Τόμος 24 (2006) – Τεύχος 1 – Άρθρο 4 – Επιθεώρηση Κλινικής Φαρμακολογίας και Φαρμακοκινητικής-Ελληνική Έκδοση – Volume 24 (2006) – Issue 1 – Article 4 – Epitheorese Klinikes Farmakologias και Farmakokinetikes-Greek Edition

Γεώργιος Παναγής, Ανδρέας Καστελλάκης

Εργαστήριο Νευροεπιστημών και Συμπεριφοράς, Τμήμα Ψυχολογίας, Σχολή Κοινωνικών Επιστημών, Πανεπιστήμιο Κρήτης, Πανεπιστημιούπολη Γάλλου, 74100 Ρέθυμνο, Κρήτη, Ελλάς

George Panagis, Andreas Kastellakis

Laboratory of Behavioral Neuroscience, De­partment of Psychology, School of Social Sci­ences, University of Crete, University Campus at Gallos, 74100 Rethymno, Crete, Greece

2. Robson P.: Therapeutic aspects of cannabis and can­nabinoids. Brit. J. Psychiat. 178: 107-115 (2001)

3. Childers S.R., Breivogel C.S.: Cannabis and endoge­nous cannabinoid systems. Drug Alcohol Depend. 51: 173-187 (1998)

4. Μαρσέλος Μ.: Εξαρτησιογόνες ουσίες. Τυπωθήτω, Αθή-να, 1997

5. Παραδέλλης Α. Ινδική κάνναβη, μια σύντομη ιστορική ανασκόπηση. Γαληνός 26: 1587-1590 (1984)

6. Gaoni Y., Mechoulam R.: Isolation, structure, and partial synthesis of an active constituent of hashish. J. Am. Chem. Soc. 86: 1646-1647 (1964)

7. Russo E.B., McPartland J.M.: Cannabis is more than simply Δ9-tetrahydrocannabinol. Psychopharmacology 165: 431-432 (2003)

8. Matsuda L.A., Lolait S.J., Brownstein M.J., Young A.C., Bonner, T.: Structure of a cannabinoid receptor and func­tional expression of the cloned cDNA. Nature 346: 561-564 (1990)

9. Hillard C.J., Harris R.A., Bloom A.S.: Effects of the can­nabinoids on physical properties of brain membranes and phospholipids vesicles: fluorescence studies. J. Pharma­col. Exp. Ther. 232: 579-588 (1985)

10. Dewey W.L.: Cannabinoid pharmacology. Pharmacol. Rev. 38: 151-178 (1986)

11. Devane W.A., Dysarz F.A.I., Johnson M.R., Melvin L.S., Howlett A.C.: Determination and characterization of a cannabinoid receptor in rat brain. Mol. Pharmacol. 34: 605-613 (1988)

12. Herkenham M., Lynn A.B., Little M.D., Johnson M.R., Melvin M.S., de Costa B.R., Rice K.C.: Cannabinoid re­ceptor localization in brain. Proc. Natl. Acad. Sci. USA 87: 1932-1936 (1990)

13. Munro S., Thomas K.L., Abu-Shaar M.: Molecular characterization of a peripheral receptor for cannabinoids. Nature 365: 61-65 (1993)

14. Howlett A.C., Fleming R.M.: Cannabinoid inhibition of adenylate cyclase: Pharmacology of the response in neuroblastoma cell membranes. Mol. Pharmacol. 26: 532-538 (1984)

15. Herkenham M., Lynn A.B., Johnson M.R., Melvin L.S., De Costa B.R., Rice K.C.: Characterization and localiza­tion of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J. Neurosci. 11: 563-583 (1991)

16. Herkenham M., Lynn A.B., De Costa B.R., Richfield E.K.: Neuronal localization of cannabinoid receptors in the basal ganglia of the rat. Brain Res. 547: 267-274 (1991)

17. Breivogel C.S., Childers S.R.: The functional neuro­anatomy of brain cannabinoid receptors. Neurobiol. Dis. 5: 417-431 (1998)

18. Gifford A.N., Makriyannis A., Volkow N.D., Gatley S.J.: In vivo imaging of the brain cannabinoid receptor. Chem. Phys. Lipids 121: 65-72 (2002)

19. Lynn A.B., Herkenham M.: Localization of cannabinoid receptors and nonsaturable high-density cannabinoid binding sites in peripheral tissues of the rat: Implications for receptor mediated immune modulation by cannabi­noids. J. Pharmacol. Exp. Ther. 268: 1612-1623 (1994)

20. Breivogel C.S., Griffin G., Di Marzo F., Martin B.R.: Evidence for a new G protein-coupled cannabinoid recep­tor in mouse brain. Mol. Pharmacol. 60: 155-163 (2001)

21. Wiley J.L., Martin B.R.: Cannabinoid pharmacology: implications for additional cannabinoid receptor subtypes. Chem. Phys. Lipids 121: 57-63 (2002)

22. Schlicker E., Kathmann M.: Modulation of neurotrans­mitter release via presynaptic cannabinoid receptors. Trends Pharmacol. Sci. 22: 565-572 (2001)

23. Wilson R.I., Nicoll R.A.: Endocannabinoid signaling in the brain. Science 296: 678-682 (2002)

24. Palmer S.L., Thakur G.A., Makriyannis A.: Can­nabinergic ligands. Chem. Phys. Lipids 121: 3-19 (2002)

25. Porter A.C., Felder C.C.: The endocannabinoid nerv­ous system: unique opportunities for therapeutic interven­tion. Pharmacol. Ther. 90: 45-60 (2001)

26. Rodriguez de Fonseca F., Del Arco I., Martin-Calderon J.L., Gorriti M.A., Navarro M.: Role of endogenous can­nabinoid system in the regulation of motor activity. Neuro­biol. Dis. 5: 483-501 (1998)

27. Devane W.A., Hanus L., Breuer A., Pertwee R.G., Stevenson L.A., Griffin G., Gibson D., Mandelbaum A., Etinger A., Mechoulam R.I.: Isolation and structure of a brain constituent that binds to the cannabinoid receptors. Science 258: 1946-1949 (1992)

28. Mechoulam R., Ben-Shabat S., Hanus L., Ligumsky M., Kaminski N.E., Schatz A.R., Gopher A., Almog S., Martin B.R., Compton D.R.: Identification of an endoge­nous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem. Pharmacol. 50: 83-90 (1995)

29. Howlett A.C., Barth F., Bonner T.I., Cabral G., Casellas P., Devane W.A., Felder C.C., Herkenham M., Mackie K., Martin B.R., Mechoulam R., Pertwee R.G.: International union of pharmacology. XXVII: Classification of cannabi­noid receptors. Pharmacol. Rev. 54: 161-202 (2002)

30. Howlett A.C., Breivogel C.S., Childres S.R., Deadwyler S.A., Hampson R.E., Porrino L.J.: Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharma­cology 47: 345-358 (2004)

31. Di Marzo V., Melck D., Bisogno T., De Petrocellis L.: Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action. Trends Neurosci. 21: 521-528 (1998)

32. Axelrod J., Felder C.C: Cannabinoid receptors and their endogenous agonist, anandamide. Neurochem. Res. 23: 575-581 (1998)

33. Piomelli D., Giuffrida A., Calignano A., Rodriguez de Fonseca F.: The endocannabinoid system as a target for therapeutic drugs. Trends Pharmacol. Sci. 21: 218-224 (2000)

34. Piomelli D.: The molecular logic of endocannabinoid signaling. Nature Rev. Neurosci. 4: 873-884 (2003)

35. Walker J.M., Hughmann A.G., Martin W.J., Strangman N.M., Tsou K.: The neurobiology of cannabinoid analgesia. Life Sciences, 65: 665-673 (1999)

36. Baker D., Pryce G., Croxford J.L., Brown P., Pertwee R.G., Makriyannis A., Khanolkar A., Layward L., Fezza F., Bisogno T., Di Marzo V.: Endocannabinoids control spas­ticity in a multiple sclerosis model. FASEB J. 15: 300-302 (2001)

37. Siegling A., Hofmann H.A., Denzer D., Mauler F., De Vry J.: Cannabinoid CB(1) receptor upregulation in a rat model of chronic neuropathic pain. Eur. J. Pharmacol. 415: R5-R7 (2001)

38. Di Marzo V., Goparaju S.K., Wang L., Liu J., Batkai S., Jarai Z., Fezza F., Miura G.I., Palmiter R.D., Sugiura T., Kunos G.: Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 410: 822-825 (2001)

39. Romero J., Lastres-Becker I., de Miquel R., Berren­dero F., Ramos J.A., Fernández-Ruiz J.: The endogenous cannabinoid system and the basal ganglia: Biochemical, pharmacological, and therapeutics aspects. Pharmacol. Ther. 95: 137-152 (2002)

40. Lastres-Becker I., Fezza F., Cebeira M., Bisogno T., Ramos J.A., Milone A., Fernandez-Ruiz J.J., Di Marzo, V.: Changes in endocannabinoid transmission in the basal ganglia in a rat model of Huntington’s disease. Neurore­port 12: 2125-2129 (2001)

41. Lastres-Becker I., Hansen H.H., Berrendero F., De Miguel R., Perez-Rosado A., Manzanares J., Ramos J.A., Fernandez-Ruiz J.: Alleviation of motor hyperactivity and neurochemical deficits by endocannabinoid uptake inhibi­tion in a rat model of Huntington’s disease. Synapse 44: 23-35 (2002)

42. Giuffrida A., Parsons L.H., Kerr T.M., Rodriguez De Fonseca F., Navarro M., Piomelli D.: Dopamine activation of endogenous cannabinoid signaling in dorsal striatum. Nat. Neurosci. 2: 358-363 (1999)

43. Sieradzan K.A., Fox S.H., Hill M., Dick J.P., Crossman A.R., Brotchie J.M.: Cannabinoids reduce levodopa-in­duced dyskinesia in Parkinson’s disease: a pilot study. Neurology 57: 2108-2111 (2001)

44. Makriyannis A., Mechoulam R., Piomelli D.: Therapeu­tic opportunities through modulation of the endocannabi­noid system. Neuropharmacology 48: 1068-1071 (2005)

45. Pertwee R.G.: Inverse agonism and neutral antago­nism at cannabinoid CB₁ receptors. Life Sci. 76: 1307-1324 (2005)

46. Boyd S.T., Fremming B.A.: Rimonabant-A selective CB1 Antagonist. Ann. Pharmacother. 39: 684-690 (2005)

47. Goutopoulos A., Makriyannis A.: From cannabis to cannabinergics: new therapeutic opportunities. Pharmacol. Ther. 95: 103-117 (2002)

48. Cravatt B.F., Lichtman A.H.: Fatty acid amide hy­drolase: An emerging therapeutic target in the endocan­nabinoid system. Curr. Opin. Chem. Biol. 7: 469-475 (2003)

49. Calignano A., La Rana G., Beltramo M., Makriyannis A., Piomelli D.: Potentiation of anandamide hypotention by the transport inhibitor AM404. Eur. J. Pharmacol. 337: R1-R2 (1997)

50. 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.: Modulation of anxiety through blockade of anandamide hydrolysis. Nat. Med. 9: 76-81 (2003)

51. Mechoulam R., Hanus L.: Cannabidiol: an overview of some chemical and pharmacological aspects. Part I: chemical aspects. Chem. Phys. Lipids 121: 35-43 (2002)

52. Walker J.M., Huang S.M.: Cannabinoid analgesia. Pharmacol. Ther. 95: 127-135 (2002)

53. Cravatt B.F., Lichtman A.H.: The endogenous can­nabinoid system and its role in nociceptive behavior. J. Neurobiol. 61: 149-160 (2004)

54. Iversen L.L., Chapman V.: Cannabinoids: a real pros­pect for pain relief ? Curr. Opin. Pharmacol. 2: 50-55 (2002)

55. Pertwee R.G.: Cannabinoid receptors and pain. Prog. Neurobiol. 63: 569-611 (2001)

56. Martin B.R., Lichtman A.H.: Cannabinoid transmission and pain perception. Neurobiol. Dis. 5: 447-461 (1998)

57. Zimmer A, Zimmer A.M., Hohmann A.G., Herkenham M., Bonner T.I.: Increased mortality, hypoactivity and hy­poalgesia in cannabinoid CB1 receptor knockout mice. Proc. Natl. Acad. Sci. USA 96: 5780-5785 (1999)

58. Di Marzo V., Breivogel C.S., Tao Q., Bridgen D.T., Razdan R.K., Zimmer A.M., Zimmer A., Martin B.R.: Lev­els, metabolism, and pharmacological activity of anan­damide in CB(1) cannabinoid receptor knockout mice: evidence for non-CB(1), non-CB(2) receptor-mediated actions of anandamide in mouse brain. J. Neurochem. 75: 2434-2444 (2000)

59. Manzanares J., Corchero J., Romero J., Fernandez Ruiz J.J., Ramos J.A., Fuentes J.A.: Pharmacological and biochemical interactions between opioids and cannabi­noids. Trends Pharmacol. Sci. 20: 287-294 (1999)

60. Corchero J., Manzanares J., Fuentes J.A.: Cannabi­noid/opioid crosstalk in the central nervous system. Crit. Rev. Neurobiol. 16: 159-172.

61. Naef M., Curatolo M., Petersen-Felix S., Arendt-Niel­sen L., Zbinden A., Brenneisen R.: The analgesic effect of oral delta-9-tetrahydrocannabinol (THC), morphine, and a THC-morphine combination in healthy subjects under experimental pain conditions. Pain 105: 79-98 (2003)

62. Cichewicz D.L.: Synergistic interactions between can­nabinoid and opioid analgesics. Life Sci. 74: 1317-1324 (2004)

63. Welch S.P., Thomas C., Patrick G.S.: Modulation of cannabinoid-induced antinociception after intracere­broventricular versus intrathecal administration to mice: possible mechanisms for interaction with morphine. J. Pharmacol. Exp. Ther. 272: 310-321 (1995)

64. Fuentes J.A., Ruiz-Gayo M., Manzanares J., Vela G., Reche I., Cochero J.: Cannabinoids as potential new anal­gesics. Life Sci. 65: 675-685 (1999)

65. Cichewicz D.L., Martin Z.L., Smith F.L., Welch S.P.: Enhancement mu opioid antinociception by oral delta9-tetrahydrocannabinol: dose-response analysis and recep­tor identification. J. Pharmacol. Exp. Ther. 289: 859-867 (1999)

66. Scott D.A., Wright C.E., Angus J.A.: Evidence that CB-1 and CB-2 cannabinoid receptors mediate antinociception in neuropathic pain in the rat. Pain 109: 124-131 (2004)

67. Russo E.: Cannabis for migraine treatment: the once and future prescription? An historical and scientific review. Pain 76: 3-8 (1998)

68. Russo E.: Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syn­drome and other treatment-resistant conditions? Neur. Endocrinol. Lett. 25: 31-39 (2004)

69. Williamson E.M., Evans F.J.: Cannabinoids in clinical practice. Drugs 6: 1303-1314 (2000)

70. Dogrul A., Gul H., Akar A., Yildiz O., Bilgin F., Guzeldemir E.: Topical cannabinoid antinociception: syn­ergy with spinal sites. Pain 105: 11-16 (2003)

71. Calignano A., La Rana G., Giuffrida A., Piomelli D.: Control of pain initiation by endogenous cannabinoids. Nature 394: 277-281 (1998)

72. Hanus L., Breuer A., Tchilibon S., Shiloah S., Golden­berg D., Horowitz M., Pertwee R.G., Ross R.A., Mechou­lam R., Fride E.: Hu-308: a specific agonist for CB₂, a pe­ripheral cannabinoid receptor. Proc. Natl. Acad. Sci. USA 96: 14228-14233 (1999)

73. Clayton N., Marshall F.H., Bountra C., O’Shaughnessy C.T.: CB1 and CB2 cannabinoid receptors are implicated in inflammatory pain. Pain 96: 253-260 (2002)

74. Ibrahim M.M., Deng H., Zvonok A., Cockayne D.A., Kwan J., Mata H.P. Vanderah T.W., Lai J., Porreca F., Makriyannis A., Malan T.P.: Activation of CB₂ cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: pain inhibition by receptors not present in the CNS. Proc. Natl. Acad. Sci. USA 100: 10529-10533 (2003)

75. Hohmann A.G., Farthing J.N., Zvonok A.M., Makriyan­nis A.: Selective activation of cannabinoid CB₂ receptors suppresses hyperalgesia evoked by intradermal capsaicin. J. Pharmacol. Exp. Ther. 308: 446-453 (2004)

76. Lichtman A.H., Leung D., Shelton C.C., Saghatelian A., Hardouin C., Boger D.L., Cravatt B.F.: Reversible in­hibitors of fatty acid amide hydrolase that promote analge­sia: evidence for an unprecedented combination of po­tency and selectivity. J. Pharmacol. Exp. Ther. 311: 441-448 (2004)

77. Campbell F.A., Tramer M.R., Carroll D., Reynolds D.J.M., Moore A.: Are cannabinoids an effective and safe treatment option in the management of pain? A qualitative systematic review. Br. Med. J. 323: 13-16 (2001)

78. Hensen B.: Cannabinoid therapeutics: high hopes for the future. Drug Discov. Today 10: 459-462 (2005)

79. Baker D., Pryce G.: The therapeutic potential of can­nabis in multiple sclerosis. Expert Opin. Investig. Drugs 12: 561-567 (2003)

80. Smith P.F.: Medicinal cannabis extracts for the treat­ment of multiple sclerosis. Curr. Opin. Investig. Drugs 5: 727-730 (2004)

81. Consroe P., Musty R., Rein J., Tillery W., Pertwee R.: The perceived effects of smoked cannabis on patients with multiple sclerosis. Eur. Neurol. 38: 44-48 (1996)

82. Pertwee R.G.: Cannabinoids and multiple sclerosis. Pharmacol. Ther. 95: 165-174 (2002)

83. Pryce G., Baker D.: Emerging properties of cannabi­noid medicines in management of multiple sclerosis. Trends Neurosci. 28: 272-276 (2005)

84. Killenstein J., Uitdehaag B.M., Polman C.H.: Cannabi­noids in multiple sclerosis: do they have a therapeutic role? Drugs 64: 1-11 (2004)

85. Baker D., Pryce G., Croxford J.L., Brown P., Pertwee R.G., Huffman J.W., Layward L.: Cannabinoids control spasticity and tremor in a multiple sclerosis model. Nature 404: 84-87 (2000)

86. Baker D., Pryce G., Croxford J.L., Brown P., Pertwee R.G., Makriyannis A., Khanolkar A., Layward L., Fezza F., Bisogno T., Di Marzo V.: Endocannabinoids control spas­ticity in a multiple sclerosis model. FASEB J. 15: 300-302 (2001)

87. Mattes R.D., Engelman K., Shaw L.M., Elsohly M.A.: Cannabinoids and appetite stimulation. Pharmacol. Bio­chem. Behav. 49: 187-195 (1994)

88. Berry E.M., Mechoulam R.: Tetrahydrocannabinol and endocannabinoids in feeding and appetite. Pharmacol. Ther. 95: 185-190 (2002)

89. Williams C.M., Kirkham T.C.: Anandamide induces overeating: mediation by central cannabinoid (CB₁) re­ceptors. Psychopharmacology 143: 315-317 (1999)

90. Jamshidi N., Taylor D.A.: Anandamide administration into the ventromedial hypothalamus stimulates appetite in rats. Br. J. Pharmacol. 134: 1151-1154 (2001)

91. Colombo G., Agapio R., Diaz G., Lobina C., Reali, R. Gessa G.L.: Appetite suppression and weight loss after the cannabinoid antagonist SR 141716. Life Sci. 63: PL113-PL117 (1998)

92. Cota D., Genghini S., Pasquali R., Pagotto U.: Antago­nizing the cannabinoid receptor type 1: A dual way to fight obesity. J. Endocrinol. Invest. 26: 1041-1044 (2003)

93. Cota D., Marsicano G., Lutz B., Vicennat V., Stalla G.K., Pasquali R., Pagotto U.: Endogenous cannabinoid system as a modulator of food intake. Int. J. Obes. Relat. Metab. Disord. 27: 289-301 (2003)

94. Lucas V.S., Laszlo J.: Δ⁹-Tetrahydrocannabinol for refractory vomiting induced by cancer chemotherapy. JAMA 243: 1241-1243 (1980)

95. Guzman M.: Cannabinoids: Potential anticancer agents. Nat. Rev. Cancer 3: 745-755 (2003)

96. Hall W., Christie M., Currow D.: Cannabinoids and cancer: causation, remediation, and palliation. Lancet Oncol. 6: 35-42 (2005)

97. Darmani N.A.: The potent emetogenic effects of the endocannabinoid 2-AG (2-arachidonylglycerol) are blocked by delta 9-tetrahydrocannabinol and other cannabinoids. J. Pharmacol. Exp. Ther. 300: 34-42 (2002)

98. Darmani N.A.: Delta 9-tetrahydrocannabinol and syn­thetic cannabinoids prevent emesis produced by the can­nabinoid CB1 receptor antagonist/inverse agonist SR141716A. Neuropsychopharmacology 24: 198-203 (2001)

99. Schwartz R.H., Voth E.A., Sheridan M.J.: Marijuana to prevent nausea and vomiting in cancer patients: A survey of clinical oncologists. South Med J. 90: 167-172 (1997)

100. Martin B.R., Wiley J.L.: Mechanism of action of can­nabinoids: How it may lead to treatment of cachexia, eme­sis, and pain. J. Support. Oncol. 2: 305-316 (2004)

101. Doblin R.E., Kleiman M.A.R.: Marijuana as anti-emetic medicine: a survey of oncologists’ experiences and attitudes. J. Clin. Oncol. 9: 1314-1319 (1991)

102. Abrahamov A., Abrahamov A., Mechoulam R.: An efficient new cannabinoid anti-emetic in pediatric oncology. Life Sci. 56: 2097-2102 (1995)

103. Grundy R.I.: The therapeutic potential of the cannabi­noids in neuroprotection. Expert Opin. Investig. Drugs 11: 1-10 (2002)

104. Mechoulam R., Panikashvili D., Shohami E.: Can­nabinoids and brain injury: therapeutic implications. Trends Mol. Med. 8: 58-61 (2002)

105. Fowler C.J.: Plant-derived, synthetic and endogenous cannabinoids as neuroprotective agents: Non-psychoac­tive cannabinoids, “entourage” compounds and inhibitors of N-acyl ethanolamine breakdown as therapeutic strate­gies to avoid psychotropic effects. Brain Res. Rev. 41: 26-43 (2003)

106. Glass M., Faull R.L.M., Dragunow M: Loss of can­nabinoid receptors in the substantia nigra in Huntington’s disease. Neuroscience 56: 523-527 (1993)

107. Glass M., Dragunow M., Faull R.L.M.: The pattern of neurodegeneration in Huntington’s disease: a comparative study of cannabinoid, dopamine, adenosine and GABA-A receptor alterations in the human basal ganglia in Hunt­ington’s disease. Neuroscience 97: 505-519 (2000)

108. Hampson A.J., Grimaldi M., Axelrod J., Wink D.: Cannabidiol and (-)Δ⁹-tetrahydrocannabinol are neuro­protective antioxidants. Proc. Natl. Acad. Sci. USA 95: 8268-8273 (1998)

109. Reddy P.H., Williams M., Tagle D.A.: Recent ad­vances in understanding the pathogenesis of Huntington’s disease. Trends Neurosci. 22: 248-255 (1999)

110. Hampson A.J., Bornheim L.M., Scanziani M., Yost C.S., Gray A.T., Hansen B.M., Leonoudakis D.J., Bickler P.E.: Dual effects of anandamide on NMDA receptor-me­diated responses and neurotransmission. J. Neurochem. 70: 671-676 (1998)

111. Beal M.F.: Aging, energy and oxidative stress in neu­rodegenerative diseases. Ann. Neurol. 38: 357-366 (1995)

112. Knoller N., Levi L., Shoshan I., Reichenthal E., Razon N., Rappaport Z.H., Biegon A.: Dexanabinol (HU-211) in the treatment of severe closed injury: a randomized, pla­cebo-controlled, phase II clinical trial. Crit. Care Med. 30: 548-554 (2002)

113. Nagayama T., Sinor A.D., Simon R.P., Chen J., Gra­ham S.H., Jin K., Greenberg D.A.: Cannabinoids and neu­roprotection in global and focal cerebral ischemia and in neuronal cultures. J. Neurosci. 19: 2987-2995 (1999)

114. Panikashvili D., Simeonidou C., Ben-Shabat S., Ha­nus L., Breuer A., Mechoulam R. Shohami E.: An endoge­nous cannabinoid (2-AG) is neuroprotective after brain injury. Nature 413: 527-531 (2001)

115. van der Stelt M., Veldhuis W.B., Bär P.R., Veldink G.A., Vliegenthart J.F.G., Nicolay K.: Neuroprotection by Δ9-tetrahydrocannabinol, the main active compound in marijuana, against ouabain-induced in vivo excitotoxicity. J. Neurosci. 21: 6475-6479 (2001)

116. Hansen H.H., Azcoitia I., Pons S., Romero J., Garcia-Segura L.M., Ramos J.A. Hansen H.S., Fernandez-Ruiz J.: Blockade of cannabinoid CB1 receptor function protects against in vivo disseminating brain damage folowing NMDA-induced excitotoxicity. J. Neurochem. 82: 154-158 (2002)

117. Muthian S., Rademacher D.J., Roelke C.T., Gross G.J., Hillard C.J.: Anandamide content is increased and CB₁ cannabinoid blockade is protective during transient, focal cerebral ischemia. Neuroscience 129: 743-750 (2004)

118. Maldonado R.: Study of cannabinoid dependence in animals. Pharmacol. Ther. 95: 153-164 (2002)

119. Maldonado R., Rodriguez de Fonseca F.: Cannabi­noid addiction: Behavioral models and neural correlates. J. Neurosci. 22: 3326-3331 (2002)

120. Παναγής Γ.Θ.: Βιοψυχολογία της ενίσχυσης και του εθισμού. Ψυχολογία 5: 71-83 (1998)

121. Παναγής Γ.Θ.: Νευροεπιστήμη της συμπεριφοράς. Ιατρικές Εκδόσεις Π.Χ. Πασχαλίδης, Αθήνα, 2001

122. Braida D., Pozzi M., Cavallini R., Sala M.: Condi­tioned place preference induced by the cannabinoid ago­nist CP 55,940: Interaction with opioid system. Neurosci­ence 104: 923-926 (2001)

123. Chaperon F., Soubrie P., Puech A.J., Thiebot M-H.: Involvement of central cannabinoid (CB1) receptors in the establishment of place conditioning in rats. Psychophar­macology 135: 324-332 (1998)

124. Cheer J.F., Kendall D.A., Marsden C.A.: Cannabinoid receptors and reward in the rat: A conditioned place pref­erence study. Psychopharmacology 151: 25-30 (2000)

125. Deroche-Gamonet V., Le Moal M., Piazza P.V., Sou­brie P.: SR141716, a CB1 receptor antagonist, decreases the sensitivity to the reinforcing effects of electrical brain stimulation in rats. Psychopharmacology 157: 254-259 (2001)

126. Fattore L., Cossu G., Martellotta C.M., Fratta W.: Intravenous self-administration of the cannabinoid CB1 receptor agonist WIN 55,212-2 in rats. Psychopharmacol­ogy 156: 410-416 (2001)

127. Gardner E.L., Paredes W., Smith D., Donner A., Milling C., Cohen D., Morrison, D.: Facilitation of brain stimulation reward by delta-9-tetrahydrocannabinol. Psy­chopharmacology 96: 142-144 (1988)

128. Harris R.T., Waters W., McLendon D.: Evaluation of reinforcing capability of delta-9-tetrahydrocannabinol in monkeys. Psychopharmacology 37: 23-29 (1974)

129. Lepore M., Vorel S., Lowinson J.H., Gardner E.L.: Conditioned place preference induced by Δ9-tetrahydro­cannabinol: Comparison with cocaine, morphine and food reward. Life Sci. 56: 2073-2080 (1995)

130. Mallet P.E., Beninger R.J.: Δ⁹-Tetrahydrocannabinol, but not the endogenous cannabinoid receptor ligand an­andamide, produces conditioned place avoidance. Life Sci. 62: 2431-2439 (1998)

131. Martelotta M.C., Cossu G., Fattore L., Gessa G.L., Fratta W.: Self-administration of the cannabinoid receptor agonist WIN 55,212-2 in drug-naive mice. Neuroscience 85: 327-330 (1998)

132. Stark P., Dews P.B.: Cannabinoids. I. Behavioral effects. J. Pharmacol. Exp. Ther. 214: 124-130 (1980)

133. Van Ree J.M., Slangen J., de Wied D.: Intravenous self-administration of drugs in rats. J. Pharmacol. Exp. Ther. 20: 547-557 (1978)

134. Vlachou S., Nomikos G.G., Panagis G.: WIN 55,212-2 decreases the reinforcing actions of cocaine through CB₁ cannabinoid receptor stimulation. Behav. Brain Res. 141: 215-222 (2003)

135. Vlachou S., Nomikos G.G., Panagis G.: CB₁ cannabi­noid receptor agonists increase intracranial self-stimulation thresholds in the rat. Psychopharmacology 179: 498-508 (2005)

136. Wickelgren I.: Marijuana: Harder than thought? Sci­ence 276: 1967-1968 (1997)

137. McGregor I.S., Issakidis C.N., Prior G.: Aversive effects of the synthetic cannabinoid CP 55,940 in rats. Pharmacol. Biochem. Behav. 53: 657-664 (1996)

138. Parker L.A., Gillies T.: THC-induced place and taste aversions in Lewis and Sprague-Dawley rats. Behav. Neu­rosci. 109: 71-78 (1995)

139. Koob G.F.: Drugs of abuse: Anatomy, pharmacology and function of reward pathways. Trends Pharmacol. Sci. 13: 177-184 (1992)

140. Παναγής Γ.Θ., Καστελλάκης Α.Α.: Ο εθισμός υπό το πρίσμα της Βιοψυχολογίας και της Ψυχοφαρμακολογίας: Νευρωνικοί μηχανισμοί και η σημασία τους στη θεραπεία. Ψυχολογία 6: 55-77 (1999)

141. Mailleux P., Vanderhaeghen J.J.: Distribution of neu­ronal cannabinoid receptor in the adult rat brain: a com­parative receptor binding radioautography and in situ hy­bridization histochemistry. Neuroscience 48: 655-668 (1992)

142. De Vries T., Schoffelmeer A.N.M.: Cannabinoid CB₁ receptors control conditioned drug seeking. Trends Phar­macol. Sci. 26: 420-426 (2005)

143. Arnold J.C.: The role of endocannabinoid transmis­sion in cocaine addiction. Pharmacol. Biochem. Behav. 81: 396-406 (2005)

144. Le Foll B., Goldberg S.R.: Cannabinoid CB₁ receptor antagonists as promising new medications for drug de­pendence. J. Pharmacol. Exp. Ther. 312: 875-883 (2005)

145. Le Foll B., Goldberg S.R.: Rimonabant, a CB₁ antago­nist, blocks nicotine-conditioned place preferences. Neu­roreport 15: 2139-2143 (2004)

146. De Vries T.J., Homberg J.R., Binnekade R., Raaso H., Schoffelmeer A.N.: Cannabinoid modulation of the reinforcing and motivational properties of heroin and her­oin-associated cues in rats. Psychopharmacology 168: 164-169 (2003)

147. Rodriguez de Fonseca F., Roberts A.J., Bilbao A., Koob G.F., Navarro M.: Cannabinoid receptor antagonist SR141716A decreases operant ethanol self administration in rats exposed to ethanol-vapor chambers. Zhongguo Yao Li Xue Bao 20: 1109-1114 (1999)

148. Cohen C., Perrault G., Voltz C., Steinberg R., Soubrie P.: SR141716, a central cannabinoid (CB(1)) receptor antagonist, blocks the motivational and dopamine releas­ing effects of nicotine in rats. Behav. Pharmacol. 13: 451-463 (2002)

149. De Vries T.J., Shaham Y., Homberg J.R., Crombag H., Schuurman K., Dieben J., Vanderschuren L.J., Schof­felmeer A.N.: A cannabinoid mechanism in relapse to cocaine seeking. Nat. Med. 7: 1151-1154 (2001)

150. Giuffrida A., Parsons L.H., Kerr T.M., de Fonseca F.R., Navarro M., Piomelli D.: Dopamine activation of endogenous cannabinoid signaling in dorsal striatum. Nat. Neurosci. 2: 358-363 (1999)

151. Viveros M.P., Marco E.M., File S.E.: Endocannabi­noid system and stress and anxiety responses. Pharma­col. Biochem. Behav. 81: 331-342 (2005)

152. Degroot A., Nomikos G.G.: Genetic deletion and pharmacological blockade of CB1 receptors modulates anxiety in the shock-probe burying test. Eur. J. Neurosci. 20: 1059-1064 (2004)

153. Manzanares J., Corchero J., Fuentes J.A.: Opioid and cannabinoid receptor mediated regulation of the increase in adrenocorticotropin hormone and corticosterone plasma concentrations induced by central administration of Δ⁹-tetrahydrocannabinol in rats. Brain Res. 839: 173-179 (1999)

154. Weidenfeld J., Feldman S., Mechoulam R.: Effect of the brain constituent anandamide, a cannabinoid receptor agonist, on the hypothalamo-pituitary-adrenal axis in the rat. Neuroendocrinology 59: 110-112 (1994)

155. Gaetani S., Cuomo V., Piomelli D.: Anandamide hydrolysis: a new target for anti-anxiety drugs? Trends Mol. Med. 9: 474-478 (2003)

156. Marsicano G., Wotjak C.T., Azad S.C., Bisogno T., Rammes G., Cascio M.G., Hermann H., Tang J., Hofmann C., Zieglgansberger W., Di Marzo V., Lutz B.: The en­dogenous cannabinoid system controls extinction of aver­sive memories. Nature 418: 488-489 (2002)

157. Galve-Roperph I., Sanchez C., Cortesz M.L., Gomez del Pulgar T., Izquierdo M., Guzman M.: Antitumoral action of cannabinoids: involvement of sustained ceramide ac­cumulation and ERK activation. Nat. Med. 6: 313-319 (2000)

158. Fride E.: Cannabinoids and cystic fibrosis: a novel approach to etiology and therapy. J. Cannabis Ther. 2: 59-71 (2002)

159. Hillard C.J.: Endocannabinoids and vascular function. J. Pharmacol. Exp. Ther. 294: 27-32 (2000)

160. Mandavilli A.: Marijuana researchers reach for pot of gold. Nat. Med. 9: 1227 (2003)

161. Julien, R.M.: Βασικές αρχές ψυχοφαρμακολογίας. Ιατρικές Εκδόσεις Π.Χ. Πασχαλίδης, Αθήνα, 2003

162. Lichtman A.H., Peart J., Poklis J.L., Bridgen D.T., Razdan R.K., Wilson D.M., Poklis A., Meng Y., Byron P.R., Martin B.R.: Pharmacological evaluation of aerosolized cannabinoids in mice. Eur. J. Pharmacol. 399: 141-149 (2000)

163. Wilson D.M., Peart J., Martin B.R., Bridgen D.T., Byron P.R., Lichtman A.H.: Physiochemical and pharma­cological characterization of a delta(9)-THC aerosol gen­erated by a metered dose inhaler. Drug Alcohol Depend. 67: 259-267 (2002)

164. Giuffrida A., Beltramo M., Piomelli D.: Mechanisms of endocannabinoid inactivation: Biochemistry and pharma­cology. J. Pharmacol. Exp. Ther. 298: 7-14 (2001)