Effects of ghrelin agonist and antagonist on endogenous desacyl-ghrelin content in the brain limbical structures under psychoemotional stress in rats

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Abstract


Background. During last years it has been shown the ghrelin signaling system not only regulates energy balance and food intake. It also takes part in reinforcement mechanisms and addiction formation. So the ghrelin system may be considered as possible molecular target to study addiction treatment and post-stressor pharmacological modulation.

The aim of this work was to study the effects of ghrelin agonist and antagonist administration on des-acyl ghrelin (DAG) content in the brain structures under stress exposure in Wistar rats.

Methods. The acute psychoemotional stress was realized by means of exposure of experimental rats to predator, a tiger python. Ghrelin or ghrelin antagonist D-Lys3-GHRP-6 (Tocris, UK) 10 µg in 20 µl administered intranasally for 7 days after stress exposure. Then brain structures were obtained, homogenized with cryogenic system “Cryomill 200” (Retsch, Germany) and investigated with high-sensitive ELISA (SP-BIO, France). Results. DAG have been detected in every brain structures studied. That are amygdala, hippocampus and hypothalamus. In control group of animals the DAG concentration in hypothalamus was 3-fold more comparning to hippocampus and 2-fold more conparning to amygdala content. The acute stress have dramatically 8-12-fold decrease of DAG concentrations in every brain structures studied. The pharmacological actions on GHSR receptor by ghrelin agonist and antagonist have not affect significant changes in DAG concentrations in every brain structures.

Conclusions. The different concentrations of DAG in brain structures in control gtoup supports the view about ghrelin releasing neurons in the hypothalamus. Intranasal administration of ghrelin agonist and antagonist changes the levels of DAG in the hippocampus and the hypothalamus but not in the amygdala nucleus. Our data confirm the opinion about ghrelin-releasing neurons in hypothalamus. The experiments showed the acute stress had caused great depression of ghrelin system in various brain structures. The response of ghrelin system to acute stress occur possibly besides GHSR receptor pathway. The last have been suggested by absence of significant response to ghrelin agonist and antagonist administration.


Platon P. Khokhlov

Author for correspondence.
platonkh@list.ru
Institute of Experimental Medicine
Russian Federation, 12, Academic Pavlov street, Saint-Petersburg, 197376

PhD (Biochemistry), Senior Researcher, S.V. Anichkov Dept. of Neuropharmacology

Sergey G. Tsikunov

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

Dr Med Sci (Physiology), Professor, Head of laboratory, I.P. Pavlov Dept. of Physiology

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
Russian Federation, 12, Academic Pavlov street, Saint-Petersburg, 197376

Dr Biol Sci (Pharmacology), Leading Researcher, S.V. Anichkov Dept. of Neuropharmacology

Eugenii R. Bychkov

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

PhD (Biochemistry), Leading Researcher, S.V. Anichkov Dept. of Neuropharmacology

Petr D. Shabanov

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

Dr Med Sci, Professor, Head, S.V. Anichkov Dept. of Neuropharmacology

  • Лебедев А.А., Морозов В.И., Роик Р.О., Шабанов П.Д. Антагонисты рецепторов орексина и грелина подавляют подкрепляющие эффекты психотропных средств // Acta Natura. – 2016. – Т. 2. – Cпецвыпуск. – C. 108. [Lebedev AA, Morozov VI, Roik RO, Shabanov PD. Antagonisty receptorov oreksina i grelina podavlyayut podkreplyayushchie effekty psihotropnyh sredstv. Acta Natura. 2016;2(Suppl):108. (In Russ.)]
  • Цикунов С.Г., Клюева Н.Н., Кусов А.Г., и др. Изменение липидного спектра сыворотки крови и печени крыс, вызванное тяжелой психогенной травмой // Бюл. эксперим. биол. и мед. – 2006. – Т. 141. – № 5. – С. 575–378. [Tsikunov SG, Klyueva NN, Kusov AG, et al. Izmenenie lipidnogo spektra syvorotki krovi i pecheni krys, vyzvannoe tyazheloj psihogennoj travmoj. Byulleten’ eksperimental’noj biologii i mediciny. 2006;141(5):575-378. (In Russ.)]
  • Шабанов П.Д., Лебедев А.А., Морозов В.И., Роик Р.О. Подкрепляющие свойства психоактивных веществ модулируются системой пептидов орексина головного мозга // Наркология. – 2016. – № 4. – С. 27–33. [Shabanov PD, Lebedev AA, Morozov VI, Roik RO. Podkreplyayushchie svojstva psihoaktivnyh veshchestv moduliruyutsya sistemoj peptidov oreksina golovnogo mozga. Narkologiya. 2016;(4):27-33. (In Russ.)]
  • Шабанов П.Д., Лебедев А.А., Морозов В.И., Роик Р.О. Нейропептиды грелин и орексин участвуют в подкрепляющих эффектах психоактивных веществ разного механизма действия // Эксперим. и клин. фармакология. – 2015. – Т. 78(Прил). – С. 63–64. [Shabanov PD, Lebedev AA, Morozov VI, Roik RO. Nejropeptidy grelin i oreksin uchastvuyut v podkreplyayushchih ehffektah psihoaktivnyh veshchestv raznogo mekhanizma dejstviya. Eksperimenta’naya i klinicheskaya farmakologiya. 2015;78(Suppl):63-64. (In Russ.)]
  • Cabral A, Suescun O, Zigman O, et al. Ghrelin indirectly activates hypophysiotropic CRF neurons in rodents. PLoS One. 2012;7(2):e31462. doi: 10.1371/journal.pone.0031462.
  • Chapman CD, Frey II WH, Craft S, et al. Intranasal treatment of central nervous system dysfunction in humans. Pharmacol Res. 2013;30:2474-2485. doi: 10.1007/s11095-012-0915-1.
  • Chuang JC, Sakata I, Kohno D, et al. Ghrelin directly stimulates glucagon secretion from pancreatic alpha-cells. Mol Endocrinol. 2011;25:1600-1611. doi: 10.1210/me.2011-1001.
  • Horxath TL, Abizaid A, Dietrich MO, et al. Ghrelin-immunopositive hypothalamic neurons tie the circadian clock and visual system to rhe lateral hypothalamic arousal center. Mol Metab. 2012;1:79-85. doi: 10.1016/j.molmet.2012.08.003.
  • Khokhlov PP, Lebedev AA, Bychkov ER, Shabanov PD. Changes in the ghrelin, orexin and CRF signaling systems in blood and in brain structures after chronic alcoholization and ethanol withdrawal in rats. Stress, Brain and Behav. 2016;5:49.
  • Narisada A, Hasegawa T, Nakahigashi M, et al. Inverse association of des-acyl ghrelin with worksite blood pressure in overweight/obese male workers. Environ Health Prev Med. 2015;20:224-231. doi: 10.1007/s12199-015-0454-6.
  • Patterson ZR, Ducharme R, Anisman H, Abizaid A. Altered metabolic and neurochemical responses to chronic unpredictable stressors in ghrelin receptor-deficient mice. Eur J Neurosci. 2010;32:632-639. doi: 10.1111/j.1460-9568.2010.07310.x.
  • Shabanov PD, Lebedev AA, Morozov VI. Effects of orexin OX(1) receptor antagonists SB-408124 and antorex on the reinforcing systems of the brain. Obzory po klinicheskoi farmakologii I lekarstvennoi terapii. 2016;15(Suppl):52-53.
  • Stengel A, Wang L, Tache Y. Stress-related alterations of acyl and desacyl ghrelin circulating levels: mechanisms and functional implications. Peptides. 2011;32:2208-2217. doi: 10.1016/j.peptides.2011.07.002.
  • Tissen I, Vinogradov PM, Khokhlov PP, et al. Orexin receptor type 1 (Ox1R) are involved in the formation and reinstatement of conditioned place preference. Eur Neuropsychopharmacol. 2015;25(Suppl2):269-270. doi: 10.1016/S0924-977X(15)30313-8.
  • Vinogradov PM, Tissen IY, Lebedev AA, et al. Ghrelin antagonist [D-Lys3]-GHRP-6 reduces the expression and reinstatement of conditioned place preference of alcohol in rat. Stress, Brain and Behav. 2016;5:40-41.

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