Different effects of GABAergic receptors located in the ventral tegmental area (VTA) on the expression of morphine-induced conditioned place preference in rat

P.5. Addiction 12.0 in group A, p=0.012; and 19.5 in group B, p=0.017); group A showed also a significant decrease in the craving scale (median: 0 in group A, p=0.038; and 45 in group B, n.s.). Furthermore, abstinence (p=0.002) and craving (p=0.004) was lower in group A than in group B. At 24, 48, 72 and 96 hours after the first administration of the drugs, the Wang Scale was significantly lower in group A than in group B (median of the area under curve: 721.7 in group A and 1268.0 in group B, p=0.005). Craving scale resulted significantly lower in group A than in group B only at 96 hour (median: 0 in group A and 10 group B, p=0.025). At the end of the opiate detoxification all 16 patients underwent naloxone test, after which they begun a therapy with naltrexone. As far as abstinence is concerned, the treatment with GHB and clonidine gives a better control of withdrawal syndrome than the treatment with clonidine alone. Moreover, in the group treated with the association of GHB and clonidine, the opiate craving is rapidly and stably reduced. It could be supposed that this craving reduction helps in mantaining the opiate-free state after detoxification.

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Antaxone influence on dopamine system functions in morphine dependent rats

I. Anokhina, A. Veretinskaya, G. Vasilieva, N. Vekshina, I. Shamakina. Research Institute on Addictions, Moscow, Russian

Federation

[1] L. Gallimberti, F. Schifano, G. Forza, L. Miconi, S.D. Ferrara, Clinical efficacy of gamma-hydroxybutyric acid in treatment of opiate withdrawal, Eur Arch Psychiatry Clin Neurosci 1994;244(3): p113-4 [2] L. Gallimberti, M. Cibin, P. Pagnin, R. Sabbion, P.P. Pani, R. Pirastu, S.D. Ferrara, G.L. Gessa, Gamma-hydroxybutyric acid for treatment of opiate withdrawal syndrome, Neuropsychopharmacology 1993 Aug;9(1): p77-81 [3] G.L. Gessa, L. Gallimberti, Gamma-hydroxybutyric acid in the treatment of alcohol dependence, Clin Neuropharmacol 1992;15 Suppl 1 Pt A:303A-304A

Opiate receptor antagonists (OR.A), including Antaxone, are widely used in the treatment of opiate addiction. There is an opinion that the therapeutic effect of ORA is only attributed to "chemical blockade". To answer the question whether ORA have an effect on biological mechanisms of opiate dependence we studied two groups of Wistar rats. One group was given morphine for 12 days. Three days after morphine withdrawal this group received Antaxone for 12 days. Group 2 was only given morphine. The HPLC method was used to determine free and conjugated DA in the blood serum and midbrain. The results showed an increased blood free DA level in group 2 and normal in group 1. The conjugated DA level in the blood of animals in group 2 tended to decrease while that in group 1 was normalized and DOPAC content increased, thus indicating an activation of DA metabolism. In the midbrain, the morphine-increased DA level was much more increased by Antaxone. DA receptor sensitivity in the midbrain increased during morphine withdrawal (group 2) and Antaxone normalized these changes (group 1). So, Antaxone was shown to influence DA system functions in the brain and blood of the morphine-dependent rats. This influence might be attributed to both the blockade of opiate receptors and the direct effect of Antaxone on DA system, including DA receptors.

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References

Dopamine dysfunction in smokers is related to degree of nicotine dependence

L.G. Schmidt 1, M. Smolka 2. 1University of Mainz, Department

of Psychiatry, Mainz, Germany," 2Central Institute of Mental Health, Mannheim, Germany Nicotine is known to be essential for maintaining tobacco smoking behavior by interacting with the brain's dopamine system. However, the mechanisms how nicotine exerts its reinforcing effects in humans are not yet clear. Therefore, this investigation was performed to study the impact of tobacco smoking on behavioral and neuroendocrine variables in nicotine addicts under normal and withdrawal conditions. Eighteen healthy nonsmokers and 37 dependent smokers were included in the study. Smokers were studied during ad libitum smoking and after an overnight abstinence. All subjects were characterized regarding the criteria of the dependence syndrome according to ICD-10, the Fagerstrom-test of nicotine dependence (FTND) and cotinine levels. Neuroendocrine assessments were performed in all subjects using apomorphine injections and measuring blood growth hormone concentration as an indicator of central dopamine function. As the result of the study it was shown that cotinine levels correlated significantly with FTND measures. Growth hormone secretion to stimulation with the dopamine D2 receptor agonist apomorphine was inversively related to FTND-scores during conditions of ad libitum smoking but not of withdrawal. The observation that higher degrees of nicotine dependence occured in patients with a more decreased dopaminergic responsivity underscores the critical role of dopamine in tobacco addiction.

Different effects of GABAergic receptors located in the ventral tegmental area (VTA) on the expression of morphine-induced conditioned place preference in rat

H. Sahraei, Y. Amiri, A. Rohani, H. Sepehri. Department of Physiology, Baghyatallah (a.s.) University of Medical Sciences, P.O.Box 19395-6558, Tehran, Iran In the present study, the effects of excitation and inhibition of GABAA and GABAB receptor subtypes on the expression of morphine-induced conditioned place preference (CPP) was investigated in the rats. Male Wistar rats (W: 250-300 g) were used in the experiments. Five days after surgical cannulation in the Ventral Tegmental Area (VTA), different doses of morphine were injected to the animals and conditioned biased method was performed. Results showed that subcutaneous (s.c.) injections of morphine sulfate (1-10 mg/kg) induced CPP in a dose-dependent manner. Intra-VTA administration of GABAA receptor agonist, muscimol (6 ng/rat) reduced the expression of morphine-induced CPP. The drug in doses 12 and 25 ng/rat increases the expression of CPP induced by morphine. Reduction of the expression of morphine-induced CPP was observed for intra-VTA injection of GABAA receptor antagonist, bicuculline (6, 12 and 25 ng/rat). Injection of baclofen as GABAB receptor agonist into the VTA (6 ng/rat) causes an increase in the expression of CPP induced by morphine. Whereas the drug in doses 12 and 25 ng/rat, reduced the expression of morphine-induced CPP. Injection of CGP38345 (a GABAB receptor antagonist) to the animals in doses 6, 12 and 25 ng/rat significantly reduced the expression of CPP induced by morphine. It could be concluded that excitation and inhibition of

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GABAA and GABAB receptor subtypes in the VTA may have different effects on the expression of CPP induced by morphine.

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Cdependence Ogene polymorphism M T

in alcohol

C.T. Lee, H.K. Lee. Uijeongbu St.Mary's Hospital Department

of Psychiatry, Uijeongbu, Republic of Korea Object: Catechol-O-Methyltransferase(COMT) is an enzyme which play a crucial role in the metabolism of dopamine. It has been suggested that COMT provide molecular role in development of alcohol dependence because of its genetic polymorphism associated with 3-4 fold variation in enzymatic activity. We carried out an association study to verify the relationship between COMT gene polymorphism and alcohol dependence with violent behavior in Korean population. Method: 109 patients who were diagnosed as alcohol dependence by DSM-IV and 133 normal controls who did not have history of psychiatric illness were selected. After extracting DNA from whole blood, we amplified COMT genes by polymerase chain reaction and assessed genotype(COMT Val/Val, COMT Val/Met, COMT Met/Met) and allele(COMT Val, COMT Met) by Restriction Fragment Length Polymorphism(RFLP). Results: (1) Frequency of heterozygous and homozygous for low activity COMT gene(COMT Val/Met, COMT Met/Met) is significantly high in patients with history of violent behavior(violent group) compared to patients without history of violent behavior(nonviolent group) (Kruskal-Wallis Statistic=8.6, df=102.5, p<0.05). (2) Frequency of low COMT allele(COMT Met) is significantly high in violent group compared to nonviolent group(Chi-Square test, X2=8.38, df=l, p<0.05). (3) Significant differences in frequencies of COMT genotype and allele between patients and controls were not found. Conclusion: In this study, we did not found the relationship between COMT gene polymophism and development of alcohol dependence, however our result suggested that low activity COMT allele and geno type be associated with clinical subtype of alcohol dependence with violent behavior. Further systemic studies with large sample and valid clinical variables can reveal the role of COMT gene in the development alcohol dependence.

~ T h e effect of papaverine on the acute opiate withdrawal in guinea pig ileum

The opium alkaloid, papaverine, and its derivatives, the 6-7dimethoxy-4-benzyl isoquinoline, have a relaxant effect on vascular and visceral smooth muscle. The mechanism by which papaverine derivatives induce smooth muscle relaxation is controversial. According to several authors, papaverine derivatives induce relaxation by inhibiting cyclic AMP phoshodiesterase (cAMP PDE) whereas according to others the relaxant effect results from an inhibition of Ca +2 movement. In a recent paper, we have demonstrated that isoquinoline alkaloids from Argemone mexicana were able to reduce electrically and acetyleholine induced contractions of isolated guineapig ileum. Furthermore, the same alkaloids were able to reduce morphine withdrawal in vitro. Considering that isoquinoline derivatives induce significative effects on guinea pig ileum by interacting with cholinergic, histaminergic as well as calcium system in the present paper we investigated the effect of papaverine on the naloxone-precipitated withdrawal contracture of the acute morphine-dependent guineapig ileum in vitro. Furthermore, the effect of papaverine was also considered on DAGO (highly selective ~t-agonist) and U50-488H (highly selective k-agonist) withdrawal to test whether the possible interaction of papaverine on opioid withdrawal involves ~t- and/or k-opioid receptors. In the present work the effect of papaverine, a non specific smooth muscle relaxant, was investigated on the naloxoneprecipitated withdrawal contracture of the acute morphinedependent guinea-pig ileum in vitro. Furthermore, the effect of papaverine was also considered on DAGO (highly selective ~t-agonist) and U50-488H (highly selective k-agonist) withdrawal to test whether the possible interaction of papaverine on opioid withdrawal involves ~t- and/or k-opioid receptors. Following a 4 min in vitro exposure to opioid agonist, the guinea-pig isolated ileum exhibited a strong contracture after the addition of naloxone. Papaverine treatment ( 1 × 10-7-5 × 10-71 × 10-6 M) before or after the opioid agonists was able of both preventing and reversing the naloxone-indueed contraeture after exposure to ~t (morphine and DAGO) or k (U50-488H) opiate agonists in a concentration-dependent fascion. Both acetylcholine response and electrical stimulation were not affected by papaverine treatment whereas the final opiate withdrawal was still reduced. The results of the present study indicate that papaverine was able to produce significative influence on the opiate withdrawal in vitro and papaverine was able to exert its effect both at ~t and k opioid agonists.

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Neurobehavioural evaluation of gammahydroxybutyric acid (GHB), a new drug with abuse potential, in male rats

A. Capasso 1, C. Casciano 1, A. Loizzo2. 1Department of Pharmaceutical Sciences, University of Salerno, via Ponte Don Melillo, 84084 Fisciano, Salerno, Italy; 2Istituto Superiore di Sanit~, Italy

E Garcia, C. Pedraza, G. Luna, J.E Navarro. University of Mdtlaga. Department of Psychobiology, Faculty of Psychology, Mdtlaga, Spain

Dependence can be induced and measured in vitro by using guinea-pig ileum. After a brief exposure to opioids, tissues from untreated animals, show a strong naloxone-induced contracture indicating that the cellular mechanisms of dependence may occur very rapidly following occupation of receptors and that these mechanisms operate within the myenteric plexus. The characteristics of dependence development and the precipitation of withdrawal by naloxone in the guinea-pig ileum are very similar to those of acute dependence in experimental animals and man.

Gammahydroxybutyrate (GHB) is a new drug with abuse potential popularly known as "liquid ecstasy" (1). It is an endogenous compound of the mammalian brain, which can traverse the bloodbrain barrier, synthesized from GABA. The existence of brain receptor sites as well as brain mechanisms for synthesis, release, and uptake provides support to the hypothesis that GHB may act as a neuromodulator on specific neuronal populations (2). The aim of this study was to examine the effects of subchronic administration of GHB on a battery of sensory-motor tests in