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MICHELE A. NOONAN
AMELIA J. EISCH
Regulation of adult
neurogenesis by cannabinoids
ABSTRACT
In the adult mammalian brain, new neurons are born
throughout life, and these new cells may influence
learning, memory, olfaction, and even mood. The putative
function of these new neurons suggests that manipulation
of adult neurogenesis could be used therapeutically in the
future, and emphasizes the importance of understanding
how neurogenesis is regulated. Voluntary exercise and
antidepressants are examples of factors that increase
neurogenesis, while stress and drugs of abuse alcohol,
nicotine, psychostimulants, opiates decrease
neurogenesis. In contrast to the clear negative influence of
these drugs of abuse, cannabinoids have mixed influence,
with some marijuana-like compounds actually enhancing
neurogenesis. Here we review the literature in an effort to
clarify the controversial impact of cannabinoids on adult
neurogenesis. Taking into account key differences in
endogenous versus exogenous cannabinoids and
nonspecific influence of various cannabinoid compounds,
we conclude that cannabinoid influence on neurogenesis
is less controversial than initially appears.
INTRODUCTION
The discovery of adult neurogenesis almost 40 years ago
opened a new chapter for neuroscience and new hope for
medicine (1). Since these new neurons incorporate into
distinct areas of the brain important for memory the
hippocampus for spatial and the olfactory bulb for
olfactory memory (2-4) understanding how neural stem
cells are regulated has tremendous potential to shed light
on mechanisms of memory formation (5, 6) as well as
generate novel approaches for repair of the injured brain.
In an attempt to unravel the regulation of adult
neurogenesis, it was discovered that positive stimuli, such
as voluntary exercise and hippocampal learning,
generally enhance neurogenesis while negative stimuli
decrease neurogenesis (7). In particular, compounds with
abuse potential, including alcohol, nicotine, cocaine,
methamphetamine, morphine, and PCP, all decrease
hippocampal neurogenesis (8-14). This led to an intriguing
hypothesis: decreased adult neurogenesis underlies or
contributes to the cognitive deficits seen after exposure to
drugs of abuse (15). If true, then normalization of adult
neurogenesis might be critical for treatment of addiction
and prevention of relapse. Marijuana contains the
cannabinoid 9-tetrahydrocannabinol (THC), and, similar
to other abused drugs, is known to cause cognitive deficits
(16-18). Adult neurogenesis correlates with cognitive
function (7), so in keeping with the hypothesis that all
drugs of abuse decrease neurogenesis (15), it was
predicted that cannabinoids would also decrease
neurogenesis. While early work was consistent with this
hypothesis (19-21), the hypothesis appeared to take a hit
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87
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88
29. W.A. Devane, J. Axelrod Proc Natl Acad Sci U S A 91, pp. 66986701 (1994)
30. T. Bisogno, et al. Biochem J 322 (Pt 2), pp. 671-677 (1997)
31. W.A. Devane, et al. Mol Pharmacol 34, pp. 605-613 (1988)
32. M. Herkenham, et al. Proc Natl Acad Sci U S A 87, pp. 1932-1936
(1990)
33. R.E. Hampson, S.A. Deadwyler J Neurosci 20, pp. 8932-8942
(2000)
34. K. Mackie Handb Exp Pharmacol, pp. 299-325 (2005)
35. S. Caille, L.H. Parsons Neuropsychopharmacology 31, pp. 804-813
(2006)
36. B. Le Foll, S.R. Goldberg J Pharmacol Exp Ther 312, pp. 875-883
(2005)
37. N.D. Volkow, R.A. Wise Nat Neurosci 8, pp. 555-560 (2005)
38. T.C. Kirkham, S.A. Tucci CNS Neurol Disord Drug Targets 5, pp.
272-292 (2006)
39. C.P. Cannon Clin Cornerstone 7, pp. 17-26 (2005)
40. R. Maldonado Pharmacol Ther 95, pp. 153-164 (2002)
41. R. Maldonado, F. Rodriguez de Fonseca J Neurosci 22, pp. 33263331 (2002)
42. A. Zangen, et al. J Neurosci 26, pp. 4901-4907 (2006)
43. M. Di, et al. Curr Pharm Des 6, pp. 1361-1380 (2000)
44. S.L. Palmer, et al. Curr Pharm Des 6, pp. 1381-1397 (2000)
45. N.M. Kogan, R. Mechoulam J Endocrinol Invest 29, pp. 3-14 (2006)
46. A. Mahadevan, R.K. Razdan Aaps J 7, pp. E496-502 (2005)
47. A. Mahadevan, et al. J Med Chem 43, pp. 3778-3785 (2000)
48. E. Fride Eur J Pharmacol 500, pp. 289-297 (2004)
49. E.T. Tzavara, et al. Br J Pharmacol 138, pp. 544-553 (2003)
50. E.T. Tzavara, et al. J Neurosci 23, pp. 9374-9384 (2003)
51. E. Sulcova, et al. Pharmacol Biochem Behav 59, pp. 347-352 (1998)
52. S.P. Welch, et al. J Pharmacol Exp Ther 273, pp. 1235-1244 (1995)
53. M.D. Randall, et al. Br J Pharmacol 142, pp. 20-26 (2004)
54. B. Lutz Biochem Pharmacol 68, pp. 1691-1698 (2004)
55. J.L. Wiley, et al. Br J Pharmacol 145, pp. 293-300 (2005)
56. M. Begg, et al. Pharmacol Ther 106, pp. 133-145 (2005)
57. N. Lozovaya, et al. J Neurosci 25, pp. 7499-7506 (2005)
58. B.R. Christie, H.A. Cameron Hippocampus 16, pp. 199-207 (2006)
59. G. Kempermann, et al. Trends Neurosci 27, pp. 447-452 (2004)
60. T. Hagg Trends Neurosci 28, pp. 589-595 (2005)
61. A. Garcia, et al. Aging Cell 3, pp. 363-371 (2004)
62. I. Galve-Roperh, et al. Nat Med 6, pp. 313-319 (2000)
63. R.S. Duman Biol Psychiatry 56, pp. 140-145 (2004)
64. L. Santarelli, et al. Science 301, pp. 805-809 (2003)
65. A. Dranovsky, R. Hen Biol Psychiatry 59, pp. 1136-1143 (2006)
66. E. Molina-Holgado, et al. J Neurosci 22, pp. 9742-9753 (2002)
67. S.R. Smith, et al. J Pharmacol Exp Ther 293, pp. 136-150 (2000)
68. J.F. Cheer, et al. Psychopharmacology (Berl) 151, pp. 25-30 (2000)
69. S.S. Newton, R.S. Duman Curr Neurovasc Res 1, pp. 261-267 (2004)
70. T.D. Palmer, et al. J Comp Neurol 425, pp. 479-494 (2000)
71. H.A. Cameron, R.D. McKay J Comp Neurol 435, pp. 406-417 (2001)
72. N.L. Hayes, R.S. Nowakowski Brain Res Dev Brain Res 134, pp. 7785 (2002)
73. J.P. Gong, et al. Brain Res 1071, pp. 10-23 (2006)
74. J.L. Croxford, T. Yamamura J Neuroimmunol 166, pp. 3-18 (2005)
75. B. Steiner, et al. Glia 46, pp. 41-52 (2004)
76. T. Namba, et al. Eur J Neurosci 22, pp. 1928-1941 (2005)
77. P. Ambrogini, et al. Brain Res 1017, pp. 21-31 (2004)
78. L.S. Overstreet-Wadiche, et al. J Neurosci 26, pp. 4095-4103 (2006)
79. H. van Praag, et al. Nature 415, pp. 1030-1034 (2002)
80. L.A. Desouza, et al. Mol Cell Neurosci 29, pp. 414-426 (2005)
81. C. Ledent, et al. Science 283, pp. 401-404 (1999)
82. B.F. Cravatt, et al. Proc Natl Acad Sci U S A 98, pp. 9371-9376 (2001)
83. G. Marsicano, et al. Science 302, pp. 84-88 (2003)
84. Z. Jarai, et al. Proc Natl Acad Sci U S A 96, pp. 14136-14141 (1999)
85. N.E. Buckley, et al. Eur J Pharmacol 396, pp. 141-149 (2000)
86. V.M. Heine, et al. Eur J Neurosci 21, pp. 1304-1314 (2005)
87. S.A. Golech, et al. Brain Res Mol Brain Res 132, pp. 87-92 (2004)
88. N. Battista, et al. Curr Neurovasc Res 1, pp. 129-140 (2004)
89. Y. Sun, et al. J Clin Invest 111, pp. 1843-1851 (2003)
90. J. Hellsten, et al. Biol Psychiatry 58, pp. 871-878 (2005)
91. R.G. Pertwee Aaps J 7, pp. E625-654 (2005)
92. L. Grinspoon, J.B. Bakalar Jama 273, pp. 1875-1876 (1995)
Note added in proof: the speed of relevant research in the field of adult
neurogenesis has forced us to omit numerous relevant articles published
after submission of this article, including S.H. Kim, et al., JPET, 2006, and
L.J. Kochman, et al., Brain Res, 2006.