The effect of the ghrelin receptors inhibitor [D-Lys3]-GHRP-6 on the levels and metabolism of monoamines in symmetric brain areas of rats treated chronically with alcohol

Cover Page

Abstract


Aim. In the course of the study, the impact of the ghrelin receptor GHS-R1a on the condition of symmetric monoaminergic systems of the rat brain was investigated. In particular, it was intended to find out whether the treatment with the ghrelin receptor antagonist [D-Lys3]-GHRP-6, recover the original content of monoamines and their metabolites in the brain of chronic alcoholic rats.

Methods. The experiments were performed on 22 Wistar male rats. Experimental animals instead of drinking water received 10 % ethanol solution. Rats of the control groups continued to consume tap water. 6 months after the beginning of forced chronic alcohol treatement, 6 rats treated with alcohol, and 6 rats received water, in a month, once in three days, were instilled intranasally with the ghrelin antagonist [D-Lys3]-GHRP-6 (1 мкг/мкл, with 10 µl to each nostril). The other animals in the same manner were administered an equivalent volume of saline. 80 minutes after the last intranasal administration of drugs, rats were decapitated. With the HPLC-method, in the hypothalamus, olfactory tubercle, striatum and hippocampus of the left and right sides of the brain the contents of noradrenaline (NA), dopamine (DA), dioxyphenylacetic acid (DOPAC), homovanillic acid (HVA), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were measured. The results were processed by Student’s t-test using the statistical software package GraphPad Prism 6.0.

Results. In the control rats (not exposed to either ethanol or drug) in the left striatum revealed a significant predominance of 5-HIAA compared to the same parameter of the other side of the brain. Under the condition of chronic ethanol intake, the initial left-sided asymmetry disappeared. Ethanol increased the content of 5-HT in the left hippocampus, 5-HIAA in the right olfactory tubercle and DA – in the right hypothalamus. [D-Lys3]-GHRP-6, when administered intranasally to the intact rats, significantly increased the 5-HIAA/5-HT ratio in the right olfactory tubercle, and the 5-HIAA, DOPAC and HVA levels – in the right striatum. In contrast, the left-sided effects in hippocampus were observed: the 5-HT levels increased and the 5-HIAA/5-HT ratio decreased. When instilled to intact rats, [D-Lys3]-GHRP-6 does not alter the monoaminergic systems of the hypothalamus. Between the monoaminergic systems of intact animals and alcoholic rats treated with [D-Lys3]-GHRP-6, the significant differences were shown. So, in the left hippocampus of alcoholic rats treated with [D-Lys3]-GHRP-6, the 5-HT level was higher, and the 5-HIAA/5-HT ratio was lower than in the control intact animals. Besides, in the right striatum of alcoholic rats treated with [D-Lys3]-GHRP-6, the DA metabolites levels were higher than those in the intact control animals. When comparing two groups of rats treated with [D-Lys3]-GHRP-6 (consumed water and alcoholic), the only difference was found: the alcoholic animals the content of DA in the left hypothalamus was lower than that of rats consumed water.

Conclusion. Thus, by its influence on the monoaminergic system of the brain, [D-Lys3]-GHRP-6 is not an antagonist of the ethanol. Rather ethanol, when administered chronically, reduces the reactivity of the majority of monoaminergic systems to the ghrelin antagonist. Herewith, the forced chronic treatement with ethanol selectively increases the sensitivity to the [D-Lys3]-GHRP-6 in the hypothalamus DA-ergic system


Inessa V. Karpova

Author for correspondence.
inessa.karpova@gmail.com
Institute of Experimental Medicine
Russian Federation, 12, Academic Pavlov street, Saint-Petersburg, 197376

PhD, Docent, Senior Researcher, S.V. Anichkov Dept. of Neuropharmacology

Eugenii R. Bychkov

bychkov@mail.ru
Institute of Experimental Medicine; S.M. Kirov Military Medical Academy; National Guard Military Academy of the Russian Federation; Saint Petersburg State Pediatric Medical University
Russian Federation, 12, Academic Pavlov street, Saint-Petersburg, 197376; 6G, Akademika Lebedeva street, Saint-Petersburg, 194044; 1, L. Pilyutova street, Saint-Petersburg, 198206; 2, Litovskay street, Saint-Peterburg, 194100

PhD (Biochemistry), Leading Researcher, S.V. Anichkov Dept. of Neuropharmacology Institute of Experimental Medicine; Assistant Professor, dept. of Pharmacology Kirov Military Medical Academy; Assistant Professor, dept. of General psychology National Guard Military Academy of the Russian Federation; Assistant Professor, dept. of Pharmacology, Saint Petersburg State Pediatric Medical University.

Ilia Yu. Tissen

iljatis@mail.ru
Institute of Experimental Medicine
Russian Federation, 12, Academic Pavlov street, Saint-Petersburg, 197376

Researcher, S.V. Anichkov Dept. of Neuropharmacology

Andrei A. Lebedev

aalebedev-iem@rambler.ru
Institute of Experimental Medicine; National Guard Military Academy of the Russian Federation
Russian Federation, 12, Academic Pavlov street, Saint-Petersburg, 197376; 1, L. Pilyutova street, Saint-Petersburg, 198206

Dr Biol Sci (Pharmacology), Leading Researcher, S.V. Anichkov Dept. of Neuropharmacology Institute of Experimental Medicine; Professor, dept. of General psychology National Guard Military Academy of the Russian Federation

Petr D. Shabanov

pdshabanov@mail.ru
Institute of Experimental Medicine; S.M. Kirov Military Medical Academy
Russian Federation, 12, Academic Pavlov street, Saint-Petersburg, 197376; 6G, Akademika Lebedeva street, Saint-Petersburg, 194044

Dr Med Sci, Professor, Head S.V. Anichkov Dept. of Neuropharmacology Institute of Experimental Medicine; Head of the dept. of Pharmacology Kirov Military Medical Academy

  • Виноградов П.М., Тиссен И.Ю., Лебедев А.А., и др. Антагонист рецепторов грелина [D-Lys3]-GHRP-6 снижает экспрессию условной реакции предпочтения места этанола у крыс // Обзоры по клинической фармакологии и лекарственной терапии. – 2015. – Т. 13. – № 2. – С. 27–33. [Vinogradov PM, Tissen IYu, Lebedev AA, et al. Antagonist receptorov grelina [D-Lys3]-GHRP-6 snizhaet ehkspressiyu uslovnoj reakcii predpochteniya mesta ehtanola u krys. Review on Clinical Pharmacology and Medicinal Therapy. 2015;13(2):27-33. (In Russ.)]
  • Карпова И.В., Михеев В.В., Марышева В.В., и др. Изменения содержания моноаминов в симметричных структурах мозга агрессивных мышей-изолянтов линии C57Bl/6 под влиянием окситоцина // Бюллетень экспериментальной биологии и медицины. – 2015. – Т. 160. – № 11. – С. 546–550. [Karpova IV, Mikheev VV, Marysheva VV, et al. Oxytocin-induced changes in monoamine level in symmetric brain structures of isolated aggressive C57Bl/6 mice. Bulletin of Experimental Biology and Medicine. 2015;160(5):605-609. (In Russ.)]. doi: 10.1007/s10517-016-3228-2.
  • Chen Ch-Y, Asakawa A, Fujimiya M, et al. Ghrelin gene products and the regulation of food intake and gut motility. Pharmacol Rev. 2009;61:430-481. doi: 10.1124/pr.109.001958.
  • Cory-Slechta DA, Weston D, Liu S, Allen JL. Brain hemispheric differences in the neurochemical effects of lead, prenatal stress, and the combination and their amelioration by behavioral experience. Toxicol Sci. 2013;132(2):419-30. doi: 10.1093/toxsci/kft015.
  • Davis KW, Wellman PJ, Clifford PS. Augmented cocaine conditioned place preference in rats pretreated with systemic ghrelin. Regul Peptides. 2007;140(3):148-152. doi: 10.1016/j.regpep.2006.12.003.
  • Diano S, Farr SA, Benoit SC, et al. Ghrelin controls hippocampal spine synapse density and memory performance. Nature Neuroscience. 2006;9:381-388. doi: 10.1038/nn1656.
  • Dickson SL, Egecioglu E, Landgren S, et al. The role of the central ghrelin system in reward from food and chemical drugs. Molecular and Cellular Endocrinology. 2011;340:80-87. doi: 10.1016/j.mce.2011.02.017.
  • Engel JA, Fahlke C, Hulthe P, et al. Biochemical and behavioral evidence for an interaction between ethanol and calcium-channel antagonists. Alcohol and Alcoholism. 1988;23(3):A13-A113. doi: 10.1007/BF01244784.
  • Ferrini F, Salio C, Lossi L, Merighi A. Ghrelin in Central Neurons. Curr Neuropharmacol. 2009;7(1):37-49. doi: 10.2174/157015909787602779.
  • Jerlhag E, Egecioglu E, Dickson SL, Engel JA. Glutamatergic regulation of ghrelin-induced activation of the mesolimbic dopamine system. Addiction Biology. 2011;16(1):82-91. doi: 10.1111/j.1369-1600.2010.00231.x.
  • Jerlhag E, Egecioglu E, Dickson SL, et al. Alpha-conotoxin MII-sensitive nicotinic acetylcholine receptors are involved in mediating the ghrelin-induced locomotor stimulation and dopamine overflow in nucleus accumbens. European Neuropsychopharmacolology. 2008;18(7):508-518. doi: 10.1016/j.euroneuro.2008.02.006.
  • Jerlhag E, Egecioglu E, Landgren S, et al. Requirement of central ghrelin signaling for alcohol reward. Proceedings of the National Academy of Sciences of the United States of America. 2009;106 (27):11318-11323. doi: 10.1073/pnas.0812809106.
  • Kaur S, Ryabinin AE. Ghrelin receptor antagonism decreases alcohol consumption and activation of perioculomotor urocortin-containing neurons. Alcoholism – Clinical and Experimental Research. 2010;34(9):1525-1534. doi: 10.1111/j.1530-0277.2010.01237.x.
  • Kern A, Mavrikaki M, Ullrich C, et al. Hippocampal Dopamine/DRD1 signaling dependent on the ghrelin receptor. Cell. 2015;163(5):1176-1190. doi: 10.1016/j.cell.2015.10.062.
  • Krasnova IN, Bychkov ER, Lioudyno VI, et al. Intracerebroventricular administration of substance P increases dopamine content in the brain of 6-hydrodopamine lesioned rats. Neuroscience. 2000;95(1):113-117. doi: 10.1016/S0306-4522(99)00400-5.
  • Moulin A, Demange L, Berge G, et al. Toward potent ghrelin receptor ligands based on trisubstituted 1 2,4-triazole structure. 2. Synthesis and pharmacological in vitro and in vivo evaluations. Journal of Medicinal Chemistry. 2007;50;5790-5806. doi: 10.1021/jm0704550.
  • Nagaya N, Itoh T, Murakami S, et al. Treatment of cachexia with ghrelin in patients with COPD. Chest. 2005;128:1187-93. doi: 10.1378/chest.128.3.1187.
  • Nass R, Pezzoli SS, Oliveri MC, et al. Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: a randomized trial. Annals of Internal Medicine. 2008;149(9):601-611. doi: 10.7326/0003-4819-149-9-200811040-00003.
  • Quarta D, Di Francesco C, Melotto S. Systemic administration of ghrelin increases extracellular dopamine in the shell but not the core subdivision of the nucleus accumbens. Neurochemistry International. 2009;54(2):89-94. doi: 10.1016/j.neuint.2008.12.006.
  • Robinson TE, Berridge KC. The neural basis of drug craving – an incentivesensitization theory of addiction. Brain Research Reviews. 1993;18(3):247-291. doi: 10.1016/0165-0173(93)90013-P.
  • Rosen GD, Finklestein S, Stoll AL, et al. Neurochemical asymmetries in the albino rat’s cortex, striatum, and nucleus accumbens. Life Sci. 1984;34(12):1143-8. doi: 10.1016/0024-3205(84)90085-7.
  • Sato T, Nakamura Y, Shiimura Y, et al. Structure, regulation and function of ghrelin. J Biochem. 2012;151(2):119-128. doi: 10.1093/jb/mvr134.
  • Schneider ER, Darby R, Leibowitz SF, Hoebel BG. Orexin, but not ghrelin, injected in the lateral hypothalamus increases alcohol intake in alcohol-drinking rats. Alcoholism – Clinical and Experimental Research. 2007;31(6):199A.

Views

Abstract - 89

PDF (Russian) - 72


Copyright (c) 2017 ECO-vector LLC

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.