Samina Bano, Iffat Ara, Warda Naseem


Background: Behavioral associated disturbance involves excitotoxic quinolinate in alcohol withdrawal syndrome in man due to increase availability of tryptophan. In present study we investigated alcoholism related clinical features in relation to tryptophan and 5-HT levels in rat’s model. Methods: Locally bred male Wistar rats, weighing 200–250 g were housed separately into 6 animals/ group with 12 h light: dark cycle at room temp 22±3 °C. They were given diet ad libitum, for three days then alcohol 8% (v/v) was added into the liquid diet. Matched control rats of each group were given maltose-dextrin as a substitute of alcohol. Alcohol withdrawal syndrome was assessed after 7 hours by replacing the alcohol-containing liquid diet with tap water. Results: Alcohol withdrawal group showed significant increase (p<0.001) in holo, apo, and total tryptophan 2, 3 dioxygenase enzyme activities, no significant change in brain tryptophan and 5HIAA however significant decrease (p<0.001) in brain 5HT was observed when compared with chow controls. Both alcohols administered and withdrawal groups showed significant rise in serum corticosterone by p<0.05 and p<0.001 respectively. Liver quinolinic acid concentrations were increased significantly (p<0.01) with robust increase in alcohol withdrawn rats. Conclusion: We conclude that the excitotoxin tryptophan metabolite quinolinic acid of peripheral origin plays significant role in the behavioral manifestation of the alcohol withdrawal syndrome. Tryptophan metabolites should be targeted to develop new strategies in the progress of pharmacological interventions related to alcoholism.

Keywords: Ethanol; Quinolinic acid; Tryptophan metabolism; Alcohol withdrawal; tryptophan 2,3 dioxygenase; 5–hydroxytryptamine; rats

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Gilpin NW, Smith AD, Cole M, Weiss F, Koob GF, Richardson HN. Operant behavior and alcohol levels in blood and brain of alcohol-dependent rats. Alcohol Clin Exp Res 2009;33(12):2113–23.

Donovan JE. Estimated blood alcohol concentrations for child and adolescent drinking and their implications for screening instruments. Pediatrics 2009;123(6):e975–81.

Vasconcelos SM, Cavalcante RA, Aguiar LM, Sousa FC, Fonteles MM, Viana GS. Effects of chronic ethanol treatment on monoamine levels in rat hippocampus and striatum. Braz J Med Biol Res 2004;37(12):1839–46.

Heinz A, Mann K, Weinberger DR, Goldman D. Serotonergic dysfunction, negative mood states, and response to alcohol. Alcohol Clin Exp Res 2001;25(4):487–95.

Krystal JH, Staley J, Mason G, Petrakis IL, Kaufman J, Harris RA, et al. Gamma-aminobutyric acid types A receptors and alcoholism: Intoxication, dependence, vulnerability, and treatment. Arch Gen Psychiatry 2006;63(9):957–68.

Kumar S, Fleming RL, Morrow AL. Ethanol regulation of gamma-aminobutyric acid receptors: Genomic and non-genomic mechanisms. Pharmacol Ther 2004;101(3):211–26.

Chastain G. Alcohol, neurotransmitter systems, and behavior. J Gen Psychol 2006;133(4):329–35.

Patkar AA, Gopalakrishnan R, Naik PC, Murray HW, Vergare MJ, Marsden CA. Changes in plasma noradrenaline and serotonin levels and craving during alcohol withdrawal. Alcohol Alcohol 2003;38(3):224–31.

Virkkunen M, Goldman D, Nielsen DA, Linnoila M. Low brain serotonin turnover rate (low CSF 5-HIAA) and impulsive violence. J Psychiatry Neurosci 1995;20(4):271–5.

Ruddick JP, Evans AK, Nutt DJ, Lightman SL, Rook GA, Lowry CA. Tryptophan metabolism in the central nervous system: medical implications. Expert Rev Mol Med 2006;8(20):1–27.

Bisaga A, Popik P, Bespalov AY, Danysz W. Therapeutic potential of NMDA receptor antagonists in the treatment of alcohol and substance use disorders. Expert Opin Investig Drugs 2000;9(10):2233–48.

Stone TW. Neuropharmacology of quinolinic and kynurenic acids. Pharmacol Rev 1993;45(3):309–79.

Schwarcz R, Pellicciari R. Manipulation of brain kynurenines: glial targets, neuronal effects, and clinical opportunities. J Pharmacol Exp Ther 2002;303(1):1–10.

Bano S, Oretti RG, Morgan CJ, Badawy AA, Buckland PR, McGuffin P. Effects of chronic administration and subsequent withdrawal of ethanol-containing liquid diet on rat liver tryptophan pyrrolase and tryptophan metabolism. Alcohol Alcohol 1996;31(2):205–15.

Oretti R, Bano S, Morgan CJ, Badawy AA, Bonner A, Buckland P, et al. Prevention by cycloheximide of the audiogenic seizures and tryptophan metabolic disturbances of ethanol withdrawal in rats. Alcohol Alcohol 1996;31(3):243–7.

Badawy AA, Aliyu SU. Antagonism of acute alcohol intoxication by naloxone. Alcohol Alcohol 1984;19(3):199–201.

Bano S, Sherkheli MA. Inhibition of tryptophan pyrrolase activity and elevation of brain tryptophan concentration by fluoxetine in rats. J Coll Physicians Surg Pak 2003;13(1):5–10.

Glick D, Voredlich D, and Levine S. Flourimetric determination of corticosterone and cortisol in 0.02 and 0.05 mls of plasma or submiligrams of adrenal tissue. Endocrinology 1964;74:653–5.

Anderson GM, Young JG, Batter DK, Young SN, Cohen DJ, Shaywitz BA. Determination of indoles and catechols in rat brain and pineal using liquid chromatography with fluorometric and amperometric detection. J Chromatogr 1981;223(2):315–2.

Badawy AA, Morgan CJ. Rapid isocratic liquid chromatographic separation and quantification of tryptophan and six kynurenine metabolites in biological samples with ultraviolet and fluorimetric detection. Int J Tryptophan Res 2010;3:175–86.

Welch AN, Badawy AA. Tryptophan pyrrolase in haem regulation. Experiments with administered haematin and the relationship between the haem saturation of tryptophan pyrrolase and the activity of 5-aminolaevulinate synthase in rat liver. Biochem J 1980;192(2):403–10.

Bano S, Gitay M, Ara I, Badawy A. Acute effects of serotonergic antidepressants on tryptophan metabolism and corticosterone levels in rats. Pak J Pharm Sci 2010;23(3):266–72.

Cowen PJ. Cortisol, serotonin and depression: all stressed out? Br J Psychiatry 2002;180:99–100.

Badawy AA. Kynurenine pathway of tryptophan metabolism: regulatory and functional aspects. Int J Tryptophan Res 2017;10:1178646917691938.

Badawy AA. Tryptophan metabolism in alcoholism. Nutr Res Rev 2002;15(1):123–52.

Oretti RG, Bano S, Azani MO, Badawy AA, Morgan CJ, McGuffin P, et al. Rat liver tryptophan pyrrolase activity and gene expression during alcohol withdrawal. Alcohol Alcohol 2000;35(5):427–34.

Lovinger DM. Excitotoxicity and alcohol-related brain damage. Alcohol Clin Exp Res 1993;17(1):19–27.

Morgan PF. Is quinolinic acid an endogenous excitotoxin in alcohol withdrawal? Med Hypotheses 1991;36(2):118–21.

Heyes MP, Morrison PF. Quantification of local de novo synthesis versus blood contributions to quinolinic acid concentrations in brain and systemic tissues. J Neurochem 1997;68(1):280–8.


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