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Emotional disorders induced by Hemopressin and RVD-hemopressin(α) administration in rats

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Abstract

Background

The endocannabinoid (eCB) system plays an important role in regulating emotional disorders, and is involved, directly or indirectly, in psychiatric diseases, such as anxiety and depression. Hemopressin, a hemoglobin α chain-derived peptide, and RVD-hemopressin(α), a N-terminally extended form of hemopressin, act as antagonist/inverse agonist and negative allosteric modulator of the cannabinoid 1 (CB1) receptor, respectively.

Methods

Considering the possible involvement of these peptides on emotional behaviour, the aim of our study was to investigate the behavioural effects of a single intraperitoneal (ip) injection of hemopressin (0.05 mg/kg) and RVD-hemopressin(α) (0.05 mg/kg), using a series of validated behavioural tests (locomotor activity/open field test, light-dark exploration test, forced swim test) in rats. Prefrontal cortex levels of norepinephrine (NE), dopamine (DA) and serotonin (5-hydroxytryptamine, 5-HT) and the gene expression of monoamine oxidase (MAO-B) and catechol-O-methyltransferase (COMT) were measured by high performance liquid chromatography (HPLC) analysis and real-time reverse transcription polymerase chain reaction (RT-PCR), respectively.

Results

Hemopressin administration induced anxiogenic and depressive behaviour, decreased monoamine steady state levels in prefrontal cortex, and increased the gene expression of the enzymes involved in their catabolism. By contrast, RVD- hemopressin(α) induced anxiolytic and antidepressive effects, increased monoamines and decreased the enzymes in prefrontal cortex.

Conclusion

In conclusion, in the present study we demonstrated behavioral effects induced by peripheral hemopressin and RVD-hemopressin(α) injections, that could involve modulatory effects on monoaminergic signaling, in the prefrontal cortex.

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Abbreviations

CB1:

cannabinoid 1

COMT:

catechol O-methyltransferase

DA:

dopamine

eCB:

encocannabinoid

Hp:

hemopressin

5-HT:

serotonin

MAO-B:

monoamine oxidase-B

NE:

norepinephrine

RVD-hp(α):

RVD-hemopressin(α)

TRPV1:

Transient Receptor Potential Vanilloid Type

References

  1. Rubino T, Zamberletti E, Parolaro D. Endocannabinoids and mental disorders. Handb Exp Pharmacol 2015;231:261–83.

    Article  CAS  PubMed  Google Scholar 

  2. Hungund BL, Vinod KY, Kassir SA, Basavarajappa BS, Yalamanchili R, Cooper TB, et al. Upregulation of CB1 receptors and agonist-stimulated [35S]GTPgammaS binding in the prefrontal cortex of depressed suicide victims. Mol Psychiatry 2004;9(2):184–90.

    Article  CAS  PubMed  Google Scholar 

  3. Koethe D, Llenos IC, Dulay JR, Hoyer C, Torrey EF, Leweke FM, et al. Expression of CB1 cannabinoid receptor in the anterior cingulate cortex in schizophrenia, bipolar disorder, and major depression. J Neural Transm (Vienna) 2007;114(8):1055–63.

    Article  CAS  Google Scholar 

  4. Hill MN, Miller GE, Ho WS, Gorzalka BB, Hillard CJ. Serum endocannabinoid content is altered in females with depressive disorders: a preliminary report. Pharmacopsychiatry 2008;41(2):48–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Zarrindast MR, Mahboobi S, Sadat-Shirazi MS, Ahmadi S. Anxiolytic-like effect induced by the cannabinoid CB1 receptor agonist, arachydonilcyclopropylamide (ACPA), in the rat amygdala is mediated through the D1 and D2 dopaminergic systems. J Psychopharmacol 2011;25(1):131–40.

    Article  CAS  PubMed  Google Scholar 

  6. Rutkowska M, Jachimczuk O. Antidepressant-like properties of ACEA (arachidonyl-2-chloroethylamide), the selective agonist of CB1 receptors. Acta Pol Pharm 2004;61(2):165–7.

    CAS  PubMed  Google Scholar 

  7. Adamczyk P, Gołda A, McCreary AC, Filip M, Przegaliński E. Activation of endocannabinoid transmission induces antidepressant-like effects in rats. J Physiol Pharmacol 2008;59(2):217–28.

    CAS  PubMed  Google Scholar 

  8. Moreira FA, Crippa JA. The psychiatric side-effects of rimonabant. Rev Bras Psiquiatr 2009;31(2):145–53.

    Article  PubMed  Google Scholar 

  9. Fišar Z. Cannabinoids and monoamine neurotransmission with focus on monoamine oxidase. Prog Neuropsychopharmacol Biol Psychiatry 2012;38(1):68–77.

    Article  PubMed  CAS  Google Scholar 

  10. Wyrofsky R, McGonigle P, Van Bockstaele EJ. Drug discovery strategies that focus on the endocannabinoid signaling system in psychiatric disease. Expert Opin Drug Discov 2015;10(1):17–36.

    Article  CAS  PubMed  Google Scholar 

  11. Heimann AS, Gomes I, Dale CS, Pagano RL, Gupta A, de Souza LL, et al. Hemopressin is an inverse agonist of CB1 cannabinoid receptors. Proc Natl Acad Sci U S A 2007;104(51):20588–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gomes I, Grushko JS, Golebiewska U, Hoogendoorn S, Gupta A, Heimann AS, et al. Novel endogenous peptide agonists of cannabinoid receptors. FASEB J 2009;23(9):3020–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Fogaça MV, Sonego AB, Rioli V, Gozzo FC, Dale CS, Ferro ES, et al. Anxiogenic-like effects induced by hemopressin in rats. Pharmacol Biochem Behav 2015;129:7–13.

    Article  PubMed  CAS  Google Scholar 

  14. Bauer M, Chicca A, Tamborrini M, Eisen D, Lerner R, Lutz B, et al. Identification and quantification of a new family of peptide endocannabinoids (Pepcans) showing negative allosteric modulation at CB1 receptors. J Biol Chem 2012;287:36944–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Han ZL, Fang Q, Wang ZL, Li XH, Li N, Chang XM, et al. Antinociceptive effects of central administration of the endogenous cannabinoid receptor type 1 agonist VDPVNFKLLSH-OH [(m)VD-hemopressin((α)], an N-terminally extended hemopressin peptide. J Pharmacol Exp Ther 2014;348(2):316–23.

    Article  PubMed  CAS  Google Scholar 

  16. Mollica A, Costante R, Akdemir A, Carradori S, Stefanucci A, Macedonio G, et al. Exploring new Probenecid-based carbonic anhydrase inhibitors: synthesis, biological evaluation and docking studies. Bioorg Med Chem 2015;23(17):5311–8.

    Article  CAS  PubMed  Google Scholar 

  17. Dvorácskó S, Tömböly C, Berkecz R, Keresztes A. Investigation of receptor binding and functional characteristics of hemopressin(1-7). Neuropeptides 2016;58:15–22.

    Article  PubMed  CAS  Google Scholar 

  18. Mollica A, Costante R, Novellino E, Stefanucci A, Pieretti S, Zador F, et al. Design, synthesis and biological evaluation of two opioid agonist and Cav 2.2 blocker multitarget ligands. Chem Biol Drug Des 2015;86(2):156–62.

    Article  CAS  PubMed  Google Scholar 

  19. Ferrante C, Recinella L, Leone S, Chiavaroli A, Di Nisio C, Martinotti S, et al. Anorexigenic effects induced by RVD-hemopressin(α) administration. Pharmacol Rep 2017;69:1402–7, doi:https://doi.org/10.1016/j.pharep.2017.05.015.

    Article  CAS  PubMed  Google Scholar 

  20. Leone S, Chiavaroli A, Shohreh R, Ferrante C, Ricciuti A, Manippa F, et al. Increased locomotor and thermogenic activity in mice with targeted ablation of the GHRH gene. Growth Horm IGF Res 2015;25(2):80–4.

    Article  CAS  PubMed  Google Scholar 

  21. Leone S, Shohreh R, Manippa F, Recinella L, Ferrante C, Orlando G, et al. Behavioural phenoty** of male growth hormone-releasing hormone (GHRH) knockout mice. Growth Horm IGF Res 2014;24(5):192–7.

    Article  CAS  PubMed  Google Scholar 

  22. Porsolt RD, Le Pichon M, Jalfre M. Depression: a new animal model sensitive to antidepressant treatments. Nature 1977;266(5604):730–2.

    Article  CAS  PubMed  Google Scholar 

  23. Taltavull JF, Chefer VI, Shippenberg TS, Kiyatkin EA. Severe brain hypothermia as a factor underlying behavioral immobility during cold-water forced swim. Brain Res 2003;975(1–2):244–7.

    Article  CAS  PubMed  Google Scholar 

  24. Brunetti L, Michelotto B, Orlando G, Recinella L, Di Nisio C, Ciabattoni G, et al. Aging increases amyloid beta-peptide-induced 8-iso-prostaglandin F2alpha release from rat brain. Neurobiol Aging 2004;25:125–9.

    Article  CAS  PubMed  Google Scholar 

  25. Brunetti L, Recinella L, Di Nisio C, Chiavaroli A, Leone S, Ferrante C, et al. Effects of visfatin/PBEF/NAMPT on feeding behaviour and hypothalamic neuromodulators in the rat. J Biol Regul Homeost Agents 2012;26(2):295–302.

    CAS  PubMed  Google Scholar 

  26. Brunetti L, Orlando G, Ferrante C, Recinella L, Leone S, Chiavaroli A, et al. Peripheral chemerin administration modulates hypothalamic control of feeding. Peptides 2014;51:115–21.

    Article  CAS  PubMed  Google Scholar 

  27. Brunetti L, Ferrante C, Orlando G, Recinella L, Leone S, Chiavaroli A, et al. Orexigenic effects of endomorphin-2 (EM-2) related to decreased CRH gene expression and increased dopamine and norepinephrine activity in the hypothalamus. Peptides 2013;48:83–8.

    Article  CAS  PubMed  Google Scholar 

  28. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using realtime quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001;25(4):402–8.

    Article  CAS  PubMed  Google Scholar 

  29. Brunetti L, Di Nisio C, Recinella L, Orlando G, Ferrante C, Chiavaroli A, et al. Obestatin inhibits dopamine release in rat hypothalamus. Eur J Pharmacol 2010;641(2–3):142–7.

    Article  CAS  PubMed  Google Scholar 

  30. Charan J, Kantharia ND. How to calculate sample size in animal studies? J Pharmacol Pharmacother 2013;4(4):303–6.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Fogaça MV, Aguiar DC, Moreira FA, Guimarães FS. The endocannabinoid and endovanilloid systems interact in the rat prelimbic medial prefrontal cortexto control anxiety-like behavior. Neuropharmacology 2012;63(2):202–10.

    Article  PubMed  CAS  Google Scholar 

  32. Hayase T. Differential effects of TRPV1 receptor ligands against nicotine-induced depression-like behaviors. BMC Pharmacol 2011;11:6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Abdelhamid RE, Kovács KJ, Nunez MG, Larson AA. Depressive behavior in the forced swim test can be induced by TRPV1 receptor activity and is dependent on NMDA receptors. Pharmacol Res 2014;79:21–7.

    Article  CAS  PubMed  Google Scholar 

  34. Socała K, Wlaź P. Evaluation of the antidepressant- and anxiolytic-like activity of α-spinasterol, a plant derivative with TRPV1 antagonistic effects, in mice. Behav Brain Res 2016;303:19–25.

    Article  PubMed  CAS  Google Scholar 

  35. Di Marzo V, Lastres-Becker I, Bisogno T, De Petrocellis L, Milone A, Davis JB, et al. Hypolocomotor effects in rats of capsaicin and two long chain capsaicin homologues. Eur J Pharmacol 2001;420(2–3):123–31.

    Article  PubMed  Google Scholar 

  36. Garami A, Pakai E, Oliveira DL, Steiner AA, Wanner SP, Almeida MC, et al. Thermoregulatory phenotype of the Trpv1 knockout mouse: thermoeffector dysbalance with hyperkinesis. J Neurosci 2011;31(5):1721–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Alawi KM, Aubdool AA, Liang L, Wilde E, Vepa A, Psefteli MP, et al. The sympathetic nervous system is controlled by transient receptor potential vanilloid 1 in the regulation of body temperature. FASEB J 2015;29(10):4285–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Griebel G, Stemmelin J, Scatton B. Effects of the cannabinoid CB1 receptor antagonist rimonabant in models of emotional reactivity in rodents. Biol Psychiatry 2005;57(3):261–7.

    Article  CAS  PubMed  Google Scholar 

  39. Navarro M, Hernández E, Muñoz RM, del Arco I, Villanúa MA, Carrera MR, et al. Acute administration of the CB1 cannabinoid receptor antagonist SR 141716A induces anxiety-like responses in the rat. Neuroreport 1997;8(2):491–6.

    Article  CAS  PubMed  Google Scholar 

  40. Laprairie RB, Bagher AM, Kelly ME, Denovan-Wright EM. Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br JPharmacol 2015;172(20):4790–805.

    Article  CAS  Google Scholar 

  41. Zanelati TV, Biojone C, Moreira FA, Guimarães FS, Joca SR. Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT1A receptors. Br J Pharmacol 2010;159(1):122–8.

    Article  CAS  PubMed  Google Scholar 

  42. Blessing EM, Steenkamp MM, Manzanares J, Marmar CR. Cannabidiol as a potential treatment for anxiety disorders. Neurotherapeutics 2015;12(4):825–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Sartim AG, Guimarães FS, Joca SR. Antidepressant-like effect of cannabidiol injection into the ventral medial prefrontal cortex-possible involvement of 5-HT1A and CB1 receptors. Behav Brain Res 2016;303:218–27.

    Article  CAS  PubMed  Google Scholar 

  44. Linge R, Jiménez-Sánchez L, Campa L, Pilar-Cuéllar F, Vidal R, Pazos A, et al. Cannabidiol induces rapid-acting antidepressant-like effects and enhances cortical 5-HT/glutamate neurotransmission: role of 5-HT1A receptors. Neuropharmacology 2016;103:16–26.

    Article  CAS  PubMed  Google Scholar 

  45. Van Bockstaele EJ. Cannabinoid receptor signaling and modulation of monoamines: implications for psychiatric and neurological disorders. Prog Neuropsychopharmacol Biol Psychiatry 2012;38(1):1–3.

    Article  PubMed  Google Scholar 

  46. Bambico FR, Katz N, Debonnel G, Gobbi G. Cannabinoids elicit antidepressant-like behavior and activate serotonergic neurons through the medial prefrontal cortex. J Neurosci 2007;27(43):11700–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Oropeza VC, Page ME, Van Bockstaele EJ. Systemic administration of WIN 55,212-2 increases norepinephrine release in the rat frontal cortex. Brain Res 2005;1046(1–2):45–54.

    Article  CAS  PubMed  Google Scholar 

  48. Chen J, Paredes W, Lowinson JH, Gardner EL. Delta 9-tetrahydrocannabinol enhances presynaptic dopamine efflux in medial prefrontal cortex. Eur J Pharmacol 1990;190(1–2):259–62.

    CAS  PubMed  Google Scholar 

  49. Chiu CQ, Puente N, Grandes P, Castillo PE. Dopaminergic modulation of endocannabinoid-mediated plasticity at GABAergic synapses in the prefrontal cortex. J Neurosci 2010;30(21):7236–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Blier P. Neurotransmitter targeting in the treatment of depression. J Clin Psychiatry 2013;74(Suppl 2):19–24.

    Article  CAS  PubMed  Google Scholar 

  51. Gainetdinov RR, Wetsel WC, Jones SR, Levin ED, Jaber M, Caron MG. Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity. Science 1999;283(5400):397–401.

    Article  CAS  PubMed  Google Scholar 

  52. Mann JJ. The serotonergic system in mood disorders and suicidal behaviour. Philos Trans R Soc Lond B Biol Sci 2013;368(1615):20120537.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Rodgers RJ, Nikulina EM, Cole JC. Dopamine D1 and D2 receptor ligands modulate the behaviour of mice in the elevated plus-maze. Pharmacol Biochem Behav 1994;49(4):985–95.

    Article  CAS  PubMed  Google Scholar 

  54. Fisar Z. Inhibition of monoamine oxidase activity by cannabinoids. Naunyn Schmiedebergs Arch Pharmacol 2010;381(6):563–72.

    Article  CAS  PubMed  Google Scholar 

  55. Macedonio G, Stefanucci A, Maccallini C, Mirzaie S, Novellino E, Mollica A. Hemopressin peptides as modulators of the endocannabinoid system and their potential applications as therapeutic tools. Protein Pept Lett 2016;23(12):1045–51.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacy, “G. d’Annunzio” University, Chieti, Italy

    Sheila Leone, Lucia Recinella, Annalisa Chiavaroli, Sara Martinotti, Claudio Ferrante, Adriano Mollica, Giorgia Macedonio, Azzurra Stefanucci, Michele Vacca, Luigi Brunetti & Giustino Orlando

  2. Laboratory of Chemical Biology, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary

    Szabolcs Dvorácskó & Csaba Tömböly

  3. Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council, Naples, Italy

    Luciano De Petrocellis

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  1. Sheila Leone
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  2. Lucia Recinella
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  3. Annalisa Chiavaroli
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Correspondence to Claudio Ferrante.

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Leone, S., Recinella, L., Chiavaroli, A. et al. Emotional disorders induced by Hemopressin and RVD-hemopressin(α) administration in rats. Pharmacol. Rep 69, 1247–1253 (2017). https://doi.org/10.1016/j.pharep.2017.06.010

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