Advertisement

Endocannabinoid Signaling and the Regulation of the Serotonin System

  • Samir Haj-Dahmane
  • Roh-Yu Shen
Chapter

Abstract

Endogenous cannabinoids, also called endocannabinoids (eCBs), are lipid signaling molecules in the mammalians’ central nervous system (CNS), where they regulate neuronal functions and behaviors by activating cannabinoid receptors. The ubiquitous distribution of eCBs in neuronal populations that are associated with stress responses, such as dorsal raphe nucleus (DRn) serotonin (5-HT) neurons suggests that eCB signaling plays a central role in the regulation of stress-related behaviors. Consistent with this notion, human and animal studies have established that eCB signaling is a key modulator of emotional homeostasis and that a dysfunction of eCB signaling contributes to stress-related psychiatric disorders, including anxiety and depression. This leads to the current view that the eCB signaling could be an excellent target for the development of novel therapeutic intervention for stress-related mood disorders. Over the past few years, extensive research has focused on the functional interaction between eCB signaling and 5-HT systems. As a result, steady progress is made in our understanding of the cellular mechanisms by which eCB signaling regulates the function of 5-HT system. In this chapter, we review the most recent advances in our understanding of the cellular mechanisms by which eCBs modulate the function of the 5-HT system and how stress mediators regulate eCB signaling in the DRn.

Keywords

Dorsal raphe Endocannabinoid Serotonin CB1 receptors Glutamate Stress Glucocorticoids 

Abbreviations

eCBs

endocannabinoids

5-HT

5-hydroxytryptamine (serotonin)

DRn

dorsal raphe nucleus

DAGLs

diacyl-glycerol lipase

COX-2

cyclooxygenase type 2

MGL

monoglyceride lipases

FAAH

fatty acid amid hydrolase

EPSC

excitatory postsynaptic current

WIN 55,212-2

R-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolol[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate

DSE

depolarization-induced suppression of excitation

PPR

paired-pulse ratio

CV

coefficient of variation

LTD

long-term depression

JZL 184

4-[Bis(1,3-benzodioxol-5-yl)hydroxymethyl]-1-piperidinecarboxyl acid 4-nitrophenyl ester

PF 750

N-phenyl-4-(3-quinolinylmethyl)-1-piperidinecarboxamide

Notes

Acknowledgements

Work in the Author’s lab was supported by research grants from the National Institutes of Health research grant MH 078009 to S. HD and AA12435 to R-Y. S.

References

  1. Aso E, Renoir T, Mengod G, Ledent C, Hamon M, Maldonado R, Lanfumey L, Valverde O (2009) Lack of CB1 receptor activity impairs serotonergic negative feedback. J Neurochem 109:935–944PubMedCrossRefGoogle Scholar
  2. Bambico FR, Katz N, Debonnel G, Gobbi G (2007) Cannabinoids elicit antidepressant-like behavior and activate serotoninergic neurons through the medial prefrontal cortex. J Neurosci 27:11700–11711PubMedCrossRefGoogle Scholar
  3. Bisogno T, Howell F, Williams G, Minassi A, Cascio MG, Ligresti A, Matias I, Schiano-Moriello A, Paul P, Williams EJ, Gangadharan U, Hobbs C, Di Marzo V, Diherty P (2003) Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. J Cell Biol 163:463–468PubMedCrossRefGoogle Scholar
  4. Beltramo M, Stella N, Calignano A, Lin SY, Makriyannis A, Piomelli D (1997) Functional role of high-affinity anandamide transport, as revealed by selective inhibition. Science 277:1094–1097PubMedCrossRefGoogle Scholar
  5. Breder CD, Dewitt D, Kraig RP (1995) Characterization of inducible cyclooxygenase in rat brain. J Comp Neurol 355:296–315PubMedCrossRefGoogle Scholar
  6. Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB (1996) Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384:83–87PubMedCrossRefGoogle Scholar
  7. Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A, Mechoulam R (1992) Isolation and structure of brain constituent that binds to cannabinoid receptor. Science 258:1946–1949PubMedCrossRefGoogle Scholar
  8. Di S, Malcher-Lopes R, Halmos KC, Tasker JG (2003) Nongenomic glucocorticoid inhibition via endocannabinoid release in the hypothalamus: a fast feedback mechanism. J Neurosci 23:4850–4857PubMedGoogle Scholar
  9. Doze VA, Handel EM, Jensen KA, Darsie B, Luger EJ, Haselton JR, Talbot JN (2009) Rorabaugh BR. α1A- and α1B-adrenergic receptors differentially modulate antidepressant-like behavior in the mouse. Brain Res 1285:148–137PubMedCrossRefGoogle Scholar
  10. Duma D, Jewell C, Cidlowski JA (2006) Multiple glucocorticoid receptor isoforms and mechanisms of post-translational modifications. J Steroid Biochem Mol Biol 102:11–21PubMedCrossRefGoogle Scholar
  11. Egashira N, Mishima K, Katsurabayashi S, Yoshitake T, Matsumoto Y, Ishida J, Yamaguchi M, Iwasaki K, Fujiwara M (2002) Involvement of 5-hydroxytryptamine neuronal system in Delta (9)-tetrahydrocannabinol-induced impairment of spatial memory. Eur J Pharmacol 445:221–229PubMedCrossRefGoogle Scholar
  12. Egertová M, Elphick MR (2000) Localization of cannabinoid receptors in the rat brain using antibodies to the intracellular C-terminal tail of CB1. J Comp Neurol 422:159–171PubMedCrossRefGoogle Scholar
  13. Egertová M, Cravatt BF, Elphick MR (2003) Comparative analysis of fatty acid amid hydrolase and CB1 cannabinoid receptor expression in the mouse brain: evidence of a widespread role of fatty acid amid hydrolase. Neuroscience 119:481–496PubMedCrossRefGoogle Scholar
  14. Englert LF, Ho BT, Taylor D (1973) The effects of (-)-∆9-tetrahydrocannabinol on reserpine-induced hypothermia in rats. Br J Pharmacol 49:243–252PubMedCrossRefGoogle Scholar
  15. Freemon FR (1976) Effects of marihuana on sleeping states. JAMA 220:1364–1365CrossRefGoogle Scholar
  16. Galiėgue S, Mary S, Marchand J, Dussossoy D, Carrière D, Carayon P, Bouaboula M, Shire D, Le Fur G, Casellas P (1995) Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem 232:54–61PubMedCrossRefGoogle Scholar
  17. Gaoni Y, Mechoulam R (1964) Isolation, structure and partial synthesis of an active constituent of hashish. J Am Chem Soc 86:1646–1647CrossRefGoogle Scholar
  18. Gobbi G, Bambico ER, Mangieri R, Bortolato M, Campolongo P, Solinas M, Cassano M, Morgese MG, Debonnel G, Duranti A, Tontini A, Tarzia G, Mor M, Trezza V, Goldberg SR, Cuomo V, Piomelli D (2005) Antidepressant-like activity and modulation of brain monoaminergic transmission by blockade of anandamide hydrolysis. Proc Natl Acad Sci USA 102:18620–18625PubMedCrossRefGoogle Scholar
  19. Goparaju SK, Ueda N, Taniguchi K, Yamamoto S (1999) Enzymes of porcine brain hydrolyzing 2-arachidonoylglycerol an endogenous ligand of cannabinoid receptors. Biochem Pharmacol 57:417–423PubMedCrossRefGoogle Scholar
  20. Grahn RE, Hammack SE, Will MJ, O’Connor KA, Deak T, Sparks PD, Watkins LR, Maier SF (2002) Blockade of alpha1 adrenoreceptors in the dorsal raphe nucleus prevents enhanced conditioned fear and impaired escape performance following uncontrollable stressor exposure in rats. Behav Brain Res 134:387–392PubMedCrossRefGoogle Scholar
  21. Griebel G, Stemmelin J, Scatton B (2005) Effects of cannabinoid CB1 receptor antagonist rimonabant in models of emotional reactivity in rodents. Biol Psychiatry 57:261–267PubMedCrossRefGoogle Scholar
  22. Haj-Dahmane S, Shen R-Y (2005) The wake-promoting peptide orexin-B inhibits glutamatergic transmission to dorsal raphe nucleus serotonin neurons through retrograde endocannabinoid signaling. J Neurosci 25:896–905PubMedCrossRefGoogle Scholar
  23. Haj-Dahmane S, Shen R-Y (2009) Endocannabinoids suppress excitatory synaptic transmission to dorsal raphe serotonin neurons through the activation of presynaptic CB1 receptors. J Pharmacol Exp Ther 331:186–196PubMedCrossRefGoogle Scholar
  24. Haller J, Varga B, Ledent C, Freund T (2004) CB1 cannabinoid receptors mediate anxiolytic effects: convergent genetic and pharmacological evidence with CB1-specific agents. Behav Pharmacol 15:299–304PubMedCrossRefGoogle Scholar
  25. Häring M, Guggenhuber S, Lutz B (2012) Neuronal populations mediating the effects of endocannabinoids on stress and emotionality. Neuroscience 204:145–158PubMedCrossRefGoogle Scholar
  26. Herkenham M, Lynn A, Johnson MR, Melvin LS, Costa BR de, Rice KC (1991) Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J Neurosci 11:563–583PubMedGoogle Scholar
  27. Hillard CJ, Weinlander KM, Stuhr KL (2012) Contribution of endocannabinoid signaling to psychiatric disorders in human: genetic and biochemical evidence. Neuroscience 204:207–229PubMedCrossRefGoogle Scholar
  28. Howlett AC (2005) Cannabinoid receptor signaling. Handb Exp Pharmacol 168:53–79PubMedCrossRefGoogle Scholar
  29. Kano M, Ohno-Shosaku T, Hashimotodani Y, Uchigashima M, Watanabe M (2009) Endocannabinoid-mediated control of synaptic transmission. Physiol Rev 89:309–380PubMedCrossRefGoogle Scholar
  30. Karst H, Berger S, Turiault M, Tronche F, Schütz G, Joëls M (2005) Mineralocorticoid receptors are indispensable for nongenomic modulation of hippocampal glutamate transmission by corticosterone. Proc natl Acd Sci USA 102:19204–19207CrossRefGoogle Scholar
  31. Kathuria S, Gaetani S, Fegley D, Valino F, Duranti A, Tontini A, Mor M, Tarzia G, La Rana G, Calignano A, Giustino A, Tattoli M, Palmery M, Cuomo V, Piomelli D (2003) Modulation of anxiety through blockade of anandamide hydrolysis. Nat Med 9:76–81PubMedCrossRefGoogle Scholar
  32. Katona I, Freund TF (2012) Multiple functions of endocannabinoid signaling in the brain. Ann Rev Neurosci 35:529–558PubMedCrossRefGoogle Scholar
  33. Kozak KR, Rowlinson SW, Marnett LJ (2000) Oxygenation of the endocannabinoid, 2-arachidonylglycerol, to glyceryl prostaglandins by cyclooxygenase-2. J Biol Chem 275:33744–33749PubMedCrossRefGoogle Scholar
  34. Krugers H, Karst H, Joels M (2012) Interaction between noradrenaline and corticosteroids in the brain: from electrical activity to cognitive performance. Front Cell Neurosci 6:15PubMedCrossRefGoogle Scholar
  35. Lanfumey L, Mongeau R, Cohen-Salmon C, Hamon M (2008) Corticosteroid-serotonin interactions in the neurobiological mechanisms of stress-related disorders. Neurosci Biobehav Rev 32:1174–1184PubMedCrossRefGoogle Scholar
  36. Long JZ, Nomura DK, Vann RE, Walentiny DM, Booker L, Jin X, Burston JJ, Sim-Selley LJ, Lichman AH, Wiley JL, Cravatt BF (2009) Dual blockade of FAAH MAGL identifies behavioral processes regulated by endocannabinoid crosstalk in vivo. Proc Natl Acad Sci 106:20270–20275PubMedCrossRefGoogle Scholar
  37. Malone DT, Taylor DA (2001) Involvement of somatodendritic 5-HT (1A) receptors in Delta (9)-tetrahydrocannabinol-induced hypothermia in the rat. Pharmacol Biochem Behav 69:595–601PubMedCrossRefGoogle Scholar
  38. Marco EM, Perez-Alverez L, Borcel E, Rubio M, Guaza C, Ambrosio E, File SE, Viveros MP (2004) Involvement of 5-HT1A receptors in behavioral effects of the cannabinoid receptor agonist CP 55, 94 in male rats. Behav Pharmacol 15:21–27PubMedCrossRefGoogle Scholar
  39. Marrs WR, Blankman JL, Horne EA, Thomazeau A, Lin YH, Coy J, Bodor AL, Muccioli GG, Hu SS-J, Woodruff G, Fung S, Lafourcade M, Alexander JP, Long JZ, Xu C, Möller T, Mackie K, Manzoni OJ, Cravatt BF, Stella N (2010) The serine hydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors. Nat Neurosci 13:651–957CrossRefGoogle Scholar
  40. Mato S, Aso E, Martin M, Valverde O, Maldonado R, Pazos A (2007) CB1 knockout mice display impaired functionality of 5-HT1A and 5-HT2A/C receptors. J Neurochem 103:2111–2120PubMedCrossRefGoogle Scholar
  41. Matsuda LA, Bonner TL, Lolait SJ (1993) Localization of cannabinoid receptor mRNA in rat brain. J Comp Neurol 327:535–550PubMedCrossRefGoogle Scholar
  42. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI (1990) Structure of cannabinoid receptor and functional expression of the cloned cDNA. Nature 346:561–564PubMedCrossRefGoogle Scholar
  43. Mechoulam R, Parker LA (2012) The endocannabinoid system and the brain. Annu Rev Psychol 64:6.1–6.27Google Scholar
  44. Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, Gopher A, Almog BR, Compton DR, Pertwee RG, Griffin G, Bayewitch M, Barg J, Vogel Z (1995) Identification of endogenous 2-monoglyceride, present in canine gut that binds to cannabinoid receptors. Biochem Pharmacol 50:83–90PubMedCrossRefGoogle Scholar
  45. Mendiguren A, Pineda J (2009) Effect of the CB1 receptor antagonists rimonabant and AM251 on the firing rate of dorsal raphe nucleus neurons in rat brain slices. Br J Pharmacol 158:1579–1587PubMedCrossRefGoogle Scholar
  46. Moranta D, Esteban S, Garcia-Sevilla JA (2009) Chronic treatment and withdrawal of the cannabinoid agonist WIN 55,212–2 modulate the sensitivity of presynaptic receptors involved in the regulation of monoamine syntheses in rat brain. Naunyn-Schmiedeberg’s Arch Pharmacol 379:61–72CrossRefGoogle Scholar
  47. Morilak DA, Barrera G, Echevarria DJ, Garcia AS, Hernandez A, Ma S, Petre CO (2005) Role of brain norepinephrine in the behavioral response to stress. Prog Neuropsychopharmacol Biol Psychiatry 29:1214–1224PubMedCrossRefGoogle Scholar
  48. Morsink MC, Steenbergen PJ, Vos JB, Karst H, Joëls M, Kloet ER de, Datson NA (2006) Acute activation of hippocampal glucocorticoid receptors results in different waves of gene. J Neuroendocrinol 18:239–252PubMedCrossRefGoogle Scholar
  49. Muccioli GG (2010) Endocannabinoid biosynthesis and inactivation, from simple to complex. Drug Discov Today 15:474–483PubMedCrossRefGoogle Scholar
  50. Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365:61–65PubMedCrossRefGoogle Scholar
  51. Murillo-Rodriguez E, Vázquez E, Millan-Aldaco D, Palomero-Rivero M, Drucker-Colin R (2007) Effects of the fatty acid amide hydrolase inhibitor URB597 on the sleep-wake cycle, c-Fos expression and dopamine levels in the rats. Eur J Pharmacol 562(1–2):82–91PubMedCrossRefGoogle Scholar
  52. Murillo-Rodriguez E, Millán-Aldaco D, Di Marzo V, Drucker-Colin R (2008) The anandamide membrane transporter inhibitor, VDM-11 modulates sleep and c-Fos expression in the rat brain. Neuroscience 157:1–11PubMedCrossRefGoogle Scholar
  53. Murillo-Rodriguez E, Palomero-Rivero M, Millan-Aldaco D, Aris-Carrion O, Drucker-Colin R (2011) Administration of URB597, oleoylethanolamide or palmitoylethanolamide increases waking and dopamine in rats. PloS One 6:e20766PubMedCrossRefGoogle Scholar
  54. Nakazi M, Bauer U, Nickel T, Kathmann M, Schlicker E (2000) Inhibition of serotonin release in the mouse brain via presynaptic CB receptors. Naunyn-Schmiedeberg’s Arch Pharmacol 361:19–24CrossRefGoogle Scholar
  55. Okamoto Y, Morishita J, Tsuboi K, Tonai T, Useda N (2004) Molecular characterization of phospholipase D generating anandamide and its congeners. J Biol Chem 279:5298–5305PubMedCrossRefGoogle Scholar
  56. O’Leary OF, Bechtholt AJ, Crowley JJ, Valentino RJ, Lucki I (2007) The role of noradrenergic tone in the dorsal raphe nucleus of the mouse in the acute behavioral effects of antidepressant drugs. Eur Neuropsychopharmacol 17:215–226PubMedCrossRefGoogle Scholar
  57. Pan B, Wang W, Long JZ, Sun D, Hillard CJ, Cravatt BF, Liu QS (2009) Blockade of 2-arachidonoylglycerol hydrolysis by selective monoacylglycerol lipase inhibitor 4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxyl)methyl)piperidine-1-carboxylate (JZL 184) enhances retrograde endocannabinoid signaling. J Pharmacol Exp Ther 331:591–597PubMedCrossRefGoogle Scholar
  58. Patel S, Hillard CJ (2006) Pharmacooogical evaluation of cannabinoid receptor ligands in a mouse model of anxiety: further evidence for an anxiolytic role for endogenous cannabinoid signaling. J Pharmacol Exp Ther 318:304–311PubMedCrossRefGoogle Scholar
  59. Patel S, Roelke CT, Rademacher DJ, Cullinan WE, Hillard CJ (2004) Endocannabinoid signaling negatively modulates stress-induced activation of the hypothalamic-pituitary-adrenal axis. Endocrinology 145:5431–5438PubMedCrossRefGoogle Scholar
  60. Patel S, Roelke CT, Rademacher DJ, Hillard CJ (2005) Inhibition of restraint stress-induced neuronal and behavioral activation of endogenous cannabinoid signaling. Eur J Neurosci 21:1057–1069PubMedCrossRefGoogle Scholar
  61. Segawa T, Takeuchi S, Nakano M (1976) Mechanism for the increase of brain 5-hydroxytryptamine and 5-hydroxyindoleacetic acid following ∆9- tetrahydrocannabinol administration to rats. Japan J Pharmacol 26:377–379CrossRefGoogle Scholar
  62. Simon GM, Cravatt BF (2008) Anandamide biosynthesis catalyzed by the phosphodiesterase GDE1 and detection glycerophospho-N-acyl ethanolamine precursors in mousebrain. J Biol Chem 283:9341–9349PubMedCrossRefGoogle Scholar
  63. Stella N, Schweittzer P, Piomelli D (1997) A second endogenous cannabinoid that modulates long-term potentiation. Nature 388:773–778PubMedCrossRefGoogle Scholar
  64. Stone EA, Quartermain D, Lin Y, Lehmann MJ (2007) Central α 1-adrenergic system in behavioral activity and depression. Biochem Pharmacol 73:1063–1075PubMedCrossRefGoogle Scholar
  65. Sugiura T, Kondo S, Sukagawa A, Nakane S, Shinoda A, Itoh K, Yamashita A (1995) Waku K. 2-arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun 215:89–97PubMedCrossRefGoogle Scholar
  66. Sugiura T, Kondo S, Sukagawa A, Tonegawa T, Nakane S, Yamashita A, Waku K (1996) Enzymatic synthesis of anandamide, an endogenous cannabinoid receptor ligand, through N-acylphosphatidylethanolamine pathway in testis: involvement of Ca(2+)-dependent trancyclase and phosphodiesterase activities. Biochem Biophys Res Commun 218:113–117PubMedCrossRefGoogle Scholar
  67. Sun YX, Tsuboi K, Okamoto Y, Tonai T, Murakami M, Kudo I, Ueda N (2004) Biosynthesis of anandamide and N-palmitoylethanolamine by sequential actions of phospholipase A2 and lysophospholipase D. Biochem J 380:749–756PubMedCrossRefGoogle Scholar
  68. Tanimura A, Yamazaki A, Hashimotodani Y, Uchigashima M, Kawata S, Abe M, Kita Y, Hashimoto K, Shimizu T, Watanabe M, Sakimura K, Kano M (2010) The endocannabinoid 2-arachidonoylglycerol produced by diacylglycerol lipase α mediates retrograde suppression of synaptic transmission. Neuron 65:320–327PubMedCrossRefGoogle Scholar
  69. Tao R, Ma Z. (2012) Neuronal circuit in the dorsal raphe nucleus responsible for cannabinoid-mediated increases in 5-Ht efflux in the nucleus accumbens of the rat. ISRN Pharmacol 2012:276902 doi: 10.5402/2012/276902PubMedGoogle Scholar
  70. Tzavara ET, Davis RJ, Perry KW, Li X, Salhoff C, Bymaster FP, Witkin JM, Nomikos GG (2003) The CB1 receptor antagonist SR 141716A selectively increases monoaminergic neurotransmission in the medial prefrontal cortex: implications for therapeutic actions. Br J Pharmacol 138:544–553PubMedCrossRefGoogle Scholar
  71. Van Sickle MD, Duncan M, Kingsley PJ, Mouihate A, Urbani P, Mackie K, Stella N, Makriyannis A, Piomelli D, Davison JS, Mernett LJ, Di Marzo V, Pittman QJ, Patel KD, Sharkey KA (2005) Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science 31:329–332CrossRefGoogle Scholar
  72. Wang J, Shen R-Y, Haj-Dahmane S (2012) Endocannabinoids mediate the glucocorticoid-induced inhibition of excitatory synaptic transmission to dorsal raphe serotonin neurons. J Physiol 590:5795–5808PubMedCrossRefGoogle Scholar
  73. Ward SJ, Lefever TW, Jackson C, Tallarida RJ, Walker EA (2008) Effect of cannabinoid 1 receptor antagonist and serotonin 2C receptor agonist alone and in combination on motivation for palatable food: a dose-addition analysis study in mice.Google Scholar
  74. Williamson EM, Evans FJ (2000) Cannabinoids in clinical practice. Drugs 60:1303–1314PubMedCrossRefGoogle Scholar
  75. Zavitsanou K, Wang H, Dalton VS, Nguyen V (2010) Cannabinoid administration increases 5HT1A receptor binding and mRNA expression in the hippocampus of adult but not adolescent rats. Neuroscience 169:315–324PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Research Institute on AddictionsUniversity at Buffalo, State University of New YorkBuffaloUSA

Personalised recommendations