A tightly regulated balance between excitatory and inhibitory neurotransmission is required for proper functioning of the brain in the long term. Although a strong excitatory drive is necessary for processes such as learning and memory, exaggerated levels of excitation may lead to the neuronal system getting out of control, possibly leading to pathological processes. They may range from epileptiform seizures to neurodegenerative disorders, finally resulting in a massive neuronal cell death. The present chapter will discuss the function of the endocannabinoid system in the maintenance of the balance between excitation and inhibition in the brain, and its possible therapeutic exploitation as a target against epilepsy.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsPreview
Unable to display preview. Download preview PDF.
References
Ames FR, Cridland S (1986) Anticonvulsant effect of cannabidiol. S Afr Med J 69:14.
Ben-Ari Y, Cossart R (2000) Kainate, a double agent that generates seizures: two decades of progress. Trends Neurosci 23:580–587.
Blair RE, Deshpande LS, Sombati S, Falenski KW, Martin BR, DeLorenzo RJ (2006) Activation of the cannabinoid type-1 receptor mediates the anticonvulsant properties of cannabinoids in the hippocampal neuronal culture models of acquired epilepsy and status epilepticus. J Pharmacol Exp Ther 317:1072–1078.
Chen K, Baram TZ, Soltesz I (1999) Febrile seizures in the developing brain result in persistent modification of neuronal excitability in limbic circuits. Nat Med 5:888–894.
Chen K, Ratzliff A, Hilgenberg L, Gulyas A, Freund TF, Smith M, Dinh TP, Piomelli D, Mackie K, Soltesz I (2003) Long-term plasticity of endocannabinoid signaling induced by developmental febrile seizures. Neuron 39:599–611.
Chen K, Neu A, Howard AL, Foldy C, Echegoyen J, Hilgenberg L, Smith M, Mackie K, Soltesz I (2007) Prevention of plasticity of endocannabinoid signaling inhibits persistent limbic hyperexcitability caused by developmental seizures. J Neurosci 27:46–58.
Chevaleyre V, Takahashi KA, Castillo PE (2006) Endocannabinoid-mediated synaptic plasticity in the CNS. Annu Rev Neurosci 29:37–76.
Clancy CE, Kass RS (2003) Pharmacogenomics in the treatment of epilepsy. Pharmacogenomics 4:747–751.
Clement AB, Hawkins EG, Lichtman AH, Cravatt BF (2003) Increased seizure susceptibility and proconvulsant activity of anandamide in mice lacking fatty acid amide hydrolase. J Neurosci 23:3916–3923.
Consroe PF, Wood GC, Buchsbaum H (1975) Anticonvulsant nature of marihuana smoking. JAMA 234:306–307.
Cunha JM, Carlini EA, Pereira AE, Ramos OL, Pimentel C, Gagliardi R, Sanvito WL, Lander N, Mechoulam R (1980) Chronic administration of cannabidiol to healthy volunteers and epileptic patients. Pharmacology 21:175–185.
DeLorenzo RJ, Sun DA, Deshpande LS (2005) Cellular mechanisms underlying acquired epilepsy: the calcium hypothesis of the induction and maintenance of epilepsy. Pharmacol Ther 105:229–266.
Deshpande LS, Blair RE, Nagarkatti N, Sombati S, Martin BR, DeLorenzo RJ (2007a) Development of pharmacoresistance to benzodiazepines but not cannabinoids in the hippocampal neuronal culture model of status epilepticus. Exp Neurol 204:705–713.
Deshpande LS, Blair RE, Ziobro JM, Sombati S, Martin BR, DeLorenzo RJ (2007b) Endocannabinoids block status epilepticus in cultured hippocampal neurons. Eur J Pharmacol 558:52–59.
Deshpande LS, Sombati S, Blair RE, Carter DS, Martin BR, DeLorenzo RJ (2007c) Cannabinoid CB1 receptor antagonists cause status epilepticus-like activity in the hippocampal neuronal culture model of acquired epilepsy. Neurosci Lett 411:11–16.
Di Marzo V, Bifulco M, De Petrocellis L (2004) The endocannabinoid system and its therapeutic exploitation. Nat Rev Drug Discov 3:771–784.
Ellison JM, Gelwan E, Ogletree J (1990) Complex partial seizure symptoms affected by marijuana abuse. J Clin Psychiatry 51:439–440.
Falenski KW, Blair RE, Sim-Selley LJ, Martin BR, DeLorenzo RJ (2007) Status epilepticus causes a long-lasting redistribution of hippocampal cannabinoid type 1 receptor expression and function in the rat pilocarpine model of acquired epilepsy. Neuroscience 146:1232–1244.
French JA, Williamson PD, Thadani VM, Darcey TM, Mattson RH, Spencer SS, Spencer DD (1993) Characteristics of medial temporal lobe epilepsy: I. Results of history and physical examination. Ann Neurol 34:774–780.
Freund TF, Katona I, Piomelli D (2003) Role of endogenous cannabinoids in synaptic signaling. Physiol Rev 83:1017–1066.
Gaoni Y, Mechoulam R (1964) Isolation, structure and partial synthesis of an active constituent of hashish. J Am Chem Soc 86:1646–1647.
Gordon E, Devinsky O (2001) Alcohol and marijuana: effects on epilepsy and use by patients with epilepsy. Epilepsia 42:1266–1272.
Iversen LL (2000) The Science of Marijuana. Oxford: Oxford University Press.
Keeler MH, Reifler CB (1967) Grand mal convulsions subsequent to marijuana use. Case report. Dis Nerv Syst 28:474–475.
Lambert DM, Vandevoorde S, Diependaele G, Govaerts SJ, Robert AR (2001) Anticonvulsant activity of N-palmitoylethanolamide, a putative endocannabinoid, in mice. Epilepsia 42:321–327.
LaRoche SM, Helmers SL (2004) The new antiepileptic drugs: scientific review. JAMA 291:605–614.
Leite JP, Cavalheiro EA (1995) Effects of conventional antiepileptic drugs in a model of spontaneous recurrent seizures in rats. Epilepsy Res 20:93–104.
Luszczki JJ, Czuczwar P, Cioczek-Czuczwar A, Czuczwar SJ (2006) Arachidonyl-2′-chloroethylamide, a highly selective cannabinoid CB1 receptor agonist, enhances the anticonvulsant action of valproate in the mouse maximal electroshock-induced seizure model. Eur J Pharmacol 547:65–74.
Lutz B (2004) On-demand activation of the endocannabinoid system in the control of neuronal excitability and epileptiform seizures. Biochem Pharmacol 68:1691–1698.
Mackie K (2006) Cannabinoid receptors as therapeutic targets. Annu Rev Pharmacol Toxicol 46:101–122.
Mackie K, Stella N (2006) Cannabinoid receptors and endocannabinoids: evidence for new players. AAPS J 8:E298–E306.
Marsicano G, Lutz B (1999) Expression of the cannabinoid receptor CB1 in distinct neuronal subpopulations in the adult mouse forebrain. Eur J Neurosci 11:4213–4225.
Marsicano G, Goodenough S, Monory K, Hermann H, Eder M, Cannich A, Azad SC, Cascio MG, Gutierrez SO, van der Stelt M, Lopez-Rodriguez 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.
Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346:561–564.
Matsuda LA, Bonner TI, Lolait SJ (1993) Localization of cannabinoid receptor mRNA in rat brain. J Comp Neurol 327:535–550.
McCormick DA, Contreras D (2001) On the cellular and network bases of epileptic seizures. Annu Rev Physiol 63:815–846.
Mechoulam R (1986) The pharmacohistory of Cannabis sativa. In: Mechoulam R (ed.), Cannabinoids as Therapeutic Agents. Boca Raton, FL: CRC Press, pp. 1–19.
Mechoulam R, Lichtman AH (2003) Neuroscience. Stout guards of the central nervous system. Science 302:65–67.
Mello LE, Cavalheiro EA, Tan AM, Kupfer WR, Pretorius JK, Babb TL, Finch DM (1993) Circuit mechanisms of seizures in the pilocarpine model of chronic epilepsy: cell loss and mossy fiber sprouting. Epilepsia 34:985–995.
Monory K, Massa F, Egertova M, Eder M, Blaudzun H, Westenbroek R, Kelsch W, Jacob W, Marsch R, Ekker M, Long J, Rubenstein JL, Goebbels S, Nave KA, During M, Klugmann M, Wolfel B, Dodt HU, Zieglgansberger W, Wotjak CT, Mackie K, Elphick MR, Marsicano G, Lutz B (2006) The endocannabinoid system controls key epileptogenic circuits in the hippocampus. Neuron 51:455–466.
Ng SK, Brust JC, Hauser WA, Susser M (1990) Illicit drug use and the risk of new-onset seizures. Am J Epidemiol 132:47–57.
Noebels JL (2003) The biology of epilepsy genes. Annu Rev Neurosci 26:599–625.
Pertwee RG (2004) The pharmacology and therapeutic potential of cannabidiol. In: Di Marzo V (ed.), Cannabinoids. New York: Kluwer Academic/Plenum Publishers, pp. 32–42.
Piomelli D (2003) The molecular logic of endocannabinoid signalling. Nat Rev Neurosci 4:873–884.
Ratzliff AH, Santhakumar V, Howard A, Soltesz I (2002) Mossy cells in epilepsy: rigor mortis or vigor mortis? Trends Neurosci 25:140–144.
Schauwecker PE, Steward O (1997) Genetic determinants of susceptibility to excitotoxic cell death: implications for gene targeting approaches. Proc Natl Acad Sci USA 94:4103–4108.
Schuchmann S, Schmitz D, Rivera C, Vanhatalo S, Salmen B, Mackie K, Sipila ST, Voipio J, Kaila K (2006) Experimental febrile seizures are precipitated by a hyperthermia-induced respiratory alkalosis. Nat Med 12:817–823.
Schwenkreis P, Tegenthoff M (2003) Therapeutic use of cannabinoids in neurology. Schmerz 17:367–373.
Sheerin AH, Zhang X, Saucier DM, Corcoran ME (2004) Selective antiepileptic effects of N-palmitoylethanolamide, a putative endocannabinoid. Epilepsia 45:1184–1188.
Shen M, Piser TM, Seybold VS, Thayer SA (1996) Cannabinoid receptor agonists inhibit glutamatergic synaptic transmission in rat hippocampal cultures. J Neurosci 16:4322–4334.
Shinnar S, Glauser TA (2002) Febrile seizures. J Child Neurol 17:S44–S52.
Straiker A, Mackie K (2007) Metabotropic suppression of excitation in murine autaptic hippocampal neurons. J Physiol 578:773–785.
Wallace MJ, Blair RE, Falenski KW, Martin BR, DeLorenzo RJ (2003) The endogenous cannabinoid system regulates seizure frequency and duration in a model of temporal lobe epilepsy. J Pharmacol Exp Ther 307:129–137.
Wettschureck N, van der SM, Tsubokawa H, Krestel H, Moers A, Petrosino S, Schutz G, Di Marzo V, Offermanns S (2006) Forebrain-specific inactivation of Gq/G11 family G proteins results in age-dependent epilepsy and impaired endocannabinoid formation. Mol Cell Biol 26:5888–5894.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2008 Springer
About this chapter
Cite this chapter
Monory, K., Lutz, B. (2008). The Endocannabinoid System as a Therapeutic Target in Epilepsy. In: Köfalvi, A. (eds) Cannabinoids and the Brain. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-74349-3_20
Download citation
DOI: https://doi.org/10.1007/978-0-387-74349-3_20
Publisher Name: Springer, Boston, MA
Print ISBN: 978-0-387-74348-6
Online ISBN: 978-0-387-74349-3
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)