Advertisement

Endocannabinoid System and Alcohol Abuse Disorders

Chapter
First Online:
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1162)

Abstract

Δ9-tetrahydrocannabinol (Δ9-THC), the primary active component in Cannabis sativa preparations such as hashish and marijuana, signals by binding to cell surface receptors. Two types of receptors have been cloned and characterized as cannabinoid (CB) receptors. CB1 receptors (CB1R) are ubiquitously present in the central nervous system (CNS) and are present in both inhibitory interneurons and excitatory neurons at the presynaptic terminal. CB2 receptors (CB2R) are demonstrated in microglial cells, astrocytes, and several neuron subpopulations and are present in both pre- and postsynaptic terminals. The majority of studies on these receptors have been conducted in the past two and half decades after the identification of the molecular constituents of the endocannabinoid (eCB) system that started with the characterization of CB1R. Subsequently, the seminal discovery was made, which suggested that alcohol (ethanol) alters the eCB system, thus establishing the contribution of the eCB system in the motivation to consume ethanol. Several preclinical studies have provided evidence that CB1R significantly contributes to the motivational and reinforcing properties of ethanol and that the chronic consumption of ethanol alters eCB transmitters and CB1R expression in the brain nuclei associated with addiction pathways. Additionally, recent seminal studies have further established the role of the eCB system in the development of ethanol-induced developmental disorders, such as fetal alcohol spectrum disorders (FASD). These results are augmented by in vitro and ex vivo studies, showing that acute and chronic treatment with ethanol produces physiologically relevant alterations in the function of the eCB system during development and in the adult stage. This chapter provides a current and comprehensive review of the literature concerning the role of the eCB system in alcohol abuse disorders (AUD).

Keywords

Marijuana Cannabinoid receptors FASD Synaptic plasticity Learning and memory CREB 

Abbreviations

Δ9-THC

Δ9-tetrahydrocannabinol

2-AG

2-arachidonylglycerol

5HT3

serotonin type 3

AA

arachidonic acid

ABHD4

abhydrolase domain 4

AC

adenylate cyclase

AEA

arachidonoyl ethanolamine, or anandamide

AMPAR

amino-3-hydroxy-5-methyl--4-isoxazolepropionic acid receptor

Arc

activity-regulated cytoskeleton-associated protein

AUD

alcohol use disorders

BLA

basolateral amygdala

CaMKIV

calcium/calmodulin-dependent protein kinase IV

CB

cannabinoid

CB1R

CB1 receptors

CB2R

CB2 receptors

CBD

cannabidiol (CBD)

CDK5

a cyclin dependent kinase 5

CeA

central nucleus

CHO

chinese hamster ovary

c-JNK

c-Jun N-terminal kinase

CREB

cAMP-response-element binding protein

DAGL

Diacylglycerol lipases

eCB

endocannabinoid

EPSP

excitatory postsynaptic potential

ERK1/2

extracellular signal-regulated kinase 1/2

ERP

evoked related potentials

FAAH

fatty acid amidohydrolase

FAK

focal adhesion kinase

FASD

fetal alcohol spectrum disorders

GABA

γ-aminobutyric acid

GDE1

glycerophosphodiesterase

GPCR

G-protein coupled receptor

IP3

inositol 1,4,5-triphosphate

IPSC

inhibitory postsynaptic currents

KO

knock-out

LTP

long-term potentiation

MAGL

monoacylglycerol lipase

MAPK

mitogen-activated protein kinase

MeCP2

methyl-CpG-binding protein 2

MetAEA

R(+)-methanandamide

MLC

mantle cell lymphoma

msP

marchigian sardinian alcohol-preferring

NAc

nucleus accumbens

NAPE-PLD

N-acylphosphatidylethanolamine-specific phospholipase D

NMDA

N-methyl-D-aspartate

PFC

prefrontal cortex

PKA

protein kinase A

PLC

phospholipase C

PPARs

peroxisome proliferator-activated receptors

PTPN22

phosphatase

Rac1

Ras-related C3 botulinum toxin substrate 1

SNP

single nucleotide polymorphism

TRPV1

transient receptor potential vanilloid 1

VTA

ventral tegmental area

WT

wild type

This is a preview of subscription content, log in to check access.

Notes

Acknowledgments

National Institute of Alcohol and Alcoholism grant (R01 AA019443) to BSB.

References

  1. 1.
    Kabelik J, Krejci Z, Santavy F (1960) Cannabis as a medicant. Bull Narc 12:5–23Google Scholar
  2. 2.
    Basavarajappa BS (2007) Neuropharmacology of the endocannabinoid signaling system-Molecular mechanisms, biological actions and synaptic plasticity. Curr Neuropharmacol 5:81–97PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Jacob A, Todd A (1940) Cannabis indica. Part II. Isolation of cannabidiol from Egyptian hashish. Observations on the structure of cannabinol. J Chem Soc:649–653Google Scholar
  4. 4.
    Adams R, Hunt M, Clark J (1940) Structure of cannabidiol, a product isolated from the marihuana extract of minnesota wild hemp. I. J Am Chem Soc 62:196–200CrossRefGoogle Scholar
  5. 5.
    Gaoni Y, Mechoulam R (1964) Isolation, structure, and partial synthesis of an active constituent of hashish. J Am Chem Soc 86:1646–1647CrossRefGoogle Scholar
  6. 6.
    Hollister LE (1986) Health aspects of cannabis. Pharmacol Rev 38:1–20PubMedGoogle Scholar
  7. 7.
    Dewey WL (1986) Cannabinoid pharmacology. Pharmacol Rev 38:151–178PubMedGoogle Scholar
  8. 8.
    Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346:561–564PubMedCrossRefGoogle Scholar
  9. 9.
    Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365:61–65PubMedCrossRefGoogle Scholar
  10. 10.
    Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G et al (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258:1946–1949PubMedCrossRefGoogle Scholar
  11. 11.
    Sugiura T, Kondo S, Sukagawa A, Nakane S, Shinoda A, Itoh K et al (1995) 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun 215:89–97PubMedCrossRefGoogle Scholar
  12. 12.
    Castillo PE, Younts TJ, Chavez AE, Hashimotodani Y (2012) Endocannabinoid signaling and synaptic function. Neuron 76:70–81PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Katona I, Freund TF (2012) Multiple functions of endocannabinoid signaling in the brain. Annu Rev Neurosci 35:529–558PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Maccarrone M, Bab I, Biro T, Cabral GA, Dey SK, Di Marzo V et al (2015) Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol Sci 36:277–296PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Mechoulam R, Parker LA (2013) The endocannabinoid system and the brain. Annu Rev Psychol 64:21–47PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Di Marzo V, Fontana A, Cadas H, Schinelli S, Cimino G, Schwartz JC et al (1994) Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature 372:686–691PubMedCrossRefGoogle Scholar
  17. 17.
    Cadas H, di Tomaso E, Piomelli D (1997) Occurrence and biosynthesis of endogenous cannabinoid precursor, N-arachidonoyl phosphatidylethanolamine, in rat brain. J Neurosci 17:1226–1242PubMedCrossRefGoogle Scholar
  18. 18.
    Mechoulam R, Fride E, Di Marzo V (1998) Endocannabinoids. Eur J Pharmacol 359:1–18PubMedCrossRefGoogle Scholar
  19. 19.
    Basavarajappa BS, Hungund BL (1999) Chronic ethanol increases the cannabinoid receptor agonist, anandamide and its precursor N-arachidonyl phosphatidyl ethanolamine in SK-N-SH cells. J Neurochem 72:522–528PubMedCrossRefGoogle Scholar
  20. 20.
    Basavarajappa BS, Saito M, Cooper TB, Hungund BL (2000) Stimulation of cannabinoid receptor agonist 2-arachidonylglycerol by chronic ethanol and its modulation by specific neuromodulators in cerebellar granule neurons. Biochemica Biophysica Acta 1535:78–86CrossRefGoogle Scholar
  21. 21.
    Basavarajappa BS, Saito M, Cooper TB, Hungund BL (2003) Chronic ethanol inhibits the anandamide transport and increases extracellular anandamide levels in cerebellar granule neurons. Eur J Pharmacol 466:73–83PubMedCrossRefGoogle Scholar
  22. 22.
    Giuffrida A, Parsons LH, Kerr TM, Rodriguez de Fonseca F, Navarro M, Piomelli D (1999) Dopamine activation of endogenous cannabinoid signaling in dorsal striatum. Nat Neurosci 2:358–363PubMedCrossRefGoogle Scholar
  23. 23.
    Basavarajappa BS, Arancio O (2008) Synaptic plasticity: emerging role for endocannabinoid system. In: Kaiser TF, Peters FJ (eds) Synaptic plasticity: new research. Nova Science Publishers, Inc, New York, pp 77–112Google Scholar
  24. 24.
    Okamoto Y, Morishita J, Tsuboi K, Tonai T, Ueda N (2004) Molecular characterization of a phospholipase D generating anandamide and its congeners. J Biol Chem 279:5298–5305PubMedCrossRefGoogle Scholar
  25. 25.
    Ueda N, Kurahashi Y, Yamamoto S, Tokunaga T (1995) Partial purification and characterization of the porcine brain enzyme hydrolyzing and synthesizing anandamide. J Biol Chem 270:23823–23827PubMedCrossRefGoogle Scholar
  26. 26.
    Simon GM, Cravatt BF (2008) Anandamide biosynthesis catalyzed by the phosphodiesterase GDE1 and detection of glycerophospho-N-acyl ethanolamine precursors in mouse brain. J Biol Chem 283:9341–9349PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Liu J, Wang L, Harvey-White J, Huang BX, Kim HY, Luquet S et al (2008) Multiple pathways involved in the biosynthesis of anandamide. Neuropharmacology 54:1–7PubMedCrossRefGoogle Scholar
  28. 28.
    Liu J, Wang L, Harvey-White J, Osei-Hyiaman D, Razdan R, Gong Q et al (2006) A biosynthetic pathway for anandamide. Proc Natl Acad Sci U S A 103:13345–13350PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Basavarajappa BS (2007) Critical enzymes involved in endocannabinoid metabolism. Protein Pept Lett 14:237–246PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Basavarajappa BS (2015) Fetal alcohol spectrum disorder: potential role of endocannabinoids signaling. Brain Sci 5:456–493PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Basavarajappa BS, Nagre NN, Xie S, Subbanna S (2014) Elevation of endogenous anandamide impairs LTP, learning, and memory through CB1 receptor signaling in mice. Hippocampus 24:808–818PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Basavarajappa BS, Subbanna S (2014) CB1 receptor-mediated signaling underlies the hippocampal synaptic, learning and memory deficits following treatment with JWH-081, a new component of spice/K2 preparations. Hippocampus 24:178–188PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Fernandez-Ruiz J, Berrendero F, Hernandez ML, Ramos JA (2000) The endogenous cannabinoid system and brain development. Trends Neurosci 23:14–20PubMedCrossRefGoogle Scholar
  34. 34.
    Murillo-Rodriguez E, Blanco-Centurion C, Sanchez C, Piomelli D, Shiromani PJ (2003) Anandamide enhances extracellular levels of adenosine and induces sleep: an in vivo microdialysis study. Sleep 26:943–947PubMedCrossRefGoogle Scholar
  35. 35.
    Murillo-Rodriguez E, Sanchez-Alavez M, Navarro L, Martinez-Gonzalez D, Drucker-Colin R, Prospero-Garcia O (1998) Anandamide modulates sleep and memory in rats. Brain Res 812:270–274PubMedCrossRefGoogle Scholar
  36. 36.
    Pacher P, Kunos G (2013) Modulating the endocannabinoid system in human health and disease – successes and failures. FEBS J 280:1918–1943PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Pertwee RG (2001) Cannabinoid receptors and pain. Prog Neurobiol 63:569–611PubMedCrossRefGoogle Scholar
  38. 38.
    Ramesh D, Ross GR, Schlosburg JE, Owens RA, Abdullah RA, Kinsey SG et al (2011) Blockade of endocannabinoid hydrolytic enzymes attenuates precipitated opioid withdrawal symptoms in mice. J Pharmacol Exp Ther 339:173–185PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Pertwee RG, Howlett AC, Abood ME, Alexander SP, Di Marzo V, Elphick MR et al (2010) International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB(1) and CB(2). Pharmacol Rev 62:588–631PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    O’Sullivan SE (2007) Cannabinoids go nuclear: evidence for activation of peroxisome proliferator-activated receptors. Br J Pharmacol 152:576–582PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Zygmunt PM, Petersson J, Andersson DA, Chuang H, Sorgard M, Di Marzo V et al (1999) Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400:452–457PubMedCrossRefGoogle Scholar
  42. 42.
    Basavarajappa BS, Shivakumar M, Joshi V, Subbanna S (2017) Endocannabinoid system in neurodegenerative disorders. J Neurochem 142:624–648PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Mackie K (2006) Mechanisms of CB1 receptor signaling: endocannabinoid modulation of synaptic strength. Int J Obes 30(Suppl 1):S19–S23CrossRefGoogle Scholar
  44. 44.
    Kano M, Ohno-Shosaku T, Hashimotodani Y, Uchigashima M, Watanabe M (2009) Endocannabinoid-mediated control of synaptic transmission. Physiol Rev 89:309–380PubMedCrossRefGoogle Scholar
  45. 45.
    Mackie K (2008) Cannabinoid receptors: where they are and what they do. J Neuroendocrinol 20(Suppl 1):10–14PubMedCrossRefGoogle Scholar
  46. 46.
    Herkenham M, Lynn AB, Johnson MR, Melvin LS, de Cost BR, Rice KC (1991) Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J Neurosci 16:8057–8066Google Scholar
  47. 47.
    Onaivi ES, Ishiguro H, Gong JP, Patel S, Perchuk A, Meozzi PA et al (2006) Discovery of the presence and functional expression of cannabinoid CB2 receptors in brain. Ann N Y Acad Sci 1074:514–536PubMedCrossRefGoogle Scholar
  48. 48.
    Van Sickle MD, Duncan M, Kingsley PJ, Mouihate A, Urbani P, Mackie K et al (2005) Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science 310:329–332PubMedCrossRefGoogle Scholar
  49. 49.
    Ramirez SH, Hasko J, Skuba A, Fan S, Dykstra H, McCormick R et al (2012) Activation of cannabinoid receptor 2 attenuates leukocyte-endothelial cell interactions and blood-brain barrier dysfunction under inflammatory conditions. J Neurosci 32:4004–4016PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Li Y, Kim J (2015) Deletion of CB2 cannabinoid receptors reduces synaptic transmission and long-term potentiation in the mouse hippocampus. Hippocampus 26(3):275–281CrossRefGoogle Scholar
  51. 51.
    Li Y, Kim J (2015) Neuronal expression of CB2 cannabinoid receptor mRNAs in the mouse hippocampus. Neuroscience 311:253–267PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Li Y, Kim J (2016) CB2 cannabinoid receptor knockout in mice impairs contextual long-term memory and enhances spatial working memory. Neural Plast 2016:1–14Google Scholar
  53. 53.
    Onaivi ES, Ishiguro H, Gong JP, Patel S, Meozzi PA, Myers L et al (2008) Brain neuronal CB2 cannabinoid receptors in drug abuse and depression: from mice to human subjects. PLoS One 3:e1640PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Zhang HY, Gao M, Liu QR, Bi GH, Li X, Yang HJ et al (2014) Cannabinoid CB2 receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice. Proc Natl Acad Sci U S A 111:E5007–E5015PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Zhang HY, Gao M, Shen H, Bi GH, Yang HJ, Liu QR et al (2016) Expression of functional cannabinoid CB receptor in VTA dopamine neurons in rats. Addict Biol 22(3):752–765PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Li Y, Kim J (2016) Deletion of CB2 cannabinoid receptors reduces synaptic transmission and long-term potentiation in the mouse hippocampus. Hippocampus 26:275–281PubMedCrossRefGoogle Scholar
  57. 57.
    Stempel AV, Stumpf A, Zhang HY, Ozdogan T, Pannasch U, Theis AK et al (2016) Cannabinoid type 2 receptors mediate a cell type-specific plasticity in the hippocampus. Neuron 90:795–809PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Viscomi MT, Oddi S, Latini L, Pasquariello N, Florenzano F, Bernardi G et al (2009) Selective CB2 receptor agonism protects central neurons from remote axotomy-induced apoptosis through the PI3K/Akt pathway. J Neurosci 29:4564–4570PubMedCrossRefGoogle Scholar
  59. 59.
    Breivogel CS, Sim LJ, Childers SR (1997) Regional differences in cannabinoid receptor/G-protein coupling in rat brain. J Pharmacol Exp Ther 282:1632–1642PubMedGoogle Scholar
  60. 60.
    Kearn CS, Greenberg MJ, DiCamelli R, Kurzawa K, Hillard CJ (1999) Relationships between ligand affinities for the cerebellar cannabinoid receptor CB1 and the induction of GDP/GTP exchange. J Neurochem 72:2379–2387PubMedCrossRefGoogle Scholar
  61. 61.
    Mukhopadhyay S, McIntosh HH, Houston DB, Howlett AC (2000) The CB(1) cannabinoid receptor juxtamembrane C-terminal peptide confers activation to specific G proteins in brain. Mol Pharmacol 57:162–170PubMedGoogle Scholar
  62. 62.
    Childers SR, Sexton T, Roy MB (1994) Effects of anandamide on cannabinoid receptors in rat brain membranes. Biochem Pharmacol 47:711–715PubMedCrossRefGoogle Scholar
  63. 63.
    Pinto JC, Potie F, Rice KC, Boring D, Johnson MR, Evans DM et al (1994) Cannabinoid receptor binding and agonist activity of amides and esters of arachidonic acid. Mol Pharmacol 46:516–522PubMedGoogle Scholar
  64. 64.
    Howlett AC, Mukhopadhyay S (2000) Cellular signal transduction by anandamide and 2-arachidonoylglycerol. Chem Phys Lipids 108:53–70PubMedCrossRefGoogle Scholar
  65. 65.
    Glass M, Felder CC (1997) Concurrent stimulation of cannabinoid CB1 and dopamine D2 receptors augments cAMP accumulation in striatal neurons: evidence for a Gs linkage to the CB1 receptor. J Neurosci 17:5327–5333PubMedCrossRefGoogle Scholar
  66. 66.
    Rhee MH, Bayewitch M, Avidor-Reiss T, Levy R, Vogel Z (1998) Cannabinoid receptor activation differentially regulates the various adenylyl cyclase isozymes. J Neurochem 71:1525–1534PubMedCrossRefGoogle Scholar
  67. 67.
    Digby GJ, Sethi PR, Lambert NA (2008) Differential dissociation of G protein heterotrimers. J Physiol 586:3325–3335PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Lambert NA (2008) Dissociation of heterotrimeric g proteins in cells. Sci Signal 1:re5PubMedCrossRefGoogle Scholar
  69. 69.
    Caulfield MP, Brown DA (1992) Cannabinoid receptor agonists inhibit Ca current in NG108-15 neuroblastoma cells via a pertussis toxin-sensitive mechanism. Br J Pharmacol 106:231–232PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Mackie K, Hille B (1992) Cannabinoids inhibit N-type calcium channels in neuroblastoma-glioma cells. Proc Natl Acad Sci U S A 89:3825–3829PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Nogueron MI, Porgilsson B, Schneider WE, Stucky CL, Hillard CJ (2001) Cannabinoid receptor agonists inhibit depolarization-induced calcium influx in cerebellar granule neurons. J Neurochem 79:371–381PubMedCrossRefGoogle Scholar
  72. 72.
    Pan X, Ikeda SR, Lewis DL (1996) Rat brain cannabinoid receptor modulates N-type Ca2+ channels in a neuronal expression system. Mol Pharmacol 49:707–714PubMedGoogle Scholar
  73. 73.
    Gebremedhin D, Lange AR, Campbell WB, Hillard CJ, Harder DR (1999) Cannabinoid CB1 receptor of cat cerebral arterial muscle functions to inhibit L-type Ca2+ channel current. Am J Phys 276:H2085–H2093Google Scholar
  74. 74.
    Mu J, Zhuang SY, Kirby MT, Hampson RE, Deadwyler SA (1999) Cannabinoid receptors differentially modulate potassium A and D currents in hippocampal neurons in culture. J Pharmacol Exp Ther 291:893–902PubMedGoogle Scholar
  75. 75.
    Childers SR, Deadwyler SA (1996) Role of cyclic AMP in the actions of cannabinoid receptors. Biochem Pharmacol 52:819–827PubMedCrossRefGoogle Scholar
  76. 76.
    Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA et al (2002) International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev 54:161–202PubMedCrossRefGoogle Scholar
  77. 77.
    Schweitzer P (2000) Cannabinoids decrease the K(+) M-current in hippocampal CA1 neurons. J Neurosci 20:51–58PubMedCrossRefGoogle Scholar
  78. 78.
    Pertwee RG (1997) Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther 74:129–180PubMedGoogle Scholar
  79. 79.
    Calandra B, Portier M, Kerneis A, Delpech M, Carillon C, Le Fur G et al (1999) Dual intracellular signaling pathways mediated by the human cannabinoid CB1 receptor. Eur J Pharmacol 374:445–455PubMedCrossRefGoogle Scholar
  80. 80.
    Hampson RE, Deadwyler SA (2000) Cannabinoids reveal the necessity of hippocampal neural encoding for short-term memory in rats. J Neurosci 20:8932–8942PubMedCrossRefGoogle Scholar
  81. 81.
    Ho BY, Uezono Y, Takada S, Takase I, Izumi F (1999) Coupling of the expressed cannabinoid CB1 and CB2 receptors to phospholipase C and G protein-coupled inwardly rectifying K+ channels. Recept Channels 6:363–374PubMedGoogle Scholar
  82. 82.
    Netzeband JG, Conroy SM, Parsons KL, Gruol DL (1999) Cannabinoids enhance NMDA-elicited Ca2+ signals in cerebellar granule neurons in culture. J Neurosci 19:8765–8777PubMedCrossRefGoogle Scholar
  83. 83.
    Sugiura T, Kodaka T, Kondo S, Tonegawa T, Nakane S, Kishimoto S et al (1996) 2-Arachidonoylglycerol, a putative endogenous cannabinoid receptor ligand, induces rapid, transient elevation of intracellular free Ca2+ in neuroblastoma x glioma hybrid NG108-15 cells. Biochem Biophys Res Commun 229:58–64PubMedCrossRefGoogle Scholar
  84. 84.
    Sugiura T, Kodaka T, Kondo S, Nakane S, Kondo H, Waku K et al (1997) Is the cannabinoid CB1 receptor a 2-arachidonoylglycerol receptor? Structural requirements for triggering a Ca2+ transient in NG108-15 cells. J Biochem (Tokyo) 122:890–895CrossRefGoogle Scholar
  85. 85.
    Sugiura T, Kodaka T, Nakane S, Miyashita T, Kondo S, Suhara Y et al (1999) Evidence that the cannabinoid CB1 receptor is a 2-arachidonylglycerol receptor. J Biol Chem 274:2794–2801PubMedCrossRefGoogle Scholar
  86. 86.
    Wartmann M, Campbell D, Subramanian A, Burstein SH, Davis RJ (1995) The MAP kinase signal transduction pathway is activated by the endogenous cannabinoid anandamide. FEBS Lett 2-3:133–136CrossRefGoogle Scholar
  87. 87.
    Bouaboula M, Poinot-Chazel C, Bourrie B, Canat X, Calandra B, Rinaldi-Carmona M et al (1995) Activation of mitogen-activated protein kinases by stimulation of the central cannabinoid receptor CB1. Biochem J 312:637–641PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Sanchez C, Galve-Roperh I, Rueda D, Guzman M (1998) Involvement of sphingomyelin hydrolysis and the mitogen-activated protein kinase cascade in the Delta9-tetrahydrocannabinol-induced stimulation of glucose metabolism in primary astrocytes. Mol Pharmacol 54:834–843PubMedCrossRefGoogle Scholar
  89. 89.
    Guzman M, Sanchez C (1999) Effects of cannabinoids on energy metabolism. Life Sci 65:657–664PubMedCrossRefGoogle Scholar
  90. 90.
    Derkinderen P, Toutant M, Burgaya F, Le Bert M, Siciliano JC, de Franciscis V et al (1996) Regulation of a neuronal form of focal adhesion kinase by anandamide. Science 273:1719–1722PubMedCrossRefGoogle Scholar
  91. 91.
    Derkinderen P, Toutant M, Kadare G, Ledent C, Parmentier M, Girault JA (2001) Dual role of Fyn in the regulation of FAK+6,7 by cannabinoids in hippocampus. J Biol Chem 276:38289–38296PubMedGoogle Scholar
  92. 92.
    Rueda D, Galve-Roperh I, Haro A, Guzman M (2000) The CB(1) cannabinoid receptor is coupled to the activation of c-Jun N-terminal kinase. Mol Pharmacol 58:814–820PubMedCrossRefGoogle Scholar
  93. 93.
    Liu J, Gao B, Mirshahi F, Sanyal AJ, Khanolkar AD, Makriyannis A et al (2000) Functional CB1 cannabinoid receptors in human vascular endothelial cells. Biochem J 346(Pt 3):835–840PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Bouaboula M, Bianchini L, McKenzie FR, Pouyssegur J, Casellas P (1999) Cannabinoid receptor CB1 activates the Na+/H+ exchanger NHE-1 isoform via Gi-mediated mitogen activated protein kinase signaling transduction pathways. FEBS Lett 449:61–65PubMedCrossRefGoogle Scholar
  95. 95.
    Bouaboula M, Bourrie B, Rinaldi-Carmona M, Shire D, Le Fur G, Casellas P (1995) Stimulation of cannabinoid receptor CB1 induces krox-24 expression in human astrocytoma cells. J Biol Chem 270:13973–13980PubMedCrossRefGoogle Scholar
  96. 96.
    Derkinderen P, Valjent E, Toutant M, Corvol JC, Enslen H, Ledent C et al (2003) Regulation of extracellular signal-regulated kinase by cannabinoids in hippocampus. J Neurosci 23:2371–2382PubMedCrossRefGoogle Scholar
  97. 97.
    Graham ES, Ball N, Scotter EL, Narayan P, Dragunow M, Glass M (2006) Induction of Krox-24 by endogenous cannabinoid type 1 receptors in Neuro2A cells is mediated by the MEK-ERK MAPK pathway and is suppressed by the phosphatidylinositol 3-kinase pathway. J Biol Chem 281:29085–29095PubMedCrossRefGoogle Scholar
  98. 98.
    Ben-Shabat S, Fride E, Sheskin T, Tamiri T, Rhee MH, Vogel Z et al (1998) An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. Eur J Pharmacol 353:23–31PubMedCrossRefGoogle Scholar
  99. 99.
    McGregor IS, Arnold JC, Weber MF, Topple AN, Hunt GE (1998) A comparison of delta 9-THC and anandamide induced c-fos expression in the rat forebrain. Brain Res 802:19–26PubMedCrossRefGoogle Scholar
  100. 100.
    Arnold JC, Topple AN, Mallet PE, Hunt GE, McGregor IS (2001) The distribution of cannabinoid-induced Fos expression in rat brain: differences between the Lewis and Wistar strain. Brain Res 921:240–255PubMedCrossRefGoogle Scholar
  101. 101.
    Mailleux P, Verslype M, Preud’homme X, Vanderhaeghen JJ (1994) Activation of multiple transcription factor genes by tetrahydrocannabinol in rat forebrain. Neuroreport 5:1265–1268PubMedCrossRefGoogle Scholar
  102. 102.
    Valjent E, Caboche J, Vanhoutte P (2001) Mitogen-activated protein kinase/extracellular signal-regulated kinase induced gene regulation in brain: a molecular substrate for learning and memory? Mol Neurobiol 23:83–99PubMedCrossRefGoogle Scholar
  103. 103.
    Patel NA, Moldow RL, Patel JA, Wu G, Chang SL (1998) Arachidonylethanolamide (AEA) activation of FOS proto-oncogene protein immunoreactivity in the rat brain. Brain Res 797:225–233PubMedCrossRefGoogle Scholar
  104. 104.
    Gomez del Pulgar T, Velasco G, Guzman M (2000) The CB1 cannabinoid receptor is coupled to the activation of protein kinase B/Akt. Biochem J 347:369–373PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Subbanna S, Nagaraja NN, Umapathy NS, Pace BS, Basavarajappa BS (2015) Ethanol exposure induces neonatal neurodegeneration by enhancing CB1R Exon1 histone H4K8 acetylation and up-regulating CB1R function causing neurobehavioral abnormalities in adult mice. Int J Neuropsychopharmacol 18(5):pyu028PubMedCentralCrossRefPubMedGoogle Scholar
  106. 106.
    Auclair N, Otani S, Soubrie P, Crepel F (2000) Cannabinoids modulate synaptic strength and plasticity at glutamatergic synapses of rat prefrontal cortex pyramidal neurons. J Neurophysiol 83:3287–3293PubMedCrossRefGoogle Scholar
  107. 107.
    Bohme GA, Laville M, Ledent C, Parmentier M, Imperato A (2000) Enhanced long-term potentiation in mice lacking cannabinoid CB1 receptors. Neuroscience 95:5–7PubMedCrossRefGoogle Scholar
  108. 108.
    Hoffman AF, Oz M, Yang R, Lichtman AH, Lupica CR (2007) Opposing actions of chronic {Delta}9-tetrahydrocannabinol and cannabinoid antagonists on hippocampal long-term potentiation. Learn Mem 14:63–74PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Monory K, Massa F, Egertova M, Eder M, Blaudzun H, Westenbroek R et al (2006) The endocannabinoid system controls key epileptogenic circuits in the hippocampus. Neuron 51:455–466PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Reibaud M, Obinu MC, Ledent C, Parmentier M, Bohme GA, Imperato A (1999) Enhancement of memory in cannabinoid CB1 receptor knock-out mice. Eur J Pharmacol 379:R1–R2PubMedCrossRefGoogle Scholar
  111. 111.
    Subbanna S, Shivakumar M, Psychoyos D, Xie S, Basavarajappa BS (2013) Anandamide-CB1 receptor signaling contributes to postnatal ethanol-induced neonatal neurodegeneration, adult synaptic and memory deficits. J Neuosci 33:6350–6366CrossRefGoogle Scholar
  112. 112.
    Terranova JP, Storme JJ, Lafon N, Perio A, Rinaldi-Carmona M, Le Fur G et al (1996) Improvement of memory in rodents by the selective CB1 cannabinoid receptor antagonist, SR 141716. Psychopharmacology 126:165–172PubMedCrossRefGoogle Scholar
  113. 113.
    Varvel SA, Lichtman AH (2002) Evaluation of CB1 receptor knockout mice in the Morris water maze. J Pharmacol Exp Ther 301:915–924PubMedCrossRefGoogle Scholar
  114. 114.
    Guzman M, Galve-Roperh I, Sanchez C (2001) Ceramide: a new second messenger of cannabinoid action. Trends Pharmacol Sci 22:19–22PubMedCrossRefGoogle Scholar
  115. 115.
    Gustafsson K, Christensson B, Sander B, Flygare J (2006) Cannabinoid receptor-mediated apoptosis induced by R(+)-methanandamide and Win55,212-2 is associated with ceramide accumulation and p38 activation in mantle cell lymphoma. Mol Pharmacol 70:1612–1620PubMedCrossRefGoogle Scholar
  116. 116.
    Sanchez C, Rueda D, Segui B, Galve-Roperh I, Levade T, Guzman M (2001) The CB(1) cannabinoid receptor of astrocytes is coupled to sphingomyelin hydrolysis through the adaptor protein fan. Mol Pharmacol 59:955–959PubMedCrossRefGoogle Scholar
  117. 117.
    Jones RT, Stone GC (1970) Psychological studies of marijuana and alcohol in man. Psychopharmacologia 18:108–117PubMedCrossRefGoogle Scholar
  118. 118.
    Friedman E, Gershon S (1974) Effect of delta8-THC on alcohol-induced sleeping time in the rat. Psychopharmacologia 39:193–198PubMedCrossRefGoogle Scholar
  119. 119.
    Phillips RN, Brown DJ, Forney RB (1971) Enhancement of depressant properties of alcohol or barbiturate in combination with aqueous suspended delta 9-tetrahydrocannabinol in rats. J Forensic Sci 16:152–161PubMedGoogle Scholar
  120. 120.
    Manno JE, Kiplinger GF, Scholz N, Forney RB (1971) The influence of alcohol and marihuana on motor and mental performance. Clin Pharmacol Ther 12:202–211PubMedCrossRefGoogle Scholar
  121. 121.
    Macavoy MG, Marks DF (1975) Divided attention performance of cannabis users and non-users following cannabis and alcohol. Psychopharmacologia 44:147–152PubMedCrossRefGoogle Scholar
  122. 122.
    Marks DF, MacAvoy MG (1989) Divided attention performance in cannabis users and non-users following alcohol and cannabis separately and in combination. Psychopharmacology (Berl) 99:397–401CrossRefGoogle Scholar
  123. 123.
    Fehr KA, Kalant H, LeBlanc AE (1976) Residual learning deficit after heavy exposure to cannabis or alcohol in rats. Science 192:1249–1251PubMedCrossRefGoogle Scholar
  124. 124.
    da Silva GE, Morato GS, Takahashi RN (2001) Rapid tolerance to Delta(9)-tetrahydrocannabinol and cross-tolerance between ethanol and Delta(9)-tetrahydrocannabinol in mice. Eur J Pharmacol 431:201–207PubMedCrossRefGoogle Scholar
  125. 125.
    Lemos JI, Takahashi RN, Morato GS (2007) Effects of SR141716 and WIN 55,212-2 on tolerance to ethanol in rats using the acute and rapid procedures. Psychopharmacology (Berl) 194:139–149CrossRefGoogle Scholar
  126. 126.
    Pava MJ, Blake EM, Green ST, Mizroch BJ, Mulholland PJ, Woodward JJ (2012) Tolerance to cannabinoid-induced behaviors in mice treated chronically with ethanol. Psychopharmacology (Berl) 219:137–147CrossRefGoogle Scholar
  127. 127.
    Basavarajappa BS, Cooper TB, Hungund BL (1998) Effect of chronic ethanol exposure on mouse brain arachidonic acid specific phospholipase A2. Biochem Pharmacol 55:515–521PubMedCrossRefGoogle Scholar
  128. 128.
    Basavarajappa BS, Saito M, Cooper TB, Hungund BL (1997) Activation of arachidonic acid-specific phospholipase A2 in human neuroblastoma cells after chronic alcohol exposure: prevention by GM1 ganglioside. Alcohol Clin Exp Res 21:1199–1203PubMedGoogle Scholar
  129. 129.
    Basavarajappa BS, Cooper TB, Hungund BL (1998) Chronic ethanol administration down-regulates cannabinoid receptors in mouse brain synaptic plasma membrane. Brain Res 793:212–218PubMedCrossRefGoogle Scholar
  130. 130.
    Basavarajappa BS, Hungund BL (1999) Down-regulation of cannabinoid receptor agonist-stimulated [35S] GTPgS binding in synaptic plasma membrane from chronic ethanol exposed mouse. Brain Res 815:89–97PubMedCrossRefGoogle Scholar
  131. 131.
    Gallate JE, Saharov T, Mallet PE, McGregor IS (1999) Increased motivation for beer in rats following administration of a cannabinoid CB1 receptor agonist. Eur J Pharmacol 370:233–240PubMedCrossRefGoogle Scholar
  132. 132.
    Arnone M, Maruani J, Chaperon F, Thiebot M, Poncelet M, Soubrie P et al (1997) Selective inhibition of sucrose and ethanol intake by SR 141716, an antagonist of central cannabinoid (CB1) receptors. Psychopharmacology 132:104–106PubMedCrossRefGoogle Scholar
  133. 133.
    Colombo G, Agabio R, Fa M, Guano L, Lobina C, Loche A et al (1998) Reduction of voluntary ethanol intake in ethanol-preferring sP rats by the cannabinoid antagonist SR-141716. Alcohol Alcohol 33:126–130PubMedCrossRefGoogle Scholar
  134. 134.
    Gallate JE, McGregor IS (1999) The motivation for beer in rats: effects of ritanserin, naloxone and SR 141716. Psychopharmacology 142:302–308PubMedCrossRefGoogle Scholar
  135. 135.
    Rodriguez de Fonseca F, Roberts AJ, Bilbao A, Koob GF, Navarro M (1999) Cannabinoid receptor antagonist SR141716A decreases operant ethanol self administration in rats exposed to ethanol-vapor chambers. Acta Pharmacol Sin 20:1109–1114Google Scholar
  136. 136.
    Davidson M, Wilce P, Shanley B (1988) Ethanol increases synaptosomal free calcium concentration. Neurosci Lett 89:165–169PubMedCrossRefGoogle Scholar
  137. 137.
    Mironov SL, Hermann A (1996) Ethanol actions on the mechanisms of Ca2+ mobilization in rat hippocampal cells are mediated by protein kinase C. Brain Res 714:27–37PubMedCrossRefGoogle Scholar
  138. 138.
    Basavarajappa BS, Ninan I, Arancio O (2008) Acute ethanol suppresses glutamatergic neurotransmission through endocannabinoids in hippocampal neurons. J Neurochem 107:1001–1013PubMedPubMedCentralGoogle Scholar
  139. 139.
    Perra S, Pillolla G, Luchicchi A, Pistis M (2008) Alcohol inhibits spontaneous activity of basolateral amygdala projection neurons in the rat: involvement of the endocannabinoid system. Alcohol Clin Exp Res 32:443–449PubMedCrossRefGoogle Scholar
  140. 140.
    Perra S, Pillolla G, Melis M, Muntoni AL, Gessa GL, Pistis M (2005) Involvement of the endogenous cannabinoid system in the effects of alcohol in the mesolimbic reward circuit: electrophysiological evidence in vivo. Psychopharmacology (Berl) 183:368–377CrossRefGoogle Scholar
  141. 141.
    Ferrer B, Bermudez-Silva FJ, Bilbao A, Alvarez-Jaimes L, Sanchez-Vera I, Giuffrida A et al (2007) Regulation of brain anandamide by acute administration of ethanol. Biochem J 404:97–104PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Rubio M, McHugh D, Fernandez-Ruiz J, Bradshaw H, Walker JM (2007) Short-term exposure to alcohol in rats affects brain levels of anandamide, other N-acylethanolamines and 2-arachidonoyl-glycerol. Neurosci Lett 421:270–274PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Rubio M, de Miguel R, Fernandez-Ruiz J, Gutierrez-Lopez D, Carai MA, Ramos JA (2009) Effects of a short-term exposure to alcohol in rats on FAAH enzyme and CB1 receptor in different brain areas. Drug Alcohol Depend 99:354–358PubMedCrossRefGoogle Scholar
  144. 144.
    Clarke RB, Adermark L (2010) Acute ethanol treatment prevents endocannabinoid-mediated long-lasting disinhibition of striatal output. Neuropharmacology 58:799–805PubMedCrossRefGoogle Scholar
  145. 145.
    Roberto M, Cruz M, Bajo M, Siggins GR, Parsons LH, Schweitzer P (2010) The endocannabinoid system tonically regulates inhibitory transmission and depresses the effect of ethanol in central amygdala. Neuropsychopharmacology 35:1962–1972PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Kelm MK, Criswell HE, Breese GR (2007) Calcium release from presynaptic internal stores is required for ethanol to increase spontaneous gamma-aminobutyric acid release onto cerebellum Purkinje neurons. J Pharmacol Exp Ther 323:356–364PubMedCrossRefGoogle Scholar
  147. 147.
    Kelm MK, Criswell HE, Breese GR (2008) The role of protein kinase A in the ethanol-induced increase in spontaneous GABA release onto cerebellar Purkinje neurons. J Neurophysiol 100:3417–3428PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Basavarajappa BS, Yalamanchili R, Cravatt BF, Cooper TB, Hungund BL (2006) Increased ethanol consumption and preference and decreased ethanol sensitivity in female FAAH knockout mice. Neuropharmacology 50:834–844PubMedCrossRefGoogle Scholar
  149. 149.
    Patel S, Wohlfeil ER, Rademacher DJ, Carrier EJ, Perry LJ, Kundu A et al (2003) The general anesthetic propofol increases brain N-arachidonylethanolamine (anandamide) content and inhibits fatty acid amide hydrolase. Br J Pharmacol 139:1005–1013PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Fattore L, Melis M, Fadda P, Pistis M, Fratta W (2010) The endocannabinoid system and nondrug rewarding behaviours. Exp Neurol 224:23–36PubMedCrossRefGoogle Scholar
  151. 151.
    Serrano A, Parsons LH (2011) Endocannabinoid influence in drug reinforcement, dependence and addiction-related behaviors. Pharmacol Ther 132:215–241PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Solinas M, Yasar S, Goldberg SR (2007) Endocannabinoid system involvement in brain reward processes related to drug abuse. Pharmacol Res 56:393–405PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Gardner EL (2005) Endocannabinoid signaling system and brain reward: emphasis on dopamine. Pharmacol Biochem Behav 81:263–284PubMedCrossRefGoogle Scholar
  154. 154.
    Melis M, Sagheddu C, De Felice M, Casti A, Madeddu C, Spiga S et al (2014) Enhanced endocannabinoid-mediated modulation of rostromedial tegmental nucleus drive onto dopamine neurons in Sardinian alcohol-preferring rats. J Neurosci 34:12716–12724PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Morikawa H, Morrisett RA (2010) Ethanol action on dopaminergic neurons in the ventral tegmental area: interaction with intrinsic ion channels and neurotransmitter inputs. Int Rev Neurobiol 91:235–288PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Cheer JF, Wassum KM, Sombers LA, Heien ML, Ariansen JL, Aragona BJ et al (2007) Phasic dopamine release evoked by abused substances requires cannabinoid receptor activation. J Neurosci 27:791–795PubMedCrossRefGoogle Scholar
  157. 157.
    Hungund BL, Szakall I, Adam A, Basavarajappa BS, Vadasz C (2003) Cannabinoid CB1 receptor knockout mice exhibit markedly reduced voluntary alcohol consumption and lack alcohol-induced dopamine release in the nucleus accumbens. J Neurochem 84:698–704PubMedCrossRefGoogle Scholar
  158. 158.
    Houchi H, Babovic D, Pierrefiche O, Ledent C, Daoust M, Naassila M (2005) CB1 receptor knockout mice display reduced ethanol-induced conditioned place preference and increased striatal dopamine D2 receptors. Neuropsychopharmacology 30:339–349PubMedCrossRefGoogle Scholar
  159. 159.
    Hutchison KE, Haughey H, Niculescu M, Schacht J, Kaiser A, Stitzel J et al (2008) The incentive salience of alcohol: translating the effects of genetic variant in CNR1. Arch Gen Psychiatry 65:841–850PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Hungund BL, Basavarajappa BS (2000) Distinct differences in the cannabinoid receptor binding in the brain of C57BL/6 and DBA/2 mice, selected for their differences in voluntary ethanol consumption. J Neurosci Res 60:122–128PubMedCrossRefGoogle Scholar
  161. 161.
    Basavarajappa BS, Hungund BL (2001) Cannabinoid receptor agonist-stimulated [35S]Guanosine TriphosphategS binding in the brain of C57BL/6 and DBA/2 mice. J Neurosci Res 64:429–436PubMedCrossRefGoogle Scholar
  162. 162.
    Blednov YA, Cravatt BF, Boehm SL II, Walker D, Harris RA (2007) Role of endocannabinoids in alcohol consumption and intoxication: studies of mice lacking fatty acid amide hydrolase. Neuropsychopharmacology 32(7):1570–1582PubMedCrossRefGoogle Scholar
  163. 163.
    Hansson AC, Bermudez-Silva FJ, Malinen H, Hyytia P, Sanchez-Vera I, Rimondini R et al (2007) Genetic impairment of frontocortical endocannabinoid degradation and high alcohol preference. Neuropsychopharmacology 32:117–126PubMedCrossRefGoogle Scholar
  164. 164.
    D’Souza DC, Cortes-Briones JA, Ranganathan M, Thurnauer H, Creatura G, Surti T et al (2016) Rapid changes in CB1 receptor availability in cannabis dependent males after abstinence from cannabis. Biol Psychiatry Cognit Neurosci Neuroimaging 1:60–67CrossRefGoogle Scholar
  165. 165.
    D’Souza DC, Cortes-Briones JA, Ranganathan M, Thurnauer H, Creatura G, Surti T et al (2016) Rapid changes in cannabinoid 1 receptor availability in cannabis-dependent male subjects after abstinence from cannabis. Biol Psychiatry Cognit Neurosci Neuroimaging 1:60–67CrossRefGoogle Scholar
  166. 166.
    Delgado-Peraza F, Ahn KH, Nogueras-Ortiz C, Mungrue IN, Mackie K, Kendall DA et al (2016) Mechanisms of biased beta-arrestin-mediated signaling downstream from the cannabinoid 1 receptor. Mol Pharmacol 89:618–629PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Nguyen PT, Schmid CL, Raehal KM, Selley DE, Bohn LM, Sim-Selley LJ (2012) beta-arrestin2 regulates cannabinoid CB1 receptor signaling and adaptation in a central nervous system region-dependent manner. Biol Psychiatry 71:714–724PubMedPubMedCentralCrossRefGoogle Scholar
  168. 168.
    Caille S, Alvarez-Jaimes L, Polis I, Stouffer DG, Parsons LH (2007) Specific alterations of extracellular endocannabinoid levels in the nucleus accumbens by ethanol, heroin, and cocaine self-administration. J Neurosci 27:3695–3702PubMedCrossRefGoogle Scholar
  169. 169.
    Gutierrez-Lopez MD, Llopis N, Feng S, Barrett DA, O’Shea E, Colado MI (2010) Involvement of 2-arachidonoyl glycerol in the increased consumption of and preference for ethanol of mice treated with neurotoxic doses of methamphetamine. Br J Pharmacol 160:772–783PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    Economidou D, Mattioli L, Cifani C, Perfumi M, Massi M, Cuomo V et al (2006) Effect of the cannabinoid CB1 receptor antagonist SR-141716A on ethanol self-administration and ethanol-seeking behaviour in rats. Psychopharmacology 183:394–403PubMedCrossRefGoogle Scholar
  171. 171.
    Freedland CS, Sharpe AL, Samson HH, Porrino LJ (2001) Effects of SR141716A on ethanol and sucrose self-administration. Alcohol Clin Exp Res 25:277–282PubMedCrossRefGoogle Scholar
  172. 172.
    Cippitelli A, Bilbao A, Hansson AC, del Arco I, Sommer W, Heilig M et al (2005) Cannabinoid CB1 receptor antagonism reduces conditioned reinstatement of ethanol-seeking behavior in rats. Eur J Neurosci 21:2243–2251PubMedCrossRefGoogle Scholar
  173. 173.
    Wang L, Liu J, Harvey-white J, Zimmer A, Kunos G (2003) Endocannabinoid signaling via CB1 receptors is involved in ethanol preference and its age-dependent decline in mice. Proc Natl Acad Sci U S A 100:1393–1398PubMedPubMedCentralCrossRefGoogle Scholar
  174. 174.
    Lallemand F, Soubrie PH, De Witte PH (2001) Effects of CB1 cannabinoid receptor blockade on ethanol preference after chronic ethanol administration. Alcohol Clin Exp Res 25:1317–1323PubMedCrossRefGoogle Scholar
  175. 175.
    Naassila M, Pierrefiche O, Ledent C, Daoust M (2004) Decreased alcohol self-administration and increased alcohol sensitivity and withdrawal in CB1 receptor knockout mice. Neuropharmacology 46:243–253PubMedCrossRefGoogle Scholar
  176. 176.
    Marcus DJ, Henderson-Redmond AN, Gonek M, Zee ML, Farnsworth JC, Amin RA et al (2017) Mice expressing a “hyper-sensitive” form of the CB1 cannabinoid receptor (CB1) show modestly enhanced alcohol preference and consumption. PLoS One 12:e0174826PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Viudez-Martinez A, Garcia-Gutierrez MS, Navarron CM, Morales-Calero MI, Navarrete F, Torres-Suarez AI et al (2018) Cannabidiol reduces ethanol consumption, motivation and relapse in mice. Addict Biol 23:154–164PubMedCrossRefGoogle Scholar
  178. 178.
    Moranta D, Esteban S, Garcia-Sevilla JA (2006) Ethanol desensitizes cannabinoid CB1 receptors modulating monoamine synthesis in the rat brain in vivo. Neurosci Lett 392:58–61PubMedCrossRefGoogle Scholar
  179. 179.
    Ortiz S, Oliva JM, Perez S, Palomo T, Manzanares J (2004) Chronic ethanol consumption regulates cannabinoid CB1 receptor gene expression in selected regions of rat brain. Alcohol Alcohol 39:88–92PubMedCrossRefGoogle Scholar
  180. 180.
    Mitrirattanakul S, Lopez-Valdes HE, Liang J, Matsuka Y, Mackie K, Faull KF et al (2007) Bidirectional alterations of hippocampal cannabinoid 1 receptors and their endogenous ligands in a rat model of alcohol withdrawal and dependence. Alcohol Clin Exp Res 31:855–867PubMedCrossRefGoogle Scholar
  181. 181.
    Rimondini R, Arlinde C, Sommer W, Heilig M (2002) Long-lasting increase in voluntary ethanol consumption and transcriptional regulation in the rat brain after intermittent exposure to alcohol. FASEB J 16:27–35PubMedCrossRefGoogle Scholar
  182. 182.
    Warnault V, Houchi H, Barbier E, Pierrefiche O, Vilpoux C, Ledent C et al (2007) The lack of CB1 receptors prevents neuroadapatations of both NMDA and GABA(A) receptors after chronic ethanol exposure. J Neurochem 102:741–752PubMedCrossRefGoogle Scholar
  183. 183.
    Hungund BL, Basavarajappa BS, Vadasz C, Kunos G, Rodriguez de Fonseca F, Colombo G et al (2002) Ethanol, endocannabinoids and cannabinoidergic signaling system. Alcohol Clin Exp Res 26:565–574PubMedCrossRefGoogle Scholar
  184. 184.
    Gonzalez S, Grazia Cascio M, Fernandez-Ruiz J, Fezza F, Di Marzo V, Ramos JA (2002) Changes in endocannabinoid contents in the brain of rats chronically exposed to nicotine, ethanol or cocaine. Brain Res 954:73PubMedCrossRefGoogle Scholar
  185. 185.
    Rubio M, Fernandez-Ruiz J, de Miguel R, Maestro B, Michael Walker J, Ramos JA (2008) CB1 receptor blockade reduces the anxiogenic-like response and ameliorates the neurochemical imbalances associated with alcohol withdrawal in rats. Neuropharmacology 54:976–988PubMedCrossRefGoogle Scholar
  186. 186.
    Vinod KY, Kassir SA, Hungund BL, Cooper TB, Mann JJ, Arango V (2010) Selective alterations of the CB1 receptors and the fatty acid amide hydrolase in the ventral striatum of alcoholics and suicides. J Psychiatr Res 44:591–597PubMedCrossRefGoogle Scholar
  187. 187.
    Serrano A, Pavon FJ, Buczynski MW, Schlosburg J, Natividad LA, Polis IY et al (2018) Deficient endocannabinoid signaling in the central amygdala contributes to alcohol dependence-related anxiety-like behavior and excessive alcohol intake. Neuropsychopharmacology 43(9):1840–1850PubMedCrossRefGoogle Scholar
  188. 188.
    Kirson D, Oleata CS, Parsons LH, Ciccocioppo R, Roberto M (2018) CB1 and ethanol effects on glutamatergic transmission in the central amygdala of male and female msP and Wistar rats. Addict Biol 23:676–688PubMedCrossRefGoogle Scholar
  189. 189.
    Alen F, Santos A, Moreno-Sanz G, Gonzalez-Cuevas G, Gine E, Franco-Ruiz L et al (2009) Cannabinoid-induced increase in relapse-like drinking is prevented by the blockade of the glycine-binding site of N-methyl-D-aspartate receptors. Neuroscience 158:465–473PubMedCrossRefGoogle Scholar
  190. 190.
    Lopez-Moreno JA, Gonzalez-Cuevas G, Rodriguez de Fonseca F, Navarro M (2004) Long-lasting increase of alcohol relapse by the cannabinoid receptor agonist WIN 55,212-2 during alcohol deprivation. J Neurosci 24:8245–8252PubMedCrossRefGoogle Scholar
  191. 191.
    Lopez-Moreno JA, Scherma M, Rodriguez de Fonseca F, Gonzalez-Cuevas G, Fratta W, Navarro M (2008) Changed accumbal responsiveness to alcohol in rats pre-treated with nicotine or the cannabinoid receptor agonist WIN 55,212-2. Neurosci Lett 433:1–5PubMedCrossRefGoogle Scholar
  192. 192.
    Economidou D, Mattioli L, Ubaldi M, Lourdusamy A, Soverchia L, Hardiman G et al (2007) Role of cannabinoidergic mechanisms in ethanol self-administration and ethanol seeking in rat adult offspring following perinatal exposure to Delta9-tetrahydrocannabinol. Toxicol Appl Pharmacol 223:73–85PubMedPubMedCentralCrossRefGoogle Scholar
  193. 193.
    Adams CL, Short JL, Lawrence AJ (2010) Cue-conditioned alcohol seeking in rats following abstinence: involvement of metabotropic glutamate 5 receptors. Br J Pharmacol 159:534–542PubMedPubMedCentralCrossRefGoogle Scholar
  194. 194.
    Johnson JP, Muhleman D, MacMurray J, Gade R, Verde R, Ask M et al (1997) Association between the cannabinoid receptor gene (CNR1) and the P300 event-related potential. Mol Psychiatry 2:169–171PubMedCrossRefGoogle Scholar
  195. 195.
    Begleiter H, Porjesz B, Bihari B, Kissin B (1984) Event-related brain potentials in boys at risk for alcoholism. Science 225:1493–1496PubMedCrossRefGoogle Scholar
  196. 196.
    Schmidt LG, Samochowiec J, Finckh U, Fiszer-Piosik E, Horodnicki J, Wendel B et al (2002) Association of a CB1 cannabinoid receptor gene (CNR1) polymorphism with severe alcohol dependence. Drug Alcohol Depend 65:221–224PubMedCrossRefGoogle Scholar
  197. 197.
    van den Wildenberg E, Janssen RG, Hutchison KE, van Breukelen GJ, Wiers RW (2007) Polymorphisms of the dopamine D4 receptor gene (DRD4 VNTR) and cannabinoid CB1 receptor gene (CNR1) are not strongly related to cue-reactivity after alcohol exposure. Addict Biol 12:210–220PubMedCrossRefGoogle Scholar
  198. 198.
    Bayewitch M, Avidor-Reiss T, Levy R, Barg J, Mechoulam R, Vogel Z (1995) The peripheral cannabinoid receptor: adenylate cyclase inhibition and G protein coupling. FEBS Lett 375:143–147PubMedCrossRefGoogle Scholar
  199. 199.
    Atwood BK, Huffman J, Straiker A, Mackie K (2010) JWH018, a common constituent of ‘Spice’ herbal blends, is a potent and efficacious cannabinoid CB receptor agonist. Br J Pharmacol 160:585–593PubMedPubMedCentralCrossRefGoogle Scholar
  200. 200.
    Onaivi ES, Ishiguro H, Gu S, Liu QR (2012) CNS effects of CB2 cannabinoid receptors: beyond neuro-immuno-cannabinoid activity. J Psychopharmacol 26:92–103PubMedCrossRefGoogle Scholar
  201. 201.
    Ortega-Alvaro A, Aracil-Fernandez A, Garcia-Gutierrez MS, Navarrete F, Manzanares J (2011) Deletion of CB2 cannabinoid receptor induces schizophrenia-related behaviors in mice. Neuropsychopharmacology 36:1489–1504PubMedPubMedCentralCrossRefGoogle Scholar
  202. 202.
    Ishiguro H, Iwasaki S, Teasenfitz L, Higuchi S, Horiuchi Y, Saito T et al (2007) Involvement of cannabinoid CB2 receptor in alcohol preference in mice and alcoholism in humans. Pharmacogenomics J 7:380–385PubMedCrossRefGoogle Scholar
  203. 203.
    Navarrete F, Garcia-Gutierrez MS, Manzanares J (2018) Pharmacological regulation of cannabinoid CB2 receptor modulates the reinforcing and motivational actions of ethanol. Biochem Pharmacol 157:227–234PubMedCrossRefGoogle Scholar
  204. 204.
    Ortega-Alvaro A, Ternianov A, Aracil-Fernandez A, Navarrete F, Garcia-Gutierrez MS, Manzanares J (2015) Role of cannabinoid CB2 receptor in the reinforcing actions of ethanol. Addict Biol 20:43–55PubMedCrossRefGoogle Scholar
  205. 205.
    Nicoletti P, Trevisani M, Manconi M, Gatti R, De Siena G, Zagli G et al (2008) Ethanol causes neurogenic vasodilation by TRPV1 activation and CGRP release in the trigeminovascular system of the guinea pig. Cephalalgia 28:9–17PubMedCrossRefGoogle Scholar
  206. 206.
    Trevisani M, Smart D, Gunthorpe MJ, Tognetto M, Barbieri M, Campi B et al (2002) Ethanol elicits and potentiates nociceptor responses via the vanilloid receptor-1. Nat Neurosci 5:546–551PubMedCrossRefGoogle Scholar
  207. 207.
    Vetter I, Wyse BD, Roberts-Thomson SJ, Monteith GR, Cabot PJ (2008) Mechanisms involved in potentiation of transient receptor potential vanilloid 1 responses by ethanol. Eur J Pain 12:441–454PubMedCrossRefGoogle Scholar
  208. 208.
    Berrendero F, Garcia-Gil L, Hernandez ML, Romero J, Cebeira M, de Miguel R et al (1998) Localization of mRNA expression and activation of signal transduction mechanisms for cannabinoid receptor in rat brain during fetal development. Development 125:3179–3188PubMedGoogle Scholar
  209. 209.
    Berrendero F, Sepe N, Ramos JA, Di Marzo V, Fernandez-Ruiz JJ (1999) Analysis of cannabinoid receptor binding and mRNA expression and endogenous cannabinoid contents in the developing rat brain during late gestation and early postnatal period. Synapse 33:181–191PubMedCrossRefGoogle Scholar
  210. 210.
    Buckley NE, Hansson S, Harta G, Mezey E (1998) Expression of the CB1 and CB2 receptor messenger RNAs during embryonic development in the rat. Neuroscience 82:1131–1149PubMedCrossRefGoogle Scholar
  211. 211.
    Romero J, Garcia-Palomero E, Berrendero F, Garcia-Gil L, Hernandez ML, Ramos JA et al (1997) Atypical location of cannabinoid receptors in white matter areas during rat brain development. Synapse 26:317–323PubMedCrossRefGoogle Scholar
  212. 212.
    Insel TR (1995) The development of brain and behavior. In: Bloom FE, Kupfer DJ (eds) Psychopharmacology: the four generation of progress. Raven Press, New York, pp 683–694Google Scholar
  213. 213.
    Glass M, Dragunow M, Faull RL (1997) Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain. Neuroscience 77:299–318PubMedCrossRefGoogle Scholar
  214. 214.
    Mailleux P, Vanderhaeghen JJ (1992) Distribution of neuronal cannabinoid receptor in the adult rat brain: a comparative receptor binding radioautography and in situ hybridization histochemistry. Neuroscience 48:655–668PubMedCrossRefGoogle Scholar
  215. 215.
    Cristino L, de Petrocellis L, Pryce G, Baker D, Guglielmotti V, Di Marzo V (2006) Immunohistochemical localization of cannabinoid type 1 and vanilloid transient receptor potential vanilloid type 1 receptors in the mouse brain. Neuroscience 139:1405–1415CrossRefGoogle Scholar
  216. 216.
    Hungund BL, Vinod KY, Kassir SA, Basavarajappa BS, Yalamanchili R, Cooper TB et al (2004) Upregulation of CB1 receptors and agonist-stimulated [35S]GTPgammaS binding in the prefrontal cortex of depressed suicide victims. Mol Psychiatry 9:184–190PubMedCrossRefGoogle Scholar
  217. 217.
    Kamprath K, Romo-Parra H, Haring M, Gaburro S, Doengi M, Lutz B et al (2011) Short-term adaptation of conditioned fear responses through endocannabinoid signaling in the central amygdala. Neuropsychopharmacology 36:652–663PubMedCrossRefGoogle Scholar
  218. 218.
    Katona I, Rancz EA, Acsady L, Ledent C, Mackie K, Hajos N et al (2001) Distribution of CB1 cannabinoid receptors in the amygdala and their role in the control of GABAergic transmission. J Neurosci 21:9506–9518PubMedCrossRefGoogle Scholar
  219. 219.
    Katona I, Sperlagh B, Sik A, Kafalvi A, Vizi ES, Mackie K et al (1999) Presynaptically located CB1 cannabinoid receptors regulate GABA release from axon terminals of specific hippocampal interneurons. J Neurosci 19:4544–4558PubMedCrossRefGoogle Scholar
  220. 220.
    Marsicano G, Lutz B (1999) Expression of the cannabinoid receptor CB1 in distinct neuronal subpopulations in the adult mouse forebrain. Eur J Neurosci 11:4213–4225PubMedCrossRefGoogle Scholar
  221. 221.
    Puente N, Elezgarai I, Lafourcade M, Reguero L, Marsicano G, Georges F et al (2010) Localization and function of the cannabinoid CB1 receptor in the anterolateral bed nucleus of the stria terminalis. PLoS One 5:e8869PubMedPubMedCentralCrossRefGoogle Scholar
  222. 222.
    Ramikie TS, Nyilas R, Bluett RJ, Gamble-George JC, Hartley ND, Mackie K et al (2014) Multiple mechanistically distinct modes of endocannabinoid mobilization at central amygdala glutamatergic synapses. Neuron 81:1111–1125PubMedPubMedCentralCrossRefGoogle Scholar
  223. 223.
    Fernández-Ruiz JJ, Bonnin A, Cebeira M, Ramos JA (1994) Ontogenic and adults changes in the activity of hypothalamic and extrahypothalamic dopaminergic neurons after perinatal cannabinoid exposure. In: Palomo T, Archer T (eds) Strategies for studying brain disorders. Farrand Press, London, pp 357–390Google Scholar
  224. 224.
    Fernández-Ruiz JJ, Rodriguez F, Navarro M, Ramos JA (1992) Maternal cannabinoid exposure and brain development: changes in the ontogeny of dopaminergic neurons. In: Murphy L, Bartke A (eds) Neurobiology and neurophysiology of cannabinoids: biochemistry and physiology of substance abuse. CRC Press, Boca Raton, pp 119–164Google Scholar
  225. 225.
    Fernández-Ruiz JJ, Romero J, Garcίa-Gil L, Garcίa-Palomero E, Ramos JA (1996) Dopaminergic neurons as neurochemical substrates of neurobehavioral effects of marihuana: developmental and adult studies. In: Beninger RJ, Archer T, Palomo T (eds) Dopamine disease states. CYM Press, Madrid, pp 359–387Google Scholar
  226. 226.
    Fernandez-Ruiz JJ, Berrendero F, Hernandez ML, Romero J, Ramos JA (1999) Role of endocannabinoids in brain development. Life Sci 65:725–736PubMedCrossRefGoogle Scholar
  227. 227.
    Dalterio SL (1980) Perinatal or adult exposure to cannabinoids alters male reproductive functions in mice. Pharmacol Biochem Behav 12:143–153PubMedCrossRefGoogle Scholar
  228. 228.
    Navarro M, Rodriguez de Fonseca F, Hernandez ML, Ramos JA, Fernandez-Ruiz JJ (1994) Motor behavior and nigrostriatal dopaminergic activity in adult rats perinatally exposed to cannabinoids. Pharmacol Biochem Behav 47:47–58PubMedCrossRefGoogle Scholar
  229. 229.
    Dalterio SL (1986) Cannabinoid exposure: effects on development. Neurobehav Toxicol Teratol 8:345–352PubMedGoogle Scholar
  230. 230.
    Mokler DJ, Robinson SE, Johnson JH, Hong JS, Rosecrans JA (1987) Neonatal administration of delta-9-tetrahydrocannabinol (THC) alters the neurochemical response to stress in the adult Fischer-344 rat. Neurotoxicol Teratol 9:321–327PubMedCrossRefGoogle Scholar
  231. 231.
    Vela G, Fuentes JA, Bonnin A, Fernandez-Ruiz J, Ruiz-Gayo M (1995) Perinatal exposure to delta 9-tetrahydrocannabinol (delta 9-THC) leads to changes in opioid-related behavioral patterns in rats. Brain Res 680:142–147PubMedCrossRefGoogle Scholar
  232. 232.
    Navarro M, de Miguel R, Rodriguez de Fonseca F, Ramos JA, Fernandez-Ruiz JJ (1996) Perinatal cannabinoid exposure modifies the sociosexual approach behavior and the mesolimbic dopaminergic activity of adult male rats. Behav Brain Res 75:91–98PubMedCrossRefGoogle Scholar
  233. 233.
    Vela G, Martin S, Garcia-Gil L, Crespo JA, Ruiz-Gayo M, Fernandez-Ruiz JJ et al (1998) Maternal exposure to delta9-tetrahydrocannabinol facilitates morphine self-administration behavior and changes regional binding to central mu opioid receptors in adult offspring female rats. Brain Res 807:101–109PubMedCrossRefGoogle Scholar
  234. 234.
    Dalterio S, Bartke A (1979) Perinatal exposure to cannabinoids alters male reproductive function in mice. Science 205:1420–1422PubMedCrossRefGoogle Scholar
  235. 235.
    Shivachar AC, Martin BR, Ellis EF (1996) Anandamide- and delta9-tetrahydrocannabinol-evoked arachidonic acid mobilization and blockade by SR141716A [N-(Piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4 -methyl-1H-pyrazole-3-carboximide hydrochloride]. Biochem Pharmacol 51:669–676PubMedCrossRefGoogle Scholar
  236. 236.
    Hansen HH, Krutz B, Sifringer M, Stefovska V, Bittigau P, Pragst F et al (2008) Cannabinoids enhance susceptibility of immature brain to ethanol neurotoxicity. Ann Neurol 64:42–52PubMedCrossRefGoogle Scholar
  237. 237.
    Harkany T, Guzman M, Galve-Roperh I, Berghuis P, Devi LA, Mackie K (2007) The emerging functions of endocannabinoid signaling during CNS development. Trends Pharmacol Sci 28:83–92PubMedCrossRefGoogle Scholar
  238. 238.
    Kim D, Thayer SA (2001) Cannabinoids inhibit the formation of new synapses between hippocampal neurons in culture. J Neurosci 21:RC146PubMedCrossRefGoogle Scholar
  239. 239.
    Berghuis P, Rajnicek AM, Morozov YM, Ross RA, Mulder J, Urban GM et al (2007) Hardwiring the brain: endocannabinoids shape neuronal connectivity. Science 316:1212–1216PubMedCrossRefGoogle Scholar
  240. 240.
    De Petrocellis L, Melck D, Palmisano A, Bisogno T, Laezza C, Bifulco M et al (1998) The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation. Proc Natl Acad Sci U S A 95:8375–8380PubMedPubMedCentralCrossRefGoogle Scholar
  241. 241.
    Galve-Roperh I, Sanchez C, Cortes ML, Gomez del Pulgar T, Izquierdo M, Guzman M (2000) Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Nat Med 6:313–319CrossRefGoogle Scholar
  242. 242.
    Stefanis NC, Delespaul P, Henquet C, Bakoula C, Stefanis CN, Van Os J (2004) Early adolescent cannabis exposure and positive and negative dimensions of psychosis. Addiction 99:1333–1341PubMedCrossRefGoogle Scholar
  243. 243.
    Wu CS, Jew CP, Lu HC (2011) Lasting impacts of prenatal cannabis exposure and the role of endogenous cannabinoids in the developing brain. Future Neurol 6:459–480PubMedPubMedCentralCrossRefGoogle Scholar
  244. 244.
    Ikonomidou C, Bosch F, Miksa M, Bittigau P, Vockler J, Dikranian K et al (1999) Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 283:70–74PubMedCrossRefGoogle Scholar
  245. 245.
    Gerdeman G, Lovinger DM (2001) CB1 cannabinoid receptor inhibits synaptic release of glutamate in rat dorsolateral striatum. J Neurophysiol 85:468–471PubMedCrossRefGoogle Scholar
  246. 246.
    Huang CC, Lo SW, Hsu KS (2001) Presynaptic mechanisms underlying cannabinoid inhibition of excitatory synaptic transmission in rat striatal neurons. J Physiol 532(Pt3):731–748PubMedPubMedCentralCrossRefGoogle Scholar
  247. 247.
    Chevaleyre V, Castillo PE (2004) Endocannabinoid-mediated metaplasticity in the hippocampus. Neuron 43:871–881PubMedCrossRefGoogle Scholar
  248. 248.
    Sullivan JM (2000) Cellular and molecular mechanisms underlying learning and memory impairments produced by cannabinoids. Learn Mem 7:132–139PubMedCrossRefGoogle Scholar
  249. 249.
    Wilson RI, Nicoll RA (2002) Endocannabinoid signaling in the brain. Science 296:678–682PubMedCrossRefGoogle Scholar
  250. 250.
    Sadrian B, Subbanna S, Wilson DA, Basavarajappa BS, Saito M (2012) Lithium prevents long-term neural and behavioral pathology induced by early alcohol exposure. Neuroscience 206:122–135PubMedPubMedCentralCrossRefGoogle Scholar
  251. 251.
    Wilson DA, Peterson J, Basavaraj BS, Saito M (2011) Local and regional network function in behaviorally relevant cortical circuits of adult mice following postnatal alcohol exposure. Alcohol Clin Exp Res 35:1974–1984PubMedPubMedCentralCrossRefGoogle Scholar
  252. 252.
    Mameli M, Zamudio PA, Carta M, Valenzuela CF (2005) Developmentally regulated actions of alcohol on hippocampal glutamatergic transmission. J Neurosci 25:8027–8036PubMedCrossRefGoogle Scholar
  253. 253.
    Twitchell W, Brown S, Mackie K (1997) Cannabinoids inhibit N- and P/Q-type calcium channels in cultured rat hippocampal neurons. J Neurophysiol 78:43–50PubMedCrossRefGoogle Scholar
  254. 254.
    Noel M, Norris EH, Strickland S (2011) Tissue plasminogen activator is required for the development of fetal alcohol syndrome in mice. Proc Natl Acad Sci U S A 108:5069–5074PubMedPubMedCentralCrossRefGoogle Scholar
  255. 255.
    Sadrian B, Lopez-Guzman M, Wilson DA, Saito M (2014) Distinct neurobehavioral dysfunction based on the timing of developmental binge-like alcohol exposure. Neuroscience 280:204–219PubMedCrossRefGoogle Scholar
  256. 256.
    Subbanna S, Basavarajappa BS (2014) Pre-administration of G9a/GLP inhibitor during synaptogenesis prevents postnatal ethanol-induced LTP deficits and neurobehavioral abnormalities in adult mice. Exp Neurol 261:34–43PubMedCrossRefGoogle Scholar
  257. 257.
    Margret CP, Li CX, Chappell TD, Elberger AJ, Matta SG, Waters RS (2006) Prenatal alcohol exposure delays the development of the cortical barrel field in neonatal rats. Exp Brain Res 172:1–13PubMedCrossRefGoogle Scholar
  258. 258.
    Medina AE, Krahe TE, Ramoa AS (2005) Early alcohol exposure induces persistent alteration of cortical columnar organization and reduced orientation selectivity in the visual cortex. J Neurophysiol 93:1317–1325PubMedCrossRefGoogle Scholar
  259. 259.
    Powrozek TA, Zhou FC (2005) Effects of prenatal alcohol exposure on the development of the vibrissal somatosensory cortical barrel network. Brain Res Dev Brain Res 155:135–146PubMedCrossRefGoogle Scholar
  260. 260.
    Zhou FC, Sari Y, Powrozek TA (2005) Fetal alcohol exposure reduces serotonin innervation and compromises development of the forebrain along the serotonergic pathway. Alcohol Clin Exp Res 29:141–149PubMedCrossRefGoogle Scholar
  261. 261.
    Fernandez-Ruiz J, Gomez M, Hernandez M, de Miguel R, Ramos JA (2004) Cannabinoids and gene expression during brain development. Neurotox Res 6:389–401PubMedCrossRefGoogle Scholar
  262. 262.
    Wang X, Dow-Edwards D, Anderson V, Minkoff H, Hurd YL (2006) Discrete opioid gene expression impairment in the human fetal brain associated with maternal marijuana use. Pharmacogenomics J 6:255–264PubMedCrossRefGoogle Scholar
  263. 263.
    Schneider M (2009) Cannabis use in pregnancy and early life and its consequences: animal models. Eur Arch Psychiatry Clin Neurosci 259:383–393PubMedCrossRefGoogle Scholar
  264. 264.
    Campolongo P, Trezza V, Ratano P, Palmery M, Cuomo V (2011) Developmental consequences of perinatal cannabis exposure: behavioral and neuroendocrine effects in adult rodents. Psychopharmacology 214:5–15PubMedPubMedCentralCrossRefGoogle Scholar
  265. 265.
    Nagre NN, Subbanna S, Shivakumar M, Psychoyos D, Basavarajappa BS (2015) CB1-receptor knockout neonatal mice are protected against ethanol-induced impairments of DNMT1, DNMT3A, and DNA methylation. J Neurochem 132:429–442PubMedPubMedCentralCrossRefGoogle Scholar
  266. 266.
    Joshi V, Subbanna S, Shivakumar M, Basavarajappa BS (2018) CB1R regulates CDK5 signaling and epigenetically controls Rac1 expression contributing to neurobehavioral abnormalities in mice postnatally exposed to ethanol. Neuropsychopharmacology 44(3):514–525PubMedCrossRefGoogle Scholar
  267. 267.
    Subbanna S, Nagre NN, Shivakumar M, Umapathy NS, Psychoyos D, Basavarajappa BS (2014) Ethanol induced acetylation of histone at G9a exon1 and G9a-mediated histone H3 dimethylation leads to neurodegeneration in neonatal mice. Neuroscience 258:422–432PubMedCrossRefGoogle Scholar
  268. 268.
    Subbanna S, Nagre NN, Shivakumar M, Joshi V, Psychoyos D, Kutlar A et al (2018) CB1R-mediated activation of caspase-3 causes epigenetic and neurobehavioral abnormalities in postnatal ethanol-exposed mice. Front Mol Neurosci 11:45PubMedPubMedCentralCrossRefGoogle Scholar
  269. 269.
    Subbanna S, Joshi V, Basavarajappa BS (2018) Activity-dependent signaling and epigenetic abnormalities in mice exposed to postnatal ethanol. Neuroscience 392:230–240PubMedCrossRefGoogle Scholar
  270. 270.
    Sun YX, Tsuboi K, Okamoto Y, Tonai T, Murakami M, Kudo I et al (2004) Biosynthesis of anandamide and N-palmitoylethanolamine by sequential actions of phospholipase A2 and lysophospholipase D. Biochem J 380:749–756PubMedPubMedCentralCrossRefGoogle Scholar
  271. 271.
    Beltramo M, Piomelli D (2000) Carrier-mediated transport and enzymatic hydrolysis of the endogenous cannabinoid 2-arachidonylglycerol. Neuroreport 11:1231–1235PubMedCrossRefGoogle Scholar
  272. 272.
    Bisogno T, MacCarrone M, De Petrocellis L, Jarrahian A, Finazzi-Agro A, Hillard C et al (2001) The uptake by cells of 2-arachidonoylglycerol, an endogenous agonist of cannabinoid receptors. Eur J Biochem 268:1982–1989PubMedCrossRefGoogle Scholar
  273. 273.
    Hillard CJ, Edgemond WS, Jarrahian A, Campbell WB (1997) Accumulation of N-arachidonoylethanolamine (anandamide) into cerebellar granule cells occurs via facilitated diffusion. J Neurochem 69:631–638PubMedCrossRefGoogle Scholar
  274. 274.
    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
  275. 275.
    Hillard CJ, Jarrahian A (2000) The movement of N-arachidonoylethanolamine (anandamide) across cellular membranes. Chem Phys Lipids 108:123–134PubMedCrossRefGoogle Scholar
  276. 276.
    Maccarrone M, van der Stelt M, Rossi A, Veldink GA, Vliegenthart JF, Agro AF (1998) Anandamide hydrolysis by human cells in culture and brain. J Biol Chem 273:32332–32339PubMedCrossRefGoogle Scholar
  277. 277.
    Giuffrida A, Beltramo M, Piomelli D (2001) Mechanisms of endocannabinoid inactivation: biochemistry and pharmacology. J Pharmacol Exp Ther 298:7–14PubMedGoogle Scholar
  278. 278.
    Deutsch DG, Glaser ST, Howell JM, Kunz JS, Puffenbarger RA, Hillard CJ et al (2001) The cellular uptake of anandamide is coupled to its breakdown by fatty-acid amide hydrolase. J Biol Chem 276:6967–6973PubMedCrossRefGoogle Scholar
  279. 279.
    Glaser ST, Abumrad NA, Fatade F, Kaczocha M, Studholme KM, Deutsch DG (2003) Evidence against the presence of an anandamide transporter. Proc Natl Acad Sci U S A 100:4269–4274PubMedPubMedCentralCrossRefGoogle Scholar
  280. 280.
    Prescott SM, Majerus PW (1983) Characterization of 1,2-diacylglycerol hydrolysis in human platelets. Demonstration of an arachidonoyl-monoacylglycerol intermediate. J Biol Chem 258:764–769PubMedGoogle Scholar
  281. 281.
    Bisogno T, Melck D, De Petrocellis L, Di Marzo V (1999) Phosphatidic acid as the biosynthetic precursor of the endocannabinoid 2-arachidonoylglycerol in intact mouse neuroblastoma cells stimulated with ionomycin. J Neurochem 72:2113–2119PubMedCrossRefGoogle Scholar
  282. 282.
    Carrier EJ, Kearn CS, Barkmeier AJ, Breese NM, Yang W, Nithipatikom K et al (2004) Cultured rat microglial cells synthesize the endocannabinoid 2-arachidonylglycerol, which increases proliferation via a CB2 receptor-dependent mechanism. Mol Pharmacol 65:999–1007PubMedCrossRefGoogle Scholar
  283. 283.
    Nakane S, Oka S, Arai S, Waku K, Ishima Y, Tokumura A et al (2002) 2-Arachidonoyl-sn-glycero-3-phosphate, an arachidonic acid-containing lysophosphatidic acid: occurrence and rapid enzymatic conversion to 2-arachidonoyl-sn-glycerol, a cannabinoid receptor ligand, in rat brain. Arch Biochem Biophys 402:51–58PubMedCrossRefGoogle Scholar
  284. 284.
    Day TA, Rakhshan F, Deutsch DG, Barker EL (2001) Role of fatty acid amide hydrolase in the transport of the endogenous cannabinoid anandamide. Mol Pharmacol 59:1369–1375PubMedCrossRefGoogle Scholar
  285. 285.
    Hampson RE, Miller F, Palchik G, Deadwyler SA (2011) Cannabinoid receptor activation modifies NMDA receptor mediated release of intracellular calcium: implications for endocannabinoid control of hippocampal neural plasticity. Neuropharmacology 60:944–952PubMedPubMedCentralCrossRefGoogle Scholar
  286. 286.
    Feuerecker M, Hauer D, Gresset T, Lassas S, Kaufmann I, Vogeser M et al (2012) Effect of an acute consumption of a moderate amount of ethanol on plasma endocannabinoid levels in humans. Alcohol Alcohol 47:226–232PubMedCrossRefGoogle Scholar
  287. 287.
    Vinod KY, Yalamanchili R, Thanos PK, Vadasz C, Cooper TB, Volkow ND et al (2008) Genetic and pharmacological manipulations of the CB(1) receptor alter ethanol preference and dependence in ethanol preferring and nonpreferring mice. Synapse 62:574–581PubMedPubMedCentralCrossRefGoogle Scholar
  288. 288.
    Linsenbardt DN, Boehm SL 2nd. (2009) Agonism of the endocannabinoid system modulates binge-like alcohol intake in male C57BL/6J mice: involvement of the posterior ventral tegmental area. Neuroscience 164:424–434PubMedPubMedCentralCrossRefGoogle Scholar
  289. 289.
    Frontera JL, Gonzalez Pini VM, Messore FL, Brusco A (2018) Exposure to cannabinoid agonist WIN 55,212-2 during early adolescence increases alcohol preference and anxiety in CD1 mice. Neuropharmacology 137:268–274PubMedCrossRefGoogle Scholar
  290. 290.
    Femenia T, Garcia-Gutierrez MS, Manzanares J (2010) CB1 receptor blockade decreases ethanol intake and associated neurochemical changes in fawn-hooded rats. Alcohol Clin Exp Res 34:131–141PubMedCrossRefGoogle Scholar
  291. 291.
    Balla A, Dong B, Shilpa BM, Vemuri K, Makriyannis A, Pandey SC et al (2018) Cannabinoid-1 receptor neutral antagonist reduces binge-like alcohol consumption and alcohol-induced accumbal dopaminergic signaling. Neuropharmacology 131:200–208PubMedCrossRefGoogle Scholar
  292. 292.
    Vinod KY, Sanguino E, Yalamanchili R, Manzanares J, Hungund BL (2008) Manipulation of fatty acid amide hydrolase functional activity alters sensitivity and dependence to ethanol. J Neurochem 104:233–243PubMedGoogle Scholar
  293. 293.
    Cippitelli A, Cannella N, Braconi S, Duranti A, Tontini A, Bilbao A et al (2008) Increase of brain endocannabinoid anandamide levels by FAAH inhibition and alcohol abuse behaviours in the rat. Psychopharmacology 198:449–460PubMedCrossRefGoogle Scholar
  294. 294.
    Zhou Y, Schwartz BI, Giza J, Gross SS, Lee FS, Kreek MJ (2017) Blockade of alcohol escalation and “relapse” drinking by pharmacological FAAH inhibition in male and female C57BL/6J mice. Psychopharmacology 234:2955–2970PubMedPubMedCentralCrossRefGoogle Scholar
  295. 295.
    Stopponi S, Fotio Y, Domi A, Borruto AM, Natividad L, Roberto M et al (2017) Inhibition of fatty acid amide hydrolase in the central amygdala alleviates co-morbid expression of innate anxiety and excessive alcohol intake. Addict Biol 23(6):1223–1232PubMedCrossRefGoogle Scholar
  296. 296.
    Figueiredo A, Hamilton J, Marion M, Blum K, Kaczocha M, Haj-Dahmane S et al (2017) Pharmacological inhibition of brain fatty acid binding protein reduces ethanol consumption in mice. J Reward Defic Syndr Addict Sci 3:21–27PubMedPubMedCentralCrossRefGoogle Scholar
  297. 297.
    Vinod KY, Yalamanchili R, Xie S, Cooper TB, Hungund BL (2006) Effect of chronic ethanol exposure and its withdrawal on the endocannabinoid system. Neurochem Int 49:619–625PubMedCrossRefGoogle Scholar
  298. 298.
    Ceccarini J, Casteels C, Koole M, Bormans G, Van Laere K (2013) Transient changes in the endocannabinoid system after acute and chronic ethanol exposure and abstinence in the rat: a combined PET and microdialysis study. Eur J Nucl Med Mol Imaging 40:1582–1594PubMedCrossRefGoogle Scholar
  299. 299.
    Garcia-Marchena N, Pavon FJ, Pastor A, Araos P, Pedraz M, Romero-Sanchiz P et al (2017) Plasma concentrations of oleoylethanolamide and other acylethanolamides are altered in alcohol-dependent patients: effect of length of abstinence. Addict Biol 22:1366–1377PubMedCrossRefGoogle Scholar
  300. 300.
    Henricks AM, Berger AL, Lugo JM, Baxter-Potter LN, Bieniasz KV, Petrie G et al (2017) Sex- and hormone-dependent alterations in alcohol withdrawal-induced anxiety and corticolimbic endocannabinoid signaling. Neuropharmacology 124:121–133PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Division of Analytical PsychopharmacologyNew York State Psychiatric InstituteNew YorkUSA
  2. 2.Department of Psychiatry, College of Physicians & SurgeonsColumbia UniversityNew YorkUSA
  3. 3.Nathan Kline Institute for Psychiatric ResearchOrangeburgUSA
  4. 4.Department of PsychiatryNew York University Langone Medical CenterNew YorkUSA

Personalised recommendations

Cite chapter

Buy options