Enhanced 5-HT2A Receptor Status in the Hypothalamus and Corpus Striatum of Ethanol-Treated Rats

  • K. G. Akash
  • K. S. Balarama
  • C. S. Paulose
Original Paper


Aim Brain is the major target for the actions of ethanol and it can affect the brain in a variety of ways. In the present study we have investigated the changes in 5-HT level and the 5-HT2A receptors in the ethanol-treated rats. Methods Wistar adult male rats of 180–200 g body weight were given free access to 15% (v/v) (approx.7.5 g/Kg body wt./day) ethanol for 15 days. Controls were given free access to water for 15 days. Brain 5-HT and its metabolites were assayed by high performance liquid chromatography (HPLC) integrated with an electrochemical detector (ECD) fitted with C-18-CLS-ODS reverse phase column. 5-HT2A receptor binding assay was done with different concentrations of [3H] MDL 100907. Results The hypothalamic 5-HT content significantly increased (< 0.001) with a decreased (< 0.001) 5-HIAA/5-HT turnover in the ethanol-treated rats when compared to control. The corpus striatum 5-HT content significantly decreased (< 0.01) with increased (< 0.01) 5-HIAA/5- HT turnovers in the ethanol-treated rats when compared to control. Scatchard analysis of [3H] MDL 100907 against ketanserin in hypothalamus showed a significant increase (< 0.001) in Bmax with a decreased affinity (< 0.001) in ethanol-treated rats when compared to control. The competition curve for [3H] MDL 100907 against ketanserin fitted one-site model in all the groups with unity as Hill slope value. An increased Ki and log (EC50) value were also observed in ethanol-treated rats when compared to control. Scatchard analysis of [3H] MDL 100907 against ketanserin in the corpus striatum of ethanol-treated rats showed a significant increase (< 0.001) in Bmax and in affinity (< 0.01) when compared to control. The change in affinity of the receptor protein in both corpus striatum and hypothalamus shows an altered receptor. The competition curve for [3H] MDL 100907 against ketanserin fitted one-site model in all the groups with unity as Hill slope value. There was no significant change in Ki and log (EC 50) value in ethanol-treated rats when compared to control. Conclusion The present study demonstrated the enhanced 5-HT2A receptor status in hypothalamus and corpus striatum. The ethanol-induced enhanced 5-HT2A receptors in the hypothalamus and corpus striatum has clinical significance in the better management of ethanol addiction. This will have therapeutic application.


5-HT2A receptor Hypothalamus Corpus striatum Ethanol treatment 



This work was supported by research grant from ICMR, DBT, DAE, DST, Government of India to Dr. C. S. Paulose.


  1. Ani DV, Savitha B, Paulose CS (2006) Decreased alpha1-adrenergic receptor binding in the cerebral cortex and brain stem during pancreatic regeneration in rats. J Neurosci Res 31:727–734Google Scholar
  2. Badawy AA, Morgan CJ, Lovett JW, Bradley DM, Thomas R (1995) Decrease in circulating tryptophan availability to the brain after acute ethanol consumption by normal volunteers: implications for alcohol-induced aggressive behaviour and depression. Pharmacopsychiatry 28:93–97PubMedCrossRefGoogle Scholar
  3. Bavanisha V, Charmaine HJ, Stefan M, Willie, P, Dan JS (2005) Pharmacological challenge with a serotonin 1D agonist in alcohol dependence. BMC Psychiatry 5:31–34CrossRefGoogle Scholar
  4. Benkelfat C, Murphy DL, Hill JL, George DT, Nutt D, Linnoila M (1991) Ethanol- like properties of the serotonergic partial agonist mchlorophenylpiperazine in chronic alcoholic patients. Arch Gen Psychiatry 48:333–336Google Scholar
  5. Berke JD, Hyman SE (2000) Addiction, dopamine, and the molecular mechanisms of memory. Neuron 25:515–532PubMedCrossRefGoogle Scholar
  6. Biju MP, Pyroja S, Rajeshkumar NV, Paulose CS (2001) Hypothalamic GABA receptor functional regulation and liver cell proliferation. Mol Cell Biochem 216:65–70PubMedCrossRefGoogle Scholar
  7. Biju MP, Pyroja S, Rajeshkumar NV, Paulose CS (2002) Brainstem GABA receptor functional regulation during rat liver cell proliferation. Neurochem Res 27:905–910PubMedCrossRefGoogle Scholar
  8. Brodie MS, Trifunovic RD, Shefner SA (1995) Serotonin potentiates ethanol -induced excitation of ventral tegmental area neurons in brain slices from three different rat strains. J Pharmacol Exp Ther 273:1139–1146PubMedGoogle Scholar
  9. Chiamulera C, Valerio E, Tessari M (1995) Resumption of ethanol- seeking behavior in rats. Behav Pharmacol 6:32–39PubMedGoogle Scholar
  10. Dar MS, Wooles WR (1984) Striatal and hypothalamic neurotransmitter changes during ethanol withdrawal in mice. Alcohol 1:453–458PubMedCrossRefGoogle Scholar
  11. David L. (1999) The role of serotonin in alcohol’s effects on the brain. Curr Sep 18:1–3Google Scholar
  12. Deitrich RA, Dunwiddie TV, Harrisui RA, Erwin VG (1989) Mechanism of action of ethanol; initial central nervous system actions. Pharmacol Rev 41:489–537PubMedGoogle Scholar
  13. Delin CR, Lee TH (1992) Drinking and the brain: current evidence. Alcohol Alcohol 27:117–126PubMedGoogle Scholar
  14. Eckardt MJ, File SE, Gessa GL, Grant KA, Guerri C, Hoffman PL, Kalant H, Koob GF, Li TK, Tabakoff B (1998) Effects of moderate alcohol consumption on the central nervous system. Alcohol Clin Exp Res 22:998–1040PubMedCrossRefGoogle Scholar
  15. Evert DL, Oscar-Berman M (1995) Alcohol-related cognitive impairments: an overview of how alcoholism may affect the workings of the brain. Alcohol Health Res World 19:89–96Google Scholar
  16. George AK, Balarama KB, Paulose CS (2007) Decreased dopamine D2 receptor function in cerebral cortex and brainstem: their role in hepatic ALDH regulation in ethanol treated rats. Mol Cell Biochem 304:181–188PubMedCrossRefGoogle Scholar
  17. Glowinski J, Iversen LL (1966) Regional studies of catecholamines in the rat brain: the disposition of [3H] Norepinephrine, [3H] DOPA in various regions of the brain. J Neurochem 13:655–699PubMedCrossRefGoogle Scholar
  18. Grant KA (1995) The role of 5-HT-3 receptors in drug dependence. Drug Alcohol Depend 38:155–171PubMedCrossRefGoogle Scholar
  19. Green AR, DeSouza RJ, Davis EM, Cross AJ (1990) The effects of Ca2+ antagonists and hydralazine on central 5-Hydroxytryptamine biochemistry biochemistry and function in rats and mice. Braz J Pharmacol 99:41–46Google Scholar
  20. Haiser LK, Tescott LH (2000) A paradoxical locomotor response in serotonin 5- HT2C receptor mutant mice. J Neurosci 20:1–5Google Scholar
  21. Hayrapetyan V, Jenschke M, Dillon GH, Machu TK (2005) Co-expression of the 5-HT (3B) subunit with the 5-HT (3A) receptor reduces alcohol sensitivity. Mol Brain Res 142:146–150PubMedGoogle Scholar
  22. Higley JD, Suomi SJ, Linnoila M (1996) A nonhuman primate model of type II excessive alcohol drinking consumption Part I. Low cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations and diminished social competence correlate with excessive alcohol consumption. Alcohol Clin Exp Res 20:629–642PubMedCrossRefGoogle Scholar
  23. Himei A, Kono Y, Yoneda H, Sakai T, Koh J, Sakai J, Inada Y, Imamichi H (2000) An association study between alcoholism and the serotonergic receptor genes. Alcoholism Clin Exp Res 24:341–342CrossRefGoogle Scholar
  24. Hoyer D, Clarke KE, Fozard JR, Hartig PR, Martin GR, Mylecharane EJ, Saxena PR, Humphrey PP (1994) A international union for pharmacology classification of receptors for 5-hydroxytryptamine. Pharmacol Rev 46:157–203PubMedGoogle Scholar
  25. Jankowska E, Bidzinski A Kostowski W (1994) Alcohol drinking in rats treated with 5, 7-dihydroxytryptamine:effect of 8-OH-DPAT and tropisetron (ICS 205–930). Alcohol 11:283–288PubMedCrossRefGoogle Scholar
  26. Jolas T, Aghajanian GK (1997) Neurotensin and the serotonergic system. Prog Neurobiol 52:455–68PubMedCrossRefGoogle Scholar
  27. Katner SN, Weiss F (1999) Ethanol- associated olfactory stimuli reinstate ethanol-seeking behaviour after extinction and modify extra-cellular dopamine levels in the nucleus accumbens. Alcohol Clin Exp Res 23:1751–1760PubMedGoogle Scholar
  28. Konishi T, Calvillo M, Leng AS, Lin KM, Wan YJ (2004) Polymorphisms of the dopamine D2 receptor, serotonin transporter, and GABA (A) receptor beta (3) subunit genes and alcoholism in Mexican-Americans. Alcohol 32:45–52PubMedCrossRefGoogle Scholar
  29. Kuhn DM, Wolf WA, Lovenberg W (1980) Review of the role of the central serotonergic neuronal system in blood pressure regulation. Hypertension 2:253–255Google Scholar
  30. Le AD, Quan B, Juzytsch W, Joharchi Y (1998) Reinstatment of alcohol- seekting by priming ijection of alcohol and exposure to stress in rats. Psychopharmacology 135:168–174Google Scholar
  31. Le AD, Hading S, Watchus J, Juztsch W, Shaham Y (1999) Effects of naltrexone and fluoxetine on alcohol self-administration and reinstatement of alcohol seeking induced by priming injections with alcohol and exposure to stress in rats. Neuropsychopharmacology 21:435–444PubMedCrossRefGoogle Scholar
  32. LeMarquandt D, Pihl RO, Benkelfat C (1994) Serotonin and alcohol intake, abuse, and dependence: findings in animal studies. Biol Psychiatry 36:395–421CrossRefGoogle Scholar
  33. Litten RZ, Allen J, Fertig J (1996) Pharmacotherapies for alcohol problems: a review of researchwith focus on developments since 1991. Alcohol Clin Exp Res 20:859–876PubMedCrossRefGoogle Scholar
  34. Lovinger DM, Peoples RW (1993) Actions of alcohols and other sedative/hypnotic compounds on cation channels associated with glutamate and 5-HT3 receptors. In: Alling C, Diamond I, Leslie SW, Sun GY, Wood WG (eds) Alcohol, cell membranes and signal transduction in brain. Plenum Press, New York, pp. 157–168Google Scholar
  35. Lovinger DM, Zhou Q (1994) The role of serotonin in alcohol’s effects on the brain. Neuropharmacol 33:1567–1572CrossRefGoogle Scholar
  36. Lowry OH, Rosenbrough NH, Farr AL, Randall RJ (1951) Protein measurement with folin phenol reagent. J Biol Chem 193:265–275PubMedGoogle Scholar
  37. McKenzie-Quirk SD, Girasa KA, Allan AM, Miczek KA (2005). 5-HT(3) receptors, alcohol and aggressive behaviour in mice. Behav Pharmacol 16:163–169PubMedCrossRefGoogle Scholar
  38. Meert TF (1993) Effects of various serotonergic agents on alcohol intake and alcohol preference in Wistar rats selected at two different levels of alcohol preference. Alcoholism 28:157–170Google Scholar
  39. Melchior CL, Tabakoff B (1986) The effect of 5, 7-dihydroxytryptamine treatment on response to ethanol in mice pharmacol. Biochem Behav 24:955–961CrossRefGoogle Scholar
  40. Pandey SC, Piano MR, Schwertz DW, Davis JM, Pandey GN (1992) Effect of ethanol administration and withdrawal on serotonin receptor subtypes and receptor-mediated phosphoinositide hydrolysis in rat brain. Alcohol Clin Exp Res 16:1110–1116PubMedCrossRefGoogle Scholar
  41. Pandey SC, Davis JM, Pandey GN (1995) Phosphoinositide system-linked serotonin receptor subtypes and their pharmacological properties and clinical correlates. J Psychiatry Neurosci 20:215–225PubMedGoogle Scholar
  42. Panocka I, Ciccocioppo R, Polidori C, Pompei P, Massi M (1995) The 5-HT4 receptor antagonist, GR113808, reduces ethanol intake in alcohol-preferring rats. Pharmacol Biochem Behav 52:255–259PubMedCrossRefGoogle Scholar
  43. Paulose CS, Dakshinamurti K (1984) Enhancement of high affinity gamma aminobutryric acid receptor binding in cerebellum of pyridoxine-deficient rat. Neurosci Lett 48:311–316PubMedCrossRefGoogle Scholar
  44. Paulose CS, Dakshinamurti K (1985) Effect of pyridoxine deficiency in young rats on high affinity serotonin and dopamine receptors. J Neurosci Res 14:263–270PubMedCrossRefGoogle Scholar
  45. Paulose CS, Dakshinamurthi K, Packer L, Stephens NL (1988) Symapathetic stimulation and hypertension in pyridoxine deficient adult rat. Hypertension 11:387–391PubMedGoogle Scholar
  46. Pediconi M, Colombo C, Galli C (1985) Effects of acute and chronic ethanol administration on thromboxane and prostacyclin levels and release in rat brain cortex. Prostaglandins 30:313–322PubMedCrossRefGoogle Scholar
  47. Pettinati HM (1996) Use of serotonin selective pharmacotherapy in the treatment of alcohol dependence. Alcohol Clin Exp Res 20:23–29CrossRefGoogle Scholar
  48. Pyroja S, Joseph B, Paulose CS (2007) Increased 5-HT2C receptor binding in the brain stem and cerebral cortex during liver regeneration and hepatic neoplasia in rats. Neurol Sci 254:3–8CrossRefGoogle Scholar
  49. Rodd-Henricks ZA, McKinzie DL, Edmundson DE, Dagon CL, Murphy JM, McBride WJ, Lumeng L, Li TK (2000) Effects of 5-HT3 receptor antagonists on daily ethanol intake under acquisition, maintenance, and relapse condition in alcohol-preferring P rats. Alcohol 21:73–85PubMedCrossRefGoogle Scholar
  50. Scatchard G (1949) The attraction of proteins for small molecules and ions. Ann N Y Acad Sci 51:660–672CrossRefGoogle Scholar
  51. Shankar PN, Joseph A, Paulose CS (2007) Decreased [3H]YM-09151–2 binding to dopamine D2 receptors in the hypothalamus, brain stem and pancreatic islets of streptozotocin-induced diabetic rats. Eur J Pharmacol 28:99–105CrossRefGoogle Scholar
  52. Sudha B, Paulose CS (1998) Induction of DNA synthesis in primary cultures of rat hepatocytes by serotonin: possible involvement of Serotonin S2 receptors. Hepatology 27:62–66CrossRefGoogle Scholar
  53. Sun HF, Chang YT, Fann CS, Chang CJ, Chen YH, Hsu YP, Yu WY, Cheng AT (2002) Association study of novel human serotonin 5-HT (1B) polymorphisms with alcohol dependence in Taiwanese Han. Biol Psychiatry 51:896–901PubMedCrossRefGoogle Scholar
  54. Tank AW (1981) Enzymology and subcellular localization of aldehyde oxidation in rat liver oxidation of 3:4-dihydroxyphenylacetaldehyde derived from dopamine to 3, 4- dihydroxyphenylacetic acid. Biochem Pharmacol 32:3265–3275CrossRefGoogle Scholar
  55. Uzbay IT, Usanmaz SE, Tapanyigit EE, Aynacioglu S, Akarsu ES (1998) Dopaminergic and serotonergic alterations in the rat brain during ethanol withdrawal: association with behavioural signs. Drug Alcohol Depend 53:39–47PubMedCrossRefGoogle Scholar
  56. Uzbay IT, Usanmaz SE, Akarsu ES (2000) Effects of chronic ethanol administration on serotonin metabolism in the various regions of the rat brain. Neurochem Res 25:257–262PubMedCrossRefGoogle Scholar
  57. Weiss F, Porrino LJ (2002) Behavioral neurobiology of alcohol addiction: recent advances and challenges. J Neurosci 22:3332–3337PubMedGoogle Scholar
  58. Wilde MI, Markham A, Ondansetron (1996) A review of its pharmacology and preliminary clinical findings in novel applications. Drugs 52:773–794PubMedCrossRefGoogle Scholar
  59. Wing MK (1998) Daidzin and its antidipsotropic analogs inhibit serotonin and dopamine metabolism in isolated mitochondria. Proc Nat Acad Sci 95:2198–2203CrossRefGoogle Scholar
  60. Yoshihara EK, Nakamura M, Itoh K, Ameno YT, Ijiri I, Iwahashi K (2000) The human serotonin receptor gene (HTR2) MspI polymorphism in Japanese schizophrenic and alcoholic patients. Neuropsychobiology 41:124–126PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  1. 1.Molecular neurobiology and Cell Biology Unit, Centre for Neuroscience, Department of BiotechnologyCochin University of Science and TechnologyCochinIndia

Personalised recommendations