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Pentylenetetrazol-induced seizure-like behavior and neural hyperactivity in the medicinal leech

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Abstract

This study examined the capacity of a known pro-epileptic drug, pentylenetetrazol (PTZ), to elicit seizure-like activity in the medicinal leech, Hirudo verbana. During in vivo experiments, PTZ elicited increased motor activity in a concentration-dependent manner with the highest concentration (10 mM) eliciting episodes of highly uncoordinated exploratory and swimming behavior. Co-application of the anti-epileptic drug, phenytoin, failed to reduce the absolute amount of PTZ-induced motor behavior, but was able to prevent expression of abnormal exploratory and swimming behaviors. During in vitro experiments in which extracellular recordings of connective nerve activity were made, bath application of 1 μM PTZ in Mg2+-free saline elicited a significant increase in spontaneous activity. This PTZ-induced increase in activity was completely inhibited by phenytoin. Interestingly, PTZ-induced hyperactivity was also blocked by co-application of the endocannabinoid 2-arachidonoyl glycerol and the selective serotonin re-uptake inhibitor (SSRI) fluoxetine. These findings suggest that the leech can be a useful system in which to study potential anti-epileptic treatments.

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References

  1. Baca SM, Marin-Burgin A, Wagenaar DA, Kristan WB Jr (2008) Widespread inhibition proportional to excitation controls the gain of a leech behavioral circuit. Neuron 57:276–289

  2. Baraban SC (2007) Emerging epilepsy models: insights from mice, flies, worms and fish. Curr Opin Neurol 20:164–168

  3. Bhaskaran MD, Smith BN (2010) Cannabinoid-mediated inhibition of recurrent excitatory circuitry in the dentate gyrus in a mouse model of temporal lobe epilepsy. PLoS One 5:e10683

  4. Brown TE, Chirila AM, Schrank BR, Kauer JA (2013) Loss of interneuron LTD and attenuated pyramidal cell LTP in Trpv1 and Trpv3 KO mice. Hippocampus 23:662–671

  5. Burton A (2000) Anti-epileptic drugs for pain management. The internet journal of pain, symptom control and palliative care 1(2)

  6. Calvino MA, Iscla IR, Szczupak L (2005) Selective serotonin reuptake inhibitors induce spontaneous interneuronal activity in the leech nervous system. J Neurophysiol 93:2644–2655

  7. Chavez AE, Chiu CQ, Castillo PE (2010) TRPV1 activation by endogenous anandamide triggers postsynaptic long-term depression in dentate gyrus. Nat Neurosci 13:1511–1518

  8. Cline HT (1983) 3H-GABA uptake selectively labels identifiable neurons in the leech central nervous system. J Comp Neurol 215:351–358

  9. Cline HT (1986) Evidence for GABA as a neurotransmitter in the leech. J Neurosci 6:2848–2856

  10. Cymbalyuk GS, Gaudry Q, Masino MA, Calabrese RL (2002) Bursting in leech heart interneurons: cell-autonomous and network-based mechanisms. J Neurosci 22:10580–10592

  11. De Petrocellis L, Melck D, Bisogno T, Milone A, Di MV (1999) Finding of the endocannabinoid signalling system in Hydra, a very primitive organism: possible role in the feeding response. Neuroscience 92:377–387

  12. Di Marzo V, De Petrocellis L (2012) Why do cannabinoid receptors have more than one endogenous ligand? Philos Trans R Soc B Biol Sci 367:3216–3228

  13. Elphick MR (2012) The evolution and comparative neurobiology of endocannabinoid signalling. Philos Trans R Soc Lond B Biol Sci 367:3201–3215

  14. Gaudry Q, Kristan WB Jr (2009) Behavioral choice by presynaptic inhibition of tactile sensory terminals. Nat Neurosci 12:1450–1457

  15. Giachello CN, Premoselli F, Montarolo PG, Ghirardi M (2013) Pentylenetetrazol-induced epileptiform activity affects basal synaptic transmission and short-term plasticity in monosynaptic connections. PLoS One 8:e56968

  16. Gibson HE, Edwards JG, Page RS, Van Hook MJ, Kauer JA (2008) TRPV1 channels mediate long-term depression at synapses on hippocampal interneurons. Neuron 57:746–759

  17. Grey KB, Burrell BD (2010) Co-induction of LTP and LTD and its regulation by protein kinases and phosphatases. J Neurophysiol 103:2737–2746

  18. Grice SJ, Sleigh JN, Liu JL, Sattelle DB (2011) Invertebrate models of spinal muscular atrophy: insights into mechanisms and potential therapeutics. Bioessays 33:956–965

  19. Grueter BA, Brasnjo G, Malenka RC (2010) Postsynaptic TRPV1 triggers cell type-specific long-term depression in the nucleus accumbens. Nat Neurosci 13:1519–U1107

  20. Hiroi R, Lacagnina AF, Hinds LR, Carbone DG, Uht RM, Handa RJ (2013) The androgen metabolite, 5α-androstane-3β, 17β-diol (3β-diol), activates the oxytocin promoter through an estrogen receptor-beta pathway. Endocrinology 154:1802–1812

  21. Igelstrom KM, Heyward PM (2012) The antidepressant drug fluoxetine inhibits persistent sodium currents and seizure-like events. Epilepsy Res 101:174–181

  22. Im SH, Galko MJ (2012) Pokes, sunburn, and hot sauce: drosophila as an emerging model for the biology of nociception. Dev Dyn 241:16–26

  23. Iskedjian M, Bereza B, Gordon A, Piwko C, Einarson TR (2007) Meta-analysis of cannabis based treatments for neuropathic and multiple sclerosis-related pain. Curr Med Res Opin 23:17–24

  24. Izzo AA, Borrelli F, Capasso R, Di Marzo V, Mechoulam R (2009) Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol Sci 30:515–527

  25. Jobe PC, Browning RA (2005) The serotonergic and noradrenergic effects of antidepressant drugs are anticonvulsant, not proconvulsant. Epilepsy Behav 7:602–619

  26. Katona I, Freund TF (2008) Endocannabinoid signaling as a synaptic circuit breaker in neurological disease. Nat Med 14:923–930

  27. Katona I, Freund TF (2012) Multiple functions of endocannabinoid signaling in the brain. Annu Rev Neurosci 35:529–558

  28. Kristan WB Jr, Calabrese RL, Friesen WO (2005) Neuronal control of leech behavior. Prog Neurobiol 76:279–327

  29. Lehtonen M, Reisner K, Auriola S, Wong G, Callaway JC (2008) Mass-spectrometric identification of anandamide and 2-arachidonoylglycerol in nematodes. Chem Biodivers 5:2431–2441

  30. Li Q, Burrell BD (2009) Two forms of long-term depression in a polysynaptic pathway in the leech CNS: one NMDA receptor-dependent and the other cannabinoid-dependent. J Comp Physiol A Neuroethol Sens Neural Behav Physiol 195:831–841

  31. Li Q, Burrell BD (2010) Properties of cannabinoid-dependent long-term depression in the leech. J Comp Physiol A Neuroethol Sens Neural Behav Physiol 196:841–851

  32. Li Q, Burrell BD (2011) Associative, bidirectional changes in neural signaling utilizing NMDA receptor- and endocannabinoid-dependent mechanisms. Learn Mem (Cold Spring Harbor, NY) 18:545–553

  33. Li J, Le W (2013) Modeling neurodegenerative diseases in Caenorhabditis elegans. Exp Neurol 250:94–103

  34. Mainardi P, Leonardi A, Albano C (2008) Potentiation of brain serotonin activity may inhibit seizures, especially in drug-resistant epilepsy. Med Hypotheses 70:876–879

  35. Marsicano G, Goodenough S, Monory K, Hermann H, Eder M, Cannich A, Azad SC, Cascio MG, Gutiérrez SO, van der Stelt M, López-Rodríguez ML, Casanova E, Schütz G, Zieglgänsberger W, Di Marzo V, Behl C, Lutz B (2003) CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science 302:84–88

  36. Matias I, Bisogno T, Melck D, Vandenbulcke F, Verger-Bocquet M, De Petrocellis L, Sergheraert C, Breton C, Di MV, Salzet M (2001) Evidence for an endocannabinoid system in the central nervous system of the leech Hirudo medicinalis. Brain Res Mol Brain Res 87:145–159

  37. Mazzoni A, Broccard FD, Garcia-Perez E, Bonifazi P, Ruaro ME, Torre V (2007) On the dynamics of the spontaneous activity in neuronal networks. PLoS One 2:e439

  38. McClung C, Hirsh J (1999) The trace amine tyramine is essential for sensitization to cocaine in Drosophila. Curr Biol 9:853–860

  39. Muller KJ, Nicholls JG, Stent GS (1981) Neurobiology of the leech. Cold Spring Harbor Laboratory Press, Cold Spring Harbor

  40. Nestler EJ, Hyman SE, Malenka RC (2001) Molecular Neuropharmacology. McGraw-Hill Companies, Inc., New York

  41. Parker L, Howlett IC, Rusan ZM, Tanouye MA (2011) Seizure and epilepsy: studies of seizure disorders in Drosophila. Int Rev Neurobiol 99:1–21

  42. Regesta G, Tanganelli P (1999) Clinical aspects and biological bases of drug-resistant epilepsies. Epilepsy Res 34:109–122

  43. Scholz H, Mustard JA (2013) Invertebrate models of alcoholism. Curr Top Behav Neurosci 13:433–457

  44. Sombati S, Delorenzo RJ (1995) Recurrent spontaneous seizure activity in hippocampal neuronal networks in culture. J Neurophysiol 73(4):1706–1711

  45. Sovik E, Barron AB (2013) Invertebrate models in addiction research. Brain Behav Evol 82:153–165

  46. Therisa KK, Desai PV (2011) Study of epileptiform activity in cerebral ganglion of mud crab Scylla serrata. Invertebr Neurosci 11:21–27

  47. Walters ET, Moroz LL (2009) Molluscan memory of injury: evolutionary insights into chronic pain and neurological disorders. Brain Behav Evol 74:206–218

  48. Yuan S, Burrell BD (2010) Endocannabinoid-dependent LTD in a nociceptive synapse requires activation of a presynaptic TRPV-like receptor. J Neurophysiol 104:2766–2777

  49. Yuan S, Burrell BD (2012) Long-term depression of nociceptive synapses by non-nociceptive afferent activity: role of endocannabinoids, Ca2+, and calcineurin. Brain Res 1460:1–11

  50. Zurolo E, Iyer AM, Spliet WG, Van Rijen PC, Troost D, Gorter JA, Aronica E (2010) CB1 and CB2 cannabinoid receptor expression during development and in epileptogenic developmental pathologies. Neuroscience 170:28–41

  51. Zygmunt PM, Petersson J, Andersson DA, Chuang H, Sorgard M, Di Marzo V, Julius D, Hogestatt ED (1999) Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400:452–457

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Acknowledgments

Supported by Grants from the National Science Foundation (IOS-0432683, B. Burrell), the University of South Dakota UDiscover Undergraduate Research Program (E. Hahn), and by a subproject of the National Institutes of Health Grant (P20 RR015567, J. Keifer), which is designated as a Center of Biomedical Research Excellence (COBRE).

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None.

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Correspondence to Brian Burrell.

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Hahn, E., Burrell, B. Pentylenetetrazol-induced seizure-like behavior and neural hyperactivity in the medicinal leech. Invert Neurosci 15, 1 (2015). https://doi.org/10.1007/s10158-014-0177-1

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Keywords

  • Leech
  • Seizure
  • Serotonin
  • Endocannabinoid