurofarmacologia del CNR di Cagliari.
receptor agonist, baclofen, has recently been shown to reduce alcohol
withdrawal syndrome (AWS) and alcohol intake in rats and alcohol consumption
and craving for alcohol in open study in humans. The present studies were aimed at
providing a first evaluation of the efficacy of baclofen in suppressing AWS in
humans and in inducing and maintaining abstinence and reducing craving for
alcohol in alcohol-dependent patients in a double-blind placebo-controlled design.
AWS STUDY – METHODS. Five active alcoholics were enrolled consecutively in
the study. The AWS symptoms were evaluated by the Clinical Institute Withdrawal
Assessment for Alcohol-revised (CIWA-Ar) scale. All patients had a total CIWA-
Ar score of more than 20 points, indicative of a severe AWS. After obtaining
informed consent, baclofen was administered in a dosage of 10 mg per os. The
CIWA-Ar was re-administered every hour for 4-8 hours. Patients were
subsequently treated with baclofen at doses of 10 mg every 8 hours. They were
monitored as out-patients every day for the first seven days and once a week for the
RESULTS. Administration of baclofen led to a rapid reduction in the CIWA score
and disappearance of the AWS symptoms within 1-3 hours from the start of
treatment in all patients. Symptoms were absent throughout the entire treatment and
suspension period. The drug was safe and no patient showed side effects.
MAINTAINING ABSTINENCE STUDY – METHODS – A total of 39 alcohol-
dependent patients were consecutively enrolled in the study. After 12-24 hours of
abstinence from alcohol, patients were randomly divided into two groups. Twenty
patients were treated with baclofen and 19 with placebo. Drug and placebo were
orally administered for 30 consecutive days. Baclofen was administered at the dose
of 15 mg/day for the first three days and 30 mg/day for the subsequent 27 days,
divided into three daily doses. Patients were monitored as out-patients on a weekly
basis. At each visit alcohol intake, abstinence from alcohol, alcohol craving and
changes in affective disorders were evaluated. RESULTS – A higher percentage of
subjects totally abstinent from alcohol and a higher number of cumulative
abstinence daysthroughout the study period were found in the baclofen respect to
the placebo group. A decrease in obsessive and compulsive components of craving
was found in the baclofen respect to the placebo group; likewise, alcohol intake was
reduced in the baclofen respect to the placebo group. A decrease in state anxiety
was found in the baclofen respect to the placebo group. No significant difference
was found between the two groups in terms of current depressive symptoms.
Baclofen proved to be easily manageable and no patient discontinued treatment due
to the presence of side effects. No patient was affected by craving for the drug
and/or drug abuse.
CONCLUSIONS – Baclofen proved to be effective suppressing AWS, in inducing
abstinence from alcohol and reducing alcohol craving and consumption in
alcoholics. With the limits posed by the small number of subjects involved, the
results of this preliminary double-blind study suggest that baclofen may represent a
potentially useful drug in the treatment of alcohol-dependent patients.
ALCOHOLISM – THE ROLE OF NICOTINIC
ACETYLCHOLINE RECEPTORS
1Institute of Clinical Neuroscience, Section of Psychiatry and 2Institute of Physiology and
Pharmacology, Department of Pharmacology, Sahlgrenska Academy, Göteborg University, Sweden
mesocorticolimbic dopamine neurons, an important part of the brain reward system.
This dopamine activation may be involved in mediating the positive reinforcing
effects of ethanol. The mechanisms of action of ethanol in its activation of this
dopamine system remain, however, to be elucidated. A selective pharmacological
properties of ethanol without simultaneously interfering with the reinforcing
properties of natural rewards. Ethanol has been shown to directly influence the
function of various ligand-gated ion-channels. Several of these are located on or
nearby mesocorticolimbic dopamine neurons. One such receptor is the nicotinic
acetylcholine receptor (nAChR). This taken together with the fact that in man
alcoholism and nicotinism are heavily associated led us to perform a series of acute
and chronic experiments in rodents investigating whether nAChR are involved in the
dopamine activating and reinforcing effects of ethanol.
the dopamine activating effects of ethanol. Furthermore, the nAChR subtype involved
appears not to be the a4b2 or the a7, as for nicotine, but may invoke a3 and
/or a6 subunits. However, the ethanol-induced activation of these receptors is probably
not
direct but rather indirect (involving endogenous ACh release) and subsequent to some
effect produced by ethanol in the nucleus accumbens. Our recent results indicate that
this accumbal effect of ethanol may be an activation of strychnine-sensitive glycine
receptors that are present in this brain region, as demonstrated by Western blot.
free-choice model, ventral tegmental nAChR may be involved. Thus, systemic or
ventral tegmental administration of the nAChR antagonist mecamylamine reduces
ethanol intake and preference. In fact, after mecamylamine in the ventral tegmental
area ethanol high-preferring Wistar rats turned into ethanol low-preferring ones and
thus neglected the ethanol bottle. Concomitantly mecamylamine totally prevented the
accumbal dopamine release otherwise associated with ethanol consumption in these
animals. In subsequent preliminary experiments we have obtained evidence
suggesting that also ethanol cue induced (conditioned) dopamine release in the
nucleus accumbens is prevented by mecamylamine in the ventral tegmental area.
the dopamine activating, rewarding and reinforcing effects of ethanol. Recent
experimental results in humans by Blomqvist et al (this meeting) support this
contention. Whether the nAChR subtypes involved in the reinforcing and conditioned
effects are the same as those mediating the dopamine activating effects after passive
systemic ethanol injections remains to be determined.
enhanced risk of developing alcoholism later in life. This correlation may be due to a
pharmacological effect of chronic nicotine, as indicated by experimental studies by us
and others demonstrating that subchronic nicotine pretreatment increases ethanol
intake and preference in rats. Surprisingly, recent results indicate that this effect may
derive from intermittent blockade of peripheral nAChR rather than from intermittent
stimulation of central nAChR and be related to development of a behavioral
disinhibitory response to both nicotine and ethanol. This disinhibitory response
appears to involve also serotonergic mechanisms. The peripheral events subsequent to
an intermittent blockade of peripheral nAChR that produce these behavioral
alterations remain to be elucidated. Some preliminary experiments suggest that
peripheral muscarinergic receptors and possibly some peripheral hormone released by
activation of these, e.g. insulin, may be involved. These results also indicate that the
consquence of the nicotine exposure.
ethanol consummatory behavior in rats. This association is interesting considering the
fact that in humans the genetic inheritance of alcoholism and nicotinism appears to be
shared, whereas that of alcoholism and other drug dependencies probably is not.
Studies in alcoholics and smokers of polymorphisms of genes encoding different
nAChR subunit proteins are of highest priority for our future work. Furthermore, our
results indicate that unselective chronic blockade of nAChR is not likely to be
effective in reducing ethanol consumption in humans, since the peripheral blockade
imposed by such a treatment is likely to increase ethanol intake, thereby counteracting
the putative intake reducing effect of the central blockade. It is therefore of great
importance to further reveal what nAChR subypes are involved in the central effects
here described and to develop molecules selectively blocking these without interfering
with peripheral nAChR. Such a development is also necessary in order to prevent the
multitude of side effects that is associated with peripheral nAChR blockade. Finally,
the role of the newly identified accumbal strychnine-sensitive glycine receptors and
the chain of events subsequent to activation of these, including a tentative ACh
release, as well as the nature of the peripheral link described above are other topics
that will be of highest priority to explore in the near future. Studies of genes related to
these pathways as well as of substances interfering with them are likely to generate
new ideas for future pharmacological treatments of alcoholism.
ALCOHOLISM COURSE
König B., Lindner H.
dopaminergic and glutamatergic actions (De Witte, 2002). Mainly the changes in the
glutamatergic systems seem to influence the severity degree of craving.
Clinically tobacco use influences the outcome in relapse prevention studies, e.g.
flupenthixol (Wiesbeck et al, 2001), acamprosate (Mann et al, 2000). Differences
between nicotine use, abuse and dependence have not been investigated yet. Also the
question of a biologicaldependence, assessed by the Fagerström questionnaire, is not
yet proved within a trial. Subgroups of alcohol dependence (Lesch types I to IV) show
different mechanisms of craving and therefore their further relapse rates might be
influenced differently by different modalities of smoking (use, abise, dependence).
Methods:
100 alcohol dependent patients (ICD-10) were included in the study. After 3 weeks of
admission, under controlled sobriety, alcohol typology according to Lesch and the
smoking behaviour were assessed by ICD-10, Fagerström questionnaire, and a