P.6.b.001 The acute effects of ethanol and acetaldehyde on physiological responses after ethanol ingestion in young healthy men

S394

P.6.b. Addiction − Alcohol (basic)

C/T polymorphisms in patients with alcohol dependence have been controversial. Furthermore, our data failed postulating that MTHFR 677 C/T polymorphism can explain a difference in degree of increased homocysteine during alcohol withdrawal period in patients with alcohol dependence. Another finding in this study indicated that elevated homocysteine levels in during acute alcohol withdrawal period can be normalized after alcohol detoxification. References [1] The methylenetetrahydrofolate reductase 677C→T polymorphism as a modulator of a B vitamin network with major effects on homocysteine metabolism. Hustad S, Midttun Ø, Schneede J, Vollset SE, Grotmol T, Ueland PM. Am J Hum Genet. 2007; 80(5): 846−55. [2] Association between MTHFR 677C-T polymorphism and alcohol dependence according to Lesch and Babor typology. Benyamina A, Saffroy R, Blecha L, Pham P, Karila L, Debuire B, Lemoine A, Reynaud M. Addict Biol. 2009; 14(4): 503−5. [3] Protective effect against alcohol dependence of the thermolabile variant of MTHFR. Saffroy R, Benyamina A, Pham P, Marill C, Karila L, Reffas M, Debuire B, Reynaud M, Lemoine A. Drug Alcohol Depend. 2008; 96(1−2): 30−6.

Mental State Examination). It seems to be particularly suitable for rapid screening of these disorders in alcohol-dependent patients. Following the study will prospectively followed for 3 months for these patients to explore the impact of these deficits on the course of the disease (abstinence and continued medical supervision). This study was never done before. The therapeutic implications could be significant and change our daily practice. The awareness of executive function disorders detected at the Moca could well lead us to define various parameters for monitoring alcohol dependent patients. We could offer them a closer monitoring and thus better adapt our practice to patient functioning. The study is ongoing, we aim at include over 200 patients. This cohort should provide us results even more meaningful and increase the clinical implications of these findings. References

P.6.a.010 Cognitive disorders among alcoholics: relevance of the Montreal Cognitive Assessment

[1] Ismail Z, Rajji TK, Shulman KI. Brief cognitive screening instruments: an update. Int J Geriatr Psychiatry. 2010 Feb; 25(2): 111−20. [2] Copersino ML, Fals-Stewart W, Fitzmaurice G, Schretlen DJ, Sokoloff J, Weiss RD. Rapid cognitive screening of patients with substance use disorders. Exp Clin Psychopharmacol. 2009 Oct; 17(5): 337−44. [3] Nasreddine ZS, Phillips NA, B´edirian V, Charbonneau S, Whitehead V, Collin I, Cummings JL, Chertkow H. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005 Apr; 53(4): 695−9.

M. Szprync1 ° , E. Hispard1 , F. Questel1 , F. Vorspan1 , A. Della Zuena1 , J.P. Lepine1 1 Hˆopital Fernand-Widal, Addictology, Paris, France

P.6.b. Addiction − Alcohol (basic)

Introduction: The occurrence of cognitive deficits in alcoholic patients is a well known phenomenon through Wernicke and Korsakoff ’s syndromes. But it appears that many patients develop more moderate cognitive impairment. These disorders can cause deep discomfort for patients in their daily lives and could be a major factor in the relapse process. It seems that the MMSE (Mini Mental Status Examination) doesn’t screen well enough executive function disorders. The Moca appear more sensitive than MMSE for screening the mild cognitive disorders [1]. Method: This study is underway, we present here the results of the first 77 patients evaluated from January 2012. It assessed the relevance of a cognitive assessment scale. The subjects admitted to the Addictology Department in Fernand Widal hospital (Paris, FRANCE) for alcohol withdrawal have all had a rapid neuropsychological assessment scale: Moca (Montreal Cognitive Assessment). This scale has already been validated for the identification of cognitive impairment secondary to many conditions [1] including addictions (all products mixed) [2], it is validated in French [3]. The link between the Moca score and variables reflecting the age and intensity of alcohol use (years of addiction and alcohol intake in grams the week before hospitalization) was tested by linear regression with adjustment for age and sociocultural level. The subjects agreed to participate in the study and signed a consent form. This study has been approved by the Ethics Committee of Paris (Saint Louis Hospital). Results: The total score on the Moca was not correlated with the consumption parameters. The sub score corresponding to the Moca executive functions is associated with the age of dependence and the amount of alcohol consumed per week (r = 0.30, p = 0.036 and r = 0.30, p = 0.035). Discussion: Exposure and duration of alcohol dependence thus appear related to executive function disorders detected by this scale assessment. The Moca was designed to detect specifically executive function disorders in comparison to the MMSE (Mini

P.6.b.001 The acute effects of ethanol and acetaldehyde on physiological responses after ethanol ingestion in young healthy men K.Y. Bae1 ° , S.W. Kim1 , J.S. Yoon1 1 Chonnam National University Hospital, Department of Psychiatry, Gwangju, South-Korea Purpose: Ethanol induces a multitude of effects in the human body that lead to changes in the cardiovascular system, subjective feelings and psychomotor behaviour. Much debate has been centred around the role of the ethanol metabolite acetaldehyde. However, to our knowledge, sufficient studies have not been conducted to confirm the role of acetaldehyde by direct measurements in human blood. The Korean people constitute a highly homogeneous ethnic group. This pilot study investigated the acute effects of ethanol on physiological responses in young healthy Korean men according to ALDH2 genotype and the role of acetaldehyde and ethanol on physiological responses to ethanol ingestion by measuring them directly in human blood. Methods: Twenty-four men, 12 with the ALDH2*1/*1 genotype and 12 with the ALDH2*1/*2 genotype, were selected. In a double-blind placebo-controlled crossover design, each subject was administered one of three doses of ethanol (0.25, 0.5 or 0.75 g/kg) or a placebo on four separate occasions. The blood ethanol concentration (BEC), blood acetaldehyde concentration (BAAC) and physiological responses including facial redness, pulse rate and systolic and diastolic blood pressures were assessed. Results: The difference of the BEC between ALDH2*1/*1 and ALDH2*1/*2 groups is not significant at each time point measured (all p values > 0.05) and the BEC of both groups were dose-dependent. The BAAC of ALDH2 *1/*2 group was significantly higher than those of the ALDH2 *1/*1 group at every time point measured (all p values < 0.001). BEC was

P.6.b. Addiction − Alcohol (basic) highest at 60 minutes, and BAAC was highest at 30 minutes after ethanol ingestion. Significant differences were observed in the physiological responses between the ALDH2*1/*2 and ALDH2*1/*1 groups. Significant gene effects were observed for pulse rate and facial flushing (F-values = 62.344; p-values <0.001 and F-values = 7.062; p-values = 0.010, respectively, by repeatedmeasures analysis of variance), which were significantly greater in subjects with the ALDH2*1/*2 genotype. In a linear regression analysis, BAAC significantly predicted increased facial redness at 30 minutes (adjusted R2 : 0.209; p-values <0.001) and pulse rate at 30, 60, 90, and 120 minutes (adjusted R2 : 0.454, 0.490, 0.428 and 0.193, respectively; all p-values <0.001), whereas BEC was not associated with any physiological response measure at any time. Conclusions: Ethanol ingestion induced various physiological changes such as facial redness, increased pulse rate and decreased blood pressure. The acute effects of ethanol on facial redness and pulse rate were mediated mainly by acetaldehyde, the active metabolite of ethanol, rather than by ethanol itself. This study demonstrated the biological background of Oriental flushing and the role of acetaldehyde in the physiological responses. The present study also suggested the possibility that the potential harmful effects of ethanol on the cardiovascular system might be mainly mediated by acetaldehyde. Future research needs to investigate the role of acetaldehyde in physiological responses in women and other age groups and the association between acetaldehyde and clinical consequences including sudden cardiac death. References [1] Zakhari, S., 2006. Overview: How is alcohol metabolized by the body? Alcohol Res Health 29, 245–254. [2] Pawlak, D., Malinowska, B., Buczko, W., 1992. Cardiovascular effects of acetaldehyde in pithed rats. Pharmacology 45, 83−89. [3] Kim, S.W., Bae, K.Y., Shin, H.Y., Kim, J.M., Shin, I.S., Youn, T., 2010. The role of acetaldehyde in human psychomotor function: a doubleblind placebo-controlled crossover study. Biol Psychiatry 67, 840–845.

P.6.b.002 Compulsive-impulsive alcohol consumption in serotonin deficient vesicular monoamine transporter 2 (Vmat2) knockout mice T. Weber1 ° , A. Bilbao2 , S. Berger3 , B. Giros4 , R. Spanagel2 , D. Bartsch3 1 Central Institute of Mental Health, department of addictive behavior and addiction medicine, Mannheim, Germany; 2 Central Institute of Mental Health, Institute of Psychopharmacology, Mannheim, Germany; 3 Central Institute of Mental Health, Department of Molecular Biology, Mannheim, Germany; 4 McGill University Douglas Hospital, Department of Psychiatry, Montreal, Canada Serotonergic (5-HT) hypofunction has been associated with impulsive and compulsive behavior in humans and rodents [1]. While impulsive tendencies, potentially involving increased cuereactivity [2], appear to be predictors of substance abuse, the transition from an impulsive, yet flexible and goal-directed substance intake to an inflexible, compulsive drug use characterizes substance addiction [3]. We generated transgenic TPH2CreERT2/Vmat2flox/Vmat2flox mice to investigate alcohol drinking behavior in 5-HT deficient mice. TPH2-CreERT2 mice were mated to transgenic mice in which both Vmat2 alleles are loxP-flanked. Starting at P75, intraperitoneal tamoxifen applications (1 mg/mouse twice daily) for 5 days in TPH2-CreERT2/Vmat2flox/Vmat2flox mice and Vmat2flox/Vmat2flox control mice induced a 5-HT neuron specific knockout of the Vmat2 gene by Cre-mediated recombination

S395

in adult TPH2-CreERT2/Vmat2flox/Vmat2flox mice. These mice showed a 75% reduction of 5-HT tissue content in all areas of the brain whereas dopamine and noradrenaline levels remained unchanged. Behavioral analysis was initiated one month after tamoxifen administration. In pavlovian conditioning, Vmat2-KO mice show increased conditioned response to a natural reward. When they were trained to associate the availability of a sweet condensed milk solution with the presentation of an orange odor (CS+), presentation of the CS+ alone led to a significantly increased water intake compared to controls. Next, we tested initial sensitivity to alcohol, motivation for alcohol using an operant conditioning paradigm, alcohol seeking behavior by means of cue-induced reinstatement, relapse to alcohol (ADE) and compulsive alcohol drinking. Vmat2-KO mice showed a significantly decreased sensitivity to the sedative effect of alcohol as assessed in the LORR (loss of righting reflex) test. During operant self administration of alcohol, 5-HT neuron specific Vmat2-KO mice showed a significantly increased lever pressing for alcohol in the CS+ context indicating a high motivation for alcohol conditioned cues. Following extinction of lever pressing, cue-induced reinstatement to the CS+ was significantly enhanced in Vmat2-KO mice, suggesting an increased cue-reactivity in these mice and thus enhanced alcohol seeking behavior. Finally, alcohol deprivation (ADE), a paradigm modeling relapse to alcohol after periods of prolonged abstinence was tested. Baseline home cage drinking was identical in both groups of mice. After two weeks of alcohol deprivation, reintroduction of alcohol in the home cage resulted in a significantly increased alcohol intake in both groups of mice indicating an ADE. After a second alcohol deprivation phase, compulsive alcohol drinking was measured. Quinine adulterated alcohol was not able to abolish relapse to alcohol in the Vmat2-KOs indicating a loss of control and therefore compulsive alcohol drinking. In adult TPH2-CreERT2/Vmat2flox/Vmat2flox mice, the induction of a hyposerotonergic state via Vmat2 deletion in 5-HT neurons leads to decreased sensitivity to alcohol, increased motivation and seeking behavior for alcohol and compulsive alcohol drinking. These findings reveal that a decrease in brain 5-HT levels in adult mice can be directly linked to an addictive alcohol phenotype. References [1] Finberg, N.A., Potenza, M.N., Chamberlain, S.R., Berlin, H.A., Menzies, L., Bechara, A., Sahakian, B.J., Robbins, T.W., Bullmore, E.T., Hollander, E. Probing compulsive and impulsive behaviors, from animal models to endophenotypes: a narrative review. Neuropsychopharmacology. 2010 Feb; 35(3): 591–604. [2] Tomie, A., Aguado, A.S., Pohorecky, L.A., Benjamin, D. Ethanol induces impulsive-like responding in a delay-of-reward operant choice procedure: impulsivity predicts autoshaping. Psychopharmacology (Berl). 1998 Oct; 139(4): 376−82. [3] Vengeliene, V., Celerier, E., Chaskiel, L., Penzo, F., Spanagel, R. Compulsive alcohol drinking in rodents. Addict Biol. 2009 Sep; 14(4): 384−96.

P.6.b.003 Liquids with negative redox potential reduce alcohol consumption and excessive motor activity in alcohol-dependent rats E. Sabitova1 ° 1 Voronezh state medical academy, Department of pharmacology, Voronezh, Russia Recently, a number of studies have been devoted to the action of liquids with negative oxidation–reduction potential (catholytes) in living organisms. Catholyte is produced in an electrochemical system by simultaneous electrochemical and electrophysical