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MDMA Increases Glutamate Release and Reduces Parvalbumin-Positive GABAergic Cells in the Dorsal Hippocampus of the Rat: Role of Cyclooxygenase

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Abstract

3,4-Methylenedioxymethamphetamine (MDMA; Ecstasy) is a popular drug of abuse with well-documented acute effects on serotonergic, dopaminergic, and cholinergic transmitter systems, as well as evidence of long-term disruption of serotoninergic systems in the rat brain. Recently, it was demonstrated that MDMA evokes a delayed and sustained increase in glutamate release in the hippocampus. The purpose of the present study was to determine the role of inflammatory mediators in the MDMA-induced increase in glutamate release, as well as the contribution of inflammatory pathways in the persistent neurochemical toxicity associated with repeated MDMA treatment. Treatment with the non-selective cyclooxygenase (COX) inhibitor ketoprofen and the COX-2 selective inhibitor nimesulide attenuated the increase in extracellular glutamate in the hippocampus evoked by repeated MDMA exposure (10 mg/kg, i.p., every 2 h); no attenuation was observed in rats treated with the COX-1 selective inhibitor piroxicam. Reverse dialysis of a major product of COX activity, prostaglandin E2, also resulted in a significant increase in extracellular glutamate in the hippocampus . Repeated exposure to MDMA diminished the number of parvalbumin-positive GABA interneurons in the dentate gyrus of the hippocampus, an effect that was attenuated by ketoprofen treatment. However, COX inhibition with ketoprofen did not prevent the long-term depletion of 5-HT in the hippocampus evoked by MDMA treatment. These data are supportive of the view that cyclooxygenase activity contributes to the mechanism underlying both the increased release of glutamate and decreased number of GABA interneurons in the rat hippocampus produced by repeated MDMA exposure.

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References

  • Able JA, Gudelsky GA, Vorhees CV, Williams MT (2006) 3,4-methylenedioxymethamphetamine in adult rats produces deficits in path integration and spatial reference memory. Biol Psychiatry 59:1219–1226

    Article  PubMed  CAS  Google Scholar 

  • Anneken JH, Gudelsky GA (2012) MDMA produces a delayed and sustained increase in the extracellular concentration of glutamate in the rat hippocampus. Neuropharmacology 63(6):1022–1027

    Google Scholar 

  • Armstrong BD, Noguchi KK (2004) The neurotoxic effects of 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine on serotonin, dopamine, and GABA-ergic terminals: an in-vitro autoradiographic study in rats. Neurotoxicology 25:905–914

    Article  PubMed  CAS  Google Scholar 

  • Asanuma M, Tsuji T, Miyazaki I, Miyoshi K, Ogawa N (2003) Methamphetamine-induced neurotoxicity in mouse brain is attenuated by ketoprofen, a non-steroidal anti-inflammatory drug. Neurosci Lett 352:13–16

    Article  PubMed  CAS  Google Scholar 

  • Asi SS, Farhadi HM, Naghdi N, Choopani S, Samzadeh-Kermani A, Mehdizadeh M (2011) Non-acute effects of different doses of 3,4-methylenedioxymethamphetamine on spatial memory in the morris water maze in Sprague–Dawley male rats. Neural Regen Res 6:1715

    Google Scholar 

  • Asi SS, Farhadi HM, Mousavizadeh K, Samadikuchaksaraei A, Soleimani M, Jameie SB, Joghataei MT, Samzadeh-Kermani A, Hashemi-Nasl H, Mehdizadeh, M (2012) Evaluation of Bcl-2 Family Gene Expression in Hippocampus of 3,4-methylenedioxymethamphetamine Treated Rats. Cell J Vol 13, No 4, Winter 2012

  • Bezzi P, Carmignoto G, Pasti L, Vesce S, Rossi D, Rizzini BL, Pozzan T, Volterra A (1998) Prostaglandins stimulate calcium-dependent glutamate release in astrocytes. Nature 391:281–285

    Article  PubMed  CAS  Google Scholar 

  • Burgess AP, Venables L, Jones H, Edwards R, Parrott AC (2011) Event related potential (ERP) evidence for selective impairment of verbal recollection in abstinent recreational methylenedioxymethamphetamine (“ecstasy”)/polydrug users. Psychopharmacol (Berl) 216:545–556

    Article  CAS  Google Scholar 

  • Candelario-Jalil E, Gonzalez-Falcon A, Garcia-Cabrera M, Leon OS, Fiebich BL (2004) Wide therapeutic time window for nimesulide neuroprotection in a model of transient focal cerebral ischemia in the rat. Brain Res 1007:98–108

    Article  PubMed  CAS  Google Scholar 

  • Capela JP, Fernandes E, Remiao F, Bastos ML, Meisel A, Carvalho F (2007) Ecstasy induces apoptosis via 5-HT(2A)-receptor stimulation in cortical neurons. Neurotoxicology 28:868–875

    Article  PubMed  CAS  Google Scholar 

  • Capela JP, da Costa Araujo S, Costa VM, Ruscher K, Fernandes E, Bastos MD, Dirnagl U, Meisel A, Carvalho F (2012) The neurotoxicity of hallucinogenic amphetamines in primary cultures of hippocampal neurons. Neurotoxicology. doi:10.1016/j.neuro.2012.09.005

  • Cunningham JI, Raudensky J, Tonkiss J, Yamamoto BK (2009) MDMA pretreatment leads to mild chronic unpredictable stress-induced impairments in spatial learning. Behav Neurosci 123:1076–1084

    Article  PubMed  CAS  Google Scholar 

  • Czeh B, Simon M, van der Hart MG, Schmelting B, Hesselink MB, Fuchs E (2005) Chronic stress decreases the number of parvalbumin-immunoreactive interneurons in the hippocampus: Prevention by treatment with a substance P receptor (NK1) antagonist. Neuropsychopharmacology 30:67–79

    Article  PubMed  CAS  Google Scholar 

  • de Sola Llopis S, Miguelez-Pan M, Pena-Casanova J, Poudevida S, Farre M, Pacifici R, Bohm P, Abanades S, Verdejo Garcia A, Langohr K, Zuccaro P, de la Torre R (2008) Cognitive performance in recreational ecstasy polydrug users: a two-year follow-up study. J Psychopharmacol 22:498–510

    Article  PubMed  Google Scholar 

  • Donzanti BA, Yamamoto BK (1988) An improved and rapid HPLC-EC method for the isocratic separation of amino acid neurotransmitters from brain tissue and microdialysis perfusates. Life Sci 43:913–922

    Article  PubMed  CAS  Google Scholar 

  • Farfel GM, Seiden LS (1995) Role of hypothermia in the mechanism of protection against serotonergic toxicity. I. experiments using 3,4-methylenedioxymethamphetamine, dizocilpine, CGS 19755 and NBQX. J Pharmacol Exp Ther 272:860–867

    PubMed  CAS  Google Scholar 

  • Garcia MC, Kim HY (1997) Mobilization of arachidonate and docosahexaenoate by stimulation of the 5-HT2A receptor in rat C6 glioma cells. Brain Res 768:43–48

    Article  PubMed  CAS  Google Scholar 

  • Green AR, Mechan AO, Elliott JM, O'Shea E, Colado MI (2003) The pharmacology and clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”). Pharmacol Rev 55:463–508

    Article  PubMed  CAS  Google Scholar 

  • Gudelsky GA, Yamamoto BK (2003) Neuropharmacology and neurotoxicity of 3,4-methylenedioxymethamphetamine. Methods Mol Med 79:55–73

    PubMed  CAS  Google Scholar 

  • Gundersen HJ, Jensen EB, Kieu K, Nielsen J (1999) The efficiency of systematic sampling in stereology–reconsidered. J Microsc 193:199–211

    Article  PubMed  CAS  Google Scholar 

  • Jacobsen LK, Mencl WE, Pugh KR, Skudlarski P, Krystal JH (2004) Preliminary evidence of hippocampal dysfunction in adolescent MDMA ("ecstasy") users: Possible relationship to neurotoxic effects. Psychopharmacol (Berl) 173:383–390

    Article  CAS  Google Scholar 

  • Kay C, Harper DN, Hunt M (2011) The effects of binge MDMA on acquisition and reversal learning in a radial-arm maze task. Neurobiol Learn Mem 95:473–483

    Article  PubMed  CAS  Google Scholar 

  • Kelley KA, Ho L, Winger D, Freire-Moar J, Borelli CB, Aisen PS, Pasinetti GM (1999) Potentiation of excitotoxicity in transgenic mice overexpressing neuronal cyclooxygenase-2. Am J Pathol 155:995–1004

    Article  PubMed  CAS  Google Scholar 

  • Kermanian F, Mehdizadeh M, Soleimani M, Ebrahimzadeh Bideskan AR, Asadi-Shekaari M, Kheradmand H, Haghir H (2012) The role of adenosine receptor agonist and antagonist on hippocampal MDMA detrimental effects; a structural and behavioral study. Metab Brain Dis

  • Kerner JA, Standaert DG, Penney JB Jr, Young AB, Landwehrmeyer GB (1997) Expression of group one metabotropic glutamate receptor subunit mRNAs in neurochemically identified neurons in the rat neostriatum, neocortex, and hippocampus. Brain Res Mol Brain Res 48:259–269

    Article  PubMed  CAS  Google Scholar 

  • Lister JP, Tonkiss J, Blatt GJ, Kemper TL, DeBassio WA, Galler JR, Rosene DL (2006) Asymmetry of neuron numbers in the hippocampal formation of prenatally malnourished and normally nourished rats: a stereological investigation. Hippocampus 16:946–958

    Article  PubMed  Google Scholar 

  • Mackowiak M, Chocyk A, Sanak M, Czyrak A, Fijal K, Wedzony K (2002) DOI, an agonist of 5-HT2A/2C serotonin receptor, alters the expression of cyclooxygenase-2 in the rat parietal cortex. J Physiol Pharmacol 53:395–407

    PubMed  CAS  Google Scholar 

  • Meller R, Harrison PJ, Elliott JM, Sharp T (2002) In vitro evidence that 5-hydroxytryptamine increases efflux of glial glutamate via 5-HT(2A) receptor activation. J Neurosci Res 67:399–405

    Article  PubMed  CAS  Google Scholar 

  • Meyer JS, Grande M, Johnson K, Ali SF (2004) Neurotoxic effects of MDMA ("ecstasy") administration to neonatal rats. Int J Dev Neurosci 22:261–271

    Article  PubMed  CAS  Google Scholar 

  • Moga DE, Janssen WG, Vissavajjhala P, Czelusniak SM, Moran TM, Hof PR, Morrison JH (2003) Glutamate receptor subunit 3 (GluR3) immunoreactivity delineates a subpopulation of parvalbumin-containing interneurons in the rat hippocampus. J Comp Neurol 462:15–28

    Article  PubMed  Google Scholar 

  • Morris AM, Churchwell JC, Kesner RP, Gilbert PE (2012) Selective lesions of the dentate gyrus produce disruptions in place learning for adjacent spatial locations. Neurobiol Learn Mem 97:326–331

    Article  PubMed  Google Scholar 

  • Muller GJ, Moller A, Johansen FF (2001) Stereological cell counts of GABAergic neurons in rat dentate hilus following transient cerebral ischemia. Exp Brain Res 141:380–388

    Article  PubMed  CAS  Google Scholar 

  • Okada K, Okaichi H (2009) Functional differentiation and cooperation among the hippocampal subregions in rats to effect spatial memory processes. Behav Brain Res 200:181–191

    Article  PubMed  Google Scholar 

  • Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates, 4th edn. Academic, San Diego

    Google Scholar 

  • Perrine SA, Ghoddoussi F, Michaels MS, Hyde EM, Kuhn DM, Galloway MP (2010) MDMA administration decreases serotonin but not N-acetylaspartate in the rat brain. Neurotoxicology 31:654–661

    Article  PubMed  CAS  Google Scholar 

  • Raj V, Liang HC, Woodward ND, Bauernfeind AL, Lee J, Dietrich MS, Park S, Cowan RL (2010) MDMA (ecstasy) use is associated with reduced BOLD signal change during semantic recognition in abstinent human polydrug users: a preliminary fMRI study. J Psychopharmacol 24:187–201

    Article  PubMed  CAS  Google Scholar 

  • Riezzo I, Cerretani D, Fiore C, Bello S, Centini F, D'Errico S, Fiaschi AI, Giorgi G, Neri M, Pomara C, Turillazzi E, Fineschi V (2010) Enzymatic-nonenzymatic cellular antioxidant defense systems response and immunohistochemical detection of MDMA, VMAT2, HSP70, and apoptosis as biomarkers for MDMA (ecstasy) neurotoxicity. J Neurosci Res 88:905–916

    PubMed  CAS  Google Scholar 

  • Sang N, Yun Y, Yao GY, Li HY, Guo L, Li GK (2011) SO(2)-induced neurotoxicity is mediated by cyclooxygenases-2-derived prostaglandin E(2) and its downstream signaling pathway in rat hippocampal neurons. Toxicol Sci 124:400–413

    Article  PubMed  CAS  Google Scholar 

  • Sanon N, Carmant L, Emond M, Congar P, Lacaille JC (2005) Short-term effects of kainic acid on CA1 hippocampal interneurons differentially vulnerable to excitotoxicity. Epilepsia 46:837–848

    Article  PubMed  CAS  Google Scholar 

  • Sanzgiri RP, Araque A, Haydon PG (1999) Prostaglandin E(2) stimulates glutamate receptor-dependent astrocyte neuromodulation in cultured hippocampal cells. J Neurobiol 41:221–229

    Article  PubMed  CAS  Google Scholar 

  • Schmued LC (2003) Demonstration and localization of neuronal degeneration in the rat forebrain following a single exposure to MDMA. Brain Res 974:127–133

    Article  PubMed  CAS  Google Scholar 

  • Shankaran M, Yamamoto BK, Gudelsky GA (2001) Ascorbic acid prevents 3,4-methylenedioxymethamphetamine (MDMA)-induced hydroxyl radical formation and the behavioral and neurochemical consequences of the depletion of brain 5-HT. Synapse 40:55–64

    Article  PubMed  CAS  Google Scholar 

  • Skelton MR, Williams MT, Vorhees CV (2006) Treatment with MDMA from P11-20 disrupts spatial learning and path integration learning in adolescent rats but only spatial learning in older rats. Psychopharmacol (Berl) 189:307–318

    Article  CAS  Google Scholar 

  • Terao A, Matsumura H, Saito M (1998) Interleukin-1 induces slow-wave sleep at the prostaglandin D2-sensitive sleep-promoting zone in the rat brain. J Neurosci 18:6599–6607

    PubMed  CAS  Google Scholar 

  • Wang X, Zhu SP, Kuang WH, Li J, Sun X, Huang MS, Sun XL (2009) Neuron apoptosis induced by 3,4-methylenedioxy methamphetamine and expression of apoptosis-related factors in rat brain. Sichuan Da Xue Xue Bao Yi Xue Ban 40(1000–2):1037

    Google Scholar 

  • Warren MW, Larner SF, Kobeissy FH, Brezing CA, Jeung JA, Hayes RL, Gold MS, Wang KK (2007) Calpain and caspase proteolytic markers co-localize with rat cortical neurons after exposure to methamphetamine and MDMA. Acta Neuropathol 114:277–286

    Article  PubMed  CAS  Google Scholar 

  • West MJ, Slomianka L, Gundersen HJ (1991) Unbiased stereological estimation of the total number of neurons in thesubdivisions of the rat hippocampus using the optical fractionator. Anat Rec 231:482–497

    Article  PubMed  CAS  Google Scholar 

  • Xie T, Tong L, McLane MW, Hatzidimitriou G, Yuan J, McCann U, Ricaurte G (2006) Loss of serotonin transporter protein after MDMA and other ring-substituted amphetamines. Neuropsychopharmacology 31:2639–2651

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by awards from the National Institute on Drug Abuse DA 07427 (GG) and DA016886 (BY).

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The authors declare no conflicts of interest.

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Correspondence to Gary A. Gudelsky.

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Anneken, J.H., Cunningham, J.I., Collins, S.A. et al. MDMA Increases Glutamate Release and Reduces Parvalbumin-Positive GABAergic Cells in the Dorsal Hippocampus of the Rat: Role of Cyclooxygenase. J Neuroimmune Pharmacol 8, 58–65 (2013). https://doi.org/10.1007/s11481-012-9420-x

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