P5 Addiction $253 E5 Addiction • Dopaminergic turnover changes on various brain regions during ethanol withdrawal syndrome in rats I.T. Uzbay 1, S.E. Usanmaz, S. Arat, E.S. Akarsu. Departments of Pharmacology Faculties of Medicine; 1 Giilhane Military Medical Academy' and Ankara University, Ankara, Turkey, Some behavioral components of ethanol withdrawal syndrome (EWS) such as increased stereotyped behavior and tremors, have strongly sug- gested a possible dopaminergic involvement. To assess the relationship between such behavioral components and dopaminergic turnover in EWS, dopamine, 3,4-dihydroxyphenyl acetic acid (DOPAC) and homovanillic acid (HVA); two major metabolites of dopamine respectively were simul- taneously measured by high performance liquid chromatograpy (HPLC) in cerebral cortex corpus striatum (CS) and hippocampus (He) at various time intervals during EWS. Male Wistar rats were used. Ethanol at 7.2% concentration was administered for 15 days by a modified liquid diet as previously described (Uzbay and Kayaalp 1995). Results: CC: Stable dopamine and DOPAC levels in controls were measured to be 1.3-5.0 and 0.86-2.91 ng/mg wet tissue, respectively. HVA was detectable only 7 of the 24 control samples. Dopamine and DOPAC did not change during EWS. Only dopamine level was increased after audiogenic stimulus (100 dB) which caused 50% seizure incidence at 6 th hour of EWS. This trend was same in convulsive and nonconvulsive rats. HVA was detectable 13 of total 24 EWS samples. The increase in HVA was significant at 4 th and 6th hours of EWS. After audiogenic stim- ulus, HVA level was significantly lower than the respective time-match control. CS: Dopamine, DOPAC and HVA were detectable all of the control samples and the values were stable throughout the time intervals (ranges: 1.03-4.96; 0.87-2.62 and 0.11~0.74 ng/mg wet tissue respectively). Dopamine and DOPAC were unchanged at the time intervals and after audiogenic stimulus during EWS. HVA levels were significantly higher than control at 2~d, 4 th and 6th hours of EWS. Following audiogenic stimulus, HVA was detected on half of the samples (n = 6). That change did not show any preference between convulsive and nonconvulsive rats. HC: Dopamine and DOPAC were detectable only 8 and 3 of total 24 control samples. None of the control samples was HVA detectable. During EWS there were no consistent changes in term of dopaminergic turnover. Conclusion: During EWS, dopaminergic turnover has changed due to time course and the external conditions applied. Increased dopaminergic turnover in CS can be proposed as the mechanism of some behavioral changes observed especially at the early stages of EWS. Increased dopamine level in CC after audiogenic stimulus may be due to the decreased metabolism. Since there is no consistency between increased dopamine level and convulsion incidence, it is unlikely, that increased dopaminergic turnover in CC is responsible for CNS hyperexcitability leading to audiogenic seizures. This study was supported by TUBITAK (grant no: SBAG-AYD-107) References Uzbay I.T, Kayaalp S.O. (1995). A modified liquid diet of chronic ethanol admin- istration: Validation by ethanol withdrawal syndrome in rats, Pharmacological Res. 31, 37~-1. • Bipolar disorders treatment with sodium valproate U.A. Alexandrovsky, A.S. Avedisova. State Research Centre of Social and Forensic Psychiatry named after V.P.Serbsky, Department of New Means and Methods of Therapy; Mosco~c, Russia During the recent years more attention is paid to drugs with antimaniac and normotimic activity, alternative to lithium. From this point of view, valproic acid chlorides are the most perspective substances with wide sphere of clinical activity and good tolerability. The aim of the study was to determine antidepressive, antimaniac and normotimic activities of sodium valproate (Depakine-Chrono (D-C)) and to evaluate its pharmacokinetic parmneters. 30 patients with bipolar affec- tive disorders were involved in this study. The 12 months study duration were split into two phases: control phase (6 months) and active treatment phase (6 months), when Depakine-Chrono was indicated e,s monotherapy, internal use daily evenings after the meals in a fixed dosage 500 mg. Pharmacokinetic study of the D-C Level was done twice (during the 1st and 24th week of active treatment period). Evaluation of the therapy effectiveness was done during the w hole study period using the affective state self-control map, and also during the active treatment period using HAM-D, MAS and Kellner scales. Evaluation of drug tolerability was clone using the adverse affects registration scale. Study Results: there were no drop-outs during the study. Adverse effects (nausea, headache, tremor) were slightly present and had limited duration period, spontaneously disappearing. Therapy effectiveness was registered already during the first month of treatment and affective disor- ders frequency at the 6th month of study was 3.5 times less in comparison with the control period. The most improved state patients were the ones with fast affective phases alteration (not less, than 3 chlring a month). Evaluation of D-C influence on the maniac sypmtomathology (MAS) showed its significant reduction during the 3rd-7th day of treatment. No drug antidepressive effect (HAM-D) was found, but significant reduction of anxious symptomathology, carried in the depression structure was noted. Anxiety and irritability/aggressiveness indicators reduced (Kell- ner). Pharmacokinetic data indicated rather stable level of the drug in blood - until the end of therapy changes did not exce, ed 0.5 mkg/ml from the background data. Stable concentration of drug in blood was accompanied with persistent clinical effect, not weakening during the 6 months treatment. This study shows a high efficacy of the D-C as a mood stabiliser during bipolar disorders, mostly of contiguity kind, acting as "swing". At the same time antimaniac and anxyolitic activity of the drug was uncovered, allowing to prescribe it when treating maniac states, and when treating depressions together with antidepressants. Long-term D-C therapy does not reduce the drug effectiveness, and low adverse effects do not prohibit from its long-term treatment. I • Pilot study of D2 dopamine receptor, ALDH2, ADH2 and ADH3 gene allelic association in polynesian alcohol and cannabis users S. Amadeo 1, E.P. Noble, X. Deparis, M.F. Brugiroux, M.L. Fourcade-Amadro, C. Tetaria. E. Beaugendre, K Chaktura, X. Zhang, T. Ritchie, A, Elbaz, E. Cheung, J. Mallet. 1 Service de l'sychiatrie Adulte, Hopiml Vaiami, BP 84, Papeete, Tahiti, PolvnFsie Franfaise Since the study by Blum, Noble and colleagues (1990) who reported a positive association between the AI allele of the D2 dopamine receptor gene and alcoholism, various studies provided new positive data, while others did not find a significant association. The variable frequency of the AI allele due to ethnic origin and the severity of alcoholism such as whether or not associated with drug abuse may be of crucial importance in these association studies. ADH and ALDH2 gene allelic association studies have also given controversial findings in alcoholism. We have performed a pilot association study in three groups of alcohol and cannabis users from French Polynesian rucially matched with respect to racial origin. Frequencies of the DRD2 Al allele in the groups of patients (n = 43) versus controls (n = 39) were: (l) pure Polynesian: 0.16 vs 0.35; (2) Polynesian with Caucasian ancestry 0.50 vs 0.27; (3) Polynesian with Asian ancestry: 0.40 vs 0.38. A trend in favour of an association beween the A1 allele of the D2 Dopamine receptor gene and alcoholism and cannabis use ~as found in the Polynesian/Caucasian group (X 2 = 3.19, p = 0.073; Odds Ratio = 2.7) but only small numbers were used in patient and control groups. We also found an association between the ADH2* 1 allele and alcoholism in group (2) and (3) (p = 0.05 and p = 0.042 respectively). In the Polynesian/Caucasian group, the combination of ADH2*I 1 homozygotes and DRD2-AI I homozygotes and A12 heterozygotes gave the most significant results (p -- 0.002). Our work may form the basis Ibr fruitful investigations in the.. future.