Alteration of Depressive-like Behaviors by Psilocybe cubensis Alkaloid Extract in Mice: the Role of Glutamate Pathway

Document Type: Original paper

Authors

1 Department of Mycology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran.

2 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

3 Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj, Iran.

Abstract

Background and objectives: Considering the increasing prevalence of depression, many studies are launched to investigate new antidepressant treatments. The present research has shown how psilocybin as an active compound of Psilocybe cubensis (Earle) Singer extract (PCE) can change the parameters related to depression and anxiety in animal models. Both serotonin (5-hydroxytryptamine: 5-HT) and glutamate modulate depressive-like behaviors and, therefore, we examined the possible interaction of psilocybin as 5-HT1 agonist with glutamate receptor N-methyl-D-aspartate (NMDA). Methods: Psilocybe cubensis extract of this mushroom was prepared by ethyl acetate. NMRI mice involved in all experiments and were treated with the vehicle, extract, or standard drug intraperitoneally. Open field (OFT), forced swimming (FST) and tail suspension tests (TST) were applied to measure the intended parameters. OFT was performed to verify the applied doses for measuring the following antidepressant activity.  Results: PCE at the doses of 100 mg/kg significantly changed the locomotion, time spent in center and velocity of the animals in OFT. While treatment of the animals with PCE 10 and 40 mg/kg or ketamine 1 mg/kg did not alter the locomotor activity, co-administration of these subeffective amounts significantly reduced the immobility time in both FST and TST. Conclusion: These effects may indicate possible implication of psilocybin with NMDA receptor which consequently produces the antidepressant effects.
 

Keywords


[1] Bromet E, Andrade LH, Hwang I, Sampson N A, Alonso J, de Girolamo G, de Graaf R, Demyttenaere K, Hu C, Iwata N, Karam AN, Kaur J, Kostyuchenko S, Lepine JP, Levinson D, Matschinger H, Mora ME, Browne MO, Posada-Villa J, Viana MC, Williams DR, Kessler RC. Cross-national epidemiology of DSM-IV major depressive episode. BMC Med. 2011; 9(90): 1-16.

[2] Nutt DJ, King LA, Nichols DE. Effects of Schedule I drug laws on neuroscience research and treatment innovation. Nat Rev Neurosci. 2013; 14(8): 577-585.

[3] Young SN. Single treatments that have lasting effects: some thoughts on the antidepressant effects of ketamine and botulinum toxin and the anxiolytic effect of psilocybin. J Psychiatry Neurosci. 2013; 38(2): 78-83.

[4] Barnes NM, Sharp T. A review of central 5-HT receptors and their function. Neuropharmacology. 1999; 38(8): 1083-1152.

[5] Malberg JE, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci. 2000; 20(24): 9104-9110.

[6] Klempin F, Babu H, de Pietri Tonelli D, Alarcon E, Fabel K, Kempermann G. Oppositional effects of serotonin receptors 5-HT1a, 2, and 2c in the regulation of adult hippocampal neurogenesis. Front Mol Neurosci. 2010; 3(14): 1-11.

[7] Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF, Kavalali ET, Monteggia LM. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature. 2011; 475(7354): 91-95.

[8]  Mantovani M, Pertile R, Calixto JB, Santos AR, Rodrigues AL. Melatonin exerts an antidepressant-like effect in the tail suspension test in mice: evidence for involvement of N-methyl-D-aspartate receptors and the L-arginine-nitric oxide pathway. Neurosci Lett. 2003; 343(1): 1-4.

[9] Plaznik A, Palejko W, Nazar M, Jessa M. Effects of antagonists at the NMDA receptor complex in two models of anxiety. Eur Neuropsychopharmacol. 1994; 4(4): 503-512.

[10] Sanacora G, Zarate CA, Krystal JH, Manji HK. Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat Rev Drug Discov. 2008; 7(5): 426-437.

[11] Diazgranados N, Ibrahim L, Brutsche NE, Newberg A, Kronstein P, Khalife S, Kammerer WA, Quezado Z, Luckenbaugh DA, Salvadore G, Machado-Vieira R, Manji HK, Zarate CA. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. 2010; 67(8): 793-802.

[12] Zarate CA,  Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006; 63(8): 856-864.

[13] Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000; 47(4): 351-354.

[14] Delgado PL, Moreno FA. Hallucinogens, serotonin and obsessive-compulsive disorder. J Psychoactive Drugs. 1998; 30(4): 359-366.

[15] Nicholas LG, Ogamé K. Psilocybin mushroom handbook: easy indoor & outdoor cultivation. 1st ed. Canada:  Quick American Archives, 2006.

[16] Catalfomo P, Tyler V. The production of psilocybin in submerged culture by Psilocybe cubensis. Lloydia. 1964; 27(1): 53-63.

[17] Nugent KG, Saville BJ. Forensic analysis of hallucinogenic fungi: a DNA-based approach. Forensic Sci Int. 2004; 140(2-3): 147-157.

[18] Sarwar M, McDonald J. A rapid extraction and GC/MS methodology for the identification of psilocyn in mushroom/chocolate concoctions. Microgram J. 2003; 1(3-4): 177-183.

[19] Adams RP. Identification of essential oil components by gas chromatography-mass spectroscopy. Carol Stream: Allured Publishing Corp, 1995.

[20] Kulesskaya N, Voikar V. Assessment of mouse anxiety-like behavior in the light-dark box and open-field arena: role of equipment and procedure. Physiol Behav. 2014; 133: 30-38.

[21] Porsolt RD, Bertin A, Jalfre M. Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther. 1977; 229(2): 327-336.

[22] Steru L, Chermat R, Thierry B, Simon P. The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology (Berl). 1985; 85(3): 367-370.

[23] Willner P, Mitchell PJ. The validity of animal models of predisposition to depression. Behav Pharmacol. 2002; 13(3): 169-188.

[24] Haj-Mirzaian A, Amiri S, Kordjazy N, Rahimi-Balaei M, Haj-Mirzaian A, Marzban H, Aminzadeh A, Dehpour AR, Mehr SE. Blockade of NMDA receptors reverses the depressant, but not anxiogenic effect of adolescence social isolation in mice. Eur J Pharmacol. 2015; 750: 160-166.

[25] Andrade R. Regulation of membrane excitability in the central nervous system by serotonin receptor subtypes. Ann N Y Acad Sci. 1998; 861: 190-203.

[26] Cull-Candy S, Brickley S, Farrant M. NMDA receptor subunits: diversity, development and disease. Curr Opin Neurobiol. 2001; 11(3): 327-335.

[27] Trullas R, Skolnick P. Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. Eur J Pharmacol. 1990; 185(1): 1-10.

[28] Preskorn SH, Baker B, Kolluri S, Menniti F S, Krams M, Landen JW. An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-methyl-D-aspartate antagonist, CP-101,606, in patients with treatment-refractory major depressive disorder. J Clin Psychopharmacol. 2008; 28(6): 631-637.

[29] Dere E, Topic B, De Souza Silva MA, Fink H, Buddenberg T, Huston JP. NMDA-receptor antagonism via dextromethorphan and ifenprodil modulates graded anxiety test performance of C57BL/6 mice. Behav Pharmacol. 2003; 14(3): 245-249.

[30] Zhong P, Yuen EY, Yan Z. Modulation of neuronal excitability by serotonin-NMDA interactions in prefrontal cortex. Mol Cell Neurosci. 2008; 38(2): 290-299.

[31] Martin-Ruiz R, Puig MV, Celada P, Shapiro DA, Roth BL, Mengod G, Artigas F. Control of serotonergic function in medial prefrontal cortex by serotonin-2A receptors through a glutamate-dependent mechanism. J Neurosci. 2001; 21(24): 9856-9866.

[32] Passie T, Seifert J, Schneider U, Emrich H M. The pharmacology of psilocybin. Addict Biol. 2002; 7(4): 357-364.

[33] Aghajanian GK, Gallager DW. Raphe origin of serotonergic nerves terminating in the cerebral ventricles. Brain Res. 1975; 88(2): 221-231.