1-4
5-8
9-12
13-16
17-20
21-24
25-28
29-32
33-36
37-40
41-44
BACLOFEN SUPPRESSES MOTIVATION FOR
ALCOHOL IN ALCOHOL-PREFERRINGsP RATS
, Salvatore Serra1,2, Giuliana Brunetti1,2, Carla Lobina1,2,
Mauro A.M. Carai1, Giancarlo Colombo2, Gian Luigi Gessa1-3
Cagliari, Italy; 3“Bernard B. Brodie” Department of Neuroscience, University of Cagliari, Cagliari,
Italy.
receptor agonist, baclofen, to suppress the acquisition and maintenance of alcohol
drinking behavior as well as relapse-like drinking in selectively bred Sardinian
alcohol-preferring (sP) rats. The present study was designed to investigate the effect
of baclofen on the motivation to consume alcohol in sP rats.
To this aim, sP rats were trained to press a lever (on a FR4 schedule) to orally self-
administer 10% alcohol in daily 30-min sessions. Once lever-pressing behavior was
well established, the effect of baclofen on the extinction responding for ethanol,
defined as the maximal number of lever responses reached by each rat in the absence
of ethanol reinforcement and used as an index of motivation, was determined.
Baclofen was administered i.p. at the doses of 0, 1, 2 and 3 mg/kg, 30 min before the
start of the extinction session.
Pretreatment with baclofen resulted in a dose-dependent suppression of extinction
responding (Fig. 1). Specifically, lever responses averaged 54.8±8.4, 19.8±7.6,
6.8±5.1 and 1.0±1.0 in the rat groups treated with 0, 1, 2 and 3 mg/kg baclofen,
respectively. A separate experiment, testing sP rats in an open field arena,
demonstrated that baclofen, at the doses that suppressed extinction responding, was
devoid of any sedative effect.
The results of the present study demonstrate that baclofen suppressed the motivation
to consume alcohol in alcohol-preferring sP rats. These results also suggest that the
reducing effect of baclofen on alcohol intake may be secondary to its ability to
suppress alcohol motivational capacities.
Each bar is the mean ± S.E.M. of n=8. *P<0.05 with respect to vehicle-
treated rats.
ALCOHOLIC PATIENTS
, Jerzy Samochowiec2, Lutz G. Schmidt3, Michael
Smolka1, Hans Rommelspacher1
University of Berlin, 1405 Berlin, Germany; 2Department of Psychiatry, Pomeranian Academy of
Medicine, 71-469 Szczecin, Poland; 3Clinic of Psychiatry, University of Mainz, 55131 Mainz,
Germany;
have been implicated as main target sites for acute and chronic effects of ethanol. The
native receptor is composed of four heteromeric subunits. The function of the
NMDAR is known to be reduced acutely by physiologically relevant concentrations
of ethanol (10-50nM). The ethanol sensitivity seems to depend on the composition of
the heteromeric receptor. Those receptors which contain the NR1a splice variant and
the NMDAR2B subunit are known to be the most sensitive to ethanol1. After chronic
ethanol exposure tolerance develops, and NMDAR function increases, possibly by up-
regulated NMDAR and/or by altered NMDAR composition2. An increased NMDAR
function is also seen during withdrawal. In this study we tested, if recently found
polymorphisms in the genes of the NMDAR1 (G2108A)3and NMDAR2B (C2664T)4
subunits are associated with ethanol dependence.
Methods: The study included 367 alcohol dependent individuals and 335 control
individuals of German origin in the case control study. The sample comprised 196
alcoholics from the out-patient clinic for addictive disorders of the department of
psychiatry of the FreeUniversity of Berlin, 126 in-patients of the department of
alcohol dependence of a state hospital in Berlin, and 45 homeless subjects of a
meeting point located in Berlin. Alcohol and family history were assessed by a
structured interview, based on the Composite International Diagnostic Interview, and
a sociodemographic questionnaire. Nine overlapping subgroups were formed with
respect to a more homogeneous etiology of the alcohol-dependent subjects according
to the following criteria: 1) positive father history of alcohol dependence; 2) positive
mother history of alcohol dependence; 3) early age at onset defined by a loss of
control under the age of 26 years; 4) history of alcohol-related delirium; 5) history of
withdrawal seizures, and 6) history of vegetative withdrawal syndrome; 7) Cloninger
type 1 alcoholics, characterized by age at onset older than 25 years and no antisocial
tendency; 8) Cloninger type 2 alcoholics, characterized by an early age at onset under
26 years, antisocial tendencies, and male gender; 9) alcoholics with antisocial
tendencies. Tridimensional Personality Questionnaire (TPQ) (Cloninger 1987) was
applied to assess personality dimensions. The respective informations were available
for 163 alcohol dependent males.
Additionally 72 trios of Polish origin were recruited in the department of psychiatry
of the Pomeranian Medical University of Szczecin for the family based study.
Informed consent was obtained from all participants. The study protocol was
approved by the Ethics Committee of the University Hospital Rudolf Virchow of the
of Berlin and of the Medical University of Szczecin.
Genomic DNA was extracted from anticoagulated venous blood sample using a saltig
out method5. Genotyping was done using both FRET-probes in a PCR/melting curve
analysis, and by conventional RFLP analysis.
The SPSS computer program was used for the statistical analysis of clinical and
genetical data. Differences between the controls and the alcoholics and the respective
subgroups were tested by the c2-test and were referred significant if the type one error
was less than 5%. The odds ratios were calculated by a 2x2 statistics comparing the
prevalence of the various samples of alcoholics with those of the controls. The
families data were analyzed with the transmission disequilibrium test (TDT).
Results:For NMDAR1, there was a significant difference in the genotype distribution
between alcoholic patients and controls (c2=7.328, df=2, p=0.026). Looking for
subgroups, patients with a vegetative withdrawal syndrome, with a history of delirium
tremens during withdrawal, with an alcoholic father, with Cloninger type 1
alcoholism and with antisocial tendencies carried more frequently an A allele.
Furthermore, patients with the homozygote mutation had a significantly less ethanol
intake than those bearing a G allele (p=0.048). This result fits well with a higher
ethanol sensitivity of the A allele, implicated by association with vegetative
withdrawal syndrome and delirium tremens.
For NMDAR2B the T allele prevalence was significantly reduced in patients with an
early age at onset (c2=4.130, df=1, p=0.042), in patients with vegetative withdrawal
syndrome (c2=3.832, df=1, p=0.050), and in Cloninger type 2 alcoholics (c2=5.939,
df=1, p=0.015). Furthermore, patients carrying the C-allele showed higher rates in the
personality trait subscale of impulsivity compared to those lacking it (p=0.042). This
finding was independent of gender. Our family based study revealed a preferred
transmission of the C allele by fathers to the affected offspring (15xC vs. 6xT;
c2=3.857, df=1, p<0.05).
Discussion: The consistent finding in NMDAR1 of a higher A allele prevalence in
alcoholics indicate a higher ethanol sensitivity of the A allele to ethanol and is most
prominent in patients with withdrawal syndrome. The lower ethanol intake in patients
withthe homozygote mutation fits well with these findings. This is consistent with
our hypothesis, that mutations in this receptor subunit may contribute to alcoholism
and especially to withdrawal complications. The association between the absence of
the T allele in alcoholic patients with an early onset and especially in the Cloninger
type 2 alcoholicsimplicate a protective action of the T allele to an early loss of
control of alcohol intake. This is consistent with the observation, that patients
homozygote for the T allele have significant lower scores in the impulsivity scale of
the TPQ, and are more reflective. This personality dimension may be protective with
respect to alcohol misuse. In our family based study the TDT revealed a preferred
transmission of the C allele by fathers. Additionally, six of the 11 known alcoholic
fathers were heterozygote and five of them transmitted the C allele. This finding is an
additional hint to an association between the C allele of the C2664T polymorphism of
the NMDAR2B subunit gene and the risk of alcoholism.
1Lovinger D. Alcohol Clin Exp Res (Suppl) 2000; 24: 183A.
2Hu XJ, Follesa P, Ticku MK. Brain Res Mol Brain Res 1996; 36: 211-218.
3Rice SR, Niu N, Berman DB, Heston LL, Sobell JL. Molecular Psychiatry2001; 6: 274-284.
4Nishigushi N, Shirakawa O, Ono H, Hashimoto T, Maeda K. Am J Psychiat2000; 157: 1329-1331.
5Miller SA, Dykes S, Plesky HF. Nucleic Acids Res1988; 16: 1215.
A way out of alcohol dependence
