Drug discovery

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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from studies suggesting that cannabinoids enhance

neurogenesis (22, 23). Why the discrepancy? Should
increased neurogenesis join the growing list of beneficial
effects of cannabinoids (24-26), perhaps providing fuel to
the medical marijuana movement? Or are there reasons
from semantic to pharmacological why the reported
enhancement of neurogenesis by cannabinoids should not
be compared to human marijuana ingestion? Here we
review the current literature on the impact of cannabinoids
on adult neurogenesis in an effort to clear the smoke about
this controversial topic.
CANNABINOIDS: INTRIGUING COMPOUNDS
FOR NEUROSCIENCE
Scientists have long been intrigued with the influence
exogenous cannabinoids, like marijuana and hashish,
have on cognition and memory (27, 28). This interest was
enhanced by the discovery that cannabinoids are made
endogenously in the brain by a variety of cell types (29,
30) and by the isolation and characterization of the seven
transmembrane G protein coupled cannabinoid receptors
in the brain (31, 32). The endocannabinoids include
arachidonylethanolamide (anandamide, or AEA) and 2arachidonoyl glycerol (2-AG). These endogenous agonists
of the cannabinoid receptors play critical roles in encoding
working and short term memory (18, 33). Two regions
involved in these memory processes, the hippocampus and
prefrontal cortex, are in highly enriched in cannabinoid
receptors (34), making memory responsive to endogenous
as well as exogenous cannabinoids. Interestingly, addictive
drugs such as morphine and cocaine alter the
cannabinoid system (35, 36), and it has been suggested
that antagonists to the cannabinoid receptors would be
useful as a treatment for addiction. Obesity can be viewed
as an addiction disorder (37), therefore cannabinoid
antagonists are also being considered for their use in
treating obesity (36, 38). Given these and other myriad
therapeutic approaches that target the endocannabinoid
system (39), a high priority has been placed on identifying
the physiological and behavioral impact of stimulating or
interfering with the endocannabinoid system.
To this end, cannabinoid research in the brain has
pursued two avenues of research. One explores the
rewarding and reinstatement properties of THC and
similar agents in an effort to understand and treat the
addicted brain (40-42). The other dissects the
physiological and biochemical targets of THC and
endocannabinoids in an effort to harness them for
medical use and enhanced understanding of brain
function (43-45). Numerous compounds have been
developed to mimic or block the binding of cannabinoids
like AEA and 2-AG to their receptors, each with a
different selectivity and potency at a cannibinoid receptor.
These compounds include the CB1 selective agonist

chimica oggi Chemistry Today Vol 24 nr 5 September/October 2006

THE BASICS OF ADULT NEUROGENESIS

Contrary to a long-held belief, we now know that new
neurons are continually added to the hippocampus and
the olfactory bulb throughout the mammalian lifespan (1,
58). The first step of adult neurogenesis cell division and
exit from the cell cycle actually occurs in two nearby
and distinct areas, the hippocampal subgranular zone
(SGZ) and the rostral subventricular zone (SVZ). After a
period of time, some cells die, but the surviving cells
differentiate and migrate to their final destination where
they integrate into hippocampal or olfactory neural
circuitry, respectively, and achieve their mature neuronal
phenotype (5). This emphasizes that adult neurogenesis
per se is a process, not a time point (59), and that each
phase of progenitor cell development should be evaluated
for the impact of an exogenous factor, like cannabinoid
exposure (60, 61). Indeed, as discussed below, the
balance of cell birth, cell death, and cell survival; the
distinction between proliferation, differentiation and
maturation; and even the distinction between different
subtypes of proliferating cells are all critical to
understanding the controversy that underlies the research
on cannabinoids and neurogenesis.

Drug discovery

arachidonyl-2-chloroethylamide/(all Z)-N-(2-cycloethyl)5,8,11,14-eicosatetraenamide (ACEA), the nonselective

CB agonists WIN 55,212-2 and (6aR)-trans-3-(1,1dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6dimethyl-6H-dibenzo[b,d]pyran-9-methanol (HU210),
and the cannabinoid antagonists N-(piperidin-1-yl)-5-(4chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1Hpyrazole-3-carboximide hydrochloride (SR141716A) and
(1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1piperidinyl-1H-pyrazole-3-carboxamide (AM251) (46,
47). Each synthesized compound has varying affinity for
the two cannabinoid receptors, CB1 and CB2, but
increasing evidence suggests that exogenous and
endogenous cannabinoids differ in many fundamental
ways, including distinct coupling with cellular signaling
pathways, dose response curves, physiological effects,
and pharmacological interactions with receptors (48-55).
To emphasize the latter point, synthetic and endogenous
cannabinoids each have their own nonspecific effects on
various receptors. Endocannabinoids AEA and
cannabidiol bind to an unknown endothelial cell receptor
(56), AEA binds to the vanilloid receptor (56), and many
cannabinoids bind to glycine receptors (57). While the
distinct receptor binding profile of each cannabinoid
agonist is useful for in vitro pharmacological studies, they
make it difficult if not impossible to interpret certain in
vivo data, and they also make it difficult to compare the
impact of distinct agonists (HU210 vs. AEA).
In sum, the development of novel synthetic cannabinoids
and the isolation of endogenous cannabinoids have
provided neuroscientists with a much fuller tool box with
which to examine the stimulation and interference of the
cannabinoid system. However, the distinct chemical and
biological profile of each compound makes it challenging
to compare across studies that use different cannabinoids,
and makes it unwise to make direct inference about the in
vivo effects of marijuana itself.

CANNABINOID REGULATION OF PROLIFERATION

Proliferation of newborn cells is the first step towards
adult neurogenesis. In the adult brain, proliferation is
commonly measured by injecting bromodeoxyuridine
(BrdU), a marker of cells that are in synthesis (S) phase of
the cell cycle, sacrificing animals at relatively short time
interval (e.g. 2 hr), and counting the number of BrdUimmunoreactive cells in the SGZ or SVZ (15). Using this
approach, it was hypothesized that cannabinoids would
decrease proliferation of neural stem cells in the adult

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Drug discovery
86

brain, similar to the antiproliferative effects of

cannabinoids on tumor cells (e.g. 62). Only one paper
has examined the impact of a cannabinoid on the adult
hippocampal SGZ at a short time interval after BrdU
injection, and the finding was surprising. Chronic
treatment with the exogenous cannabinoid agonist
HU210 was found to increase the number of BrdU cells in
the hippocampal SGZ (23). This finding was interpreted a
proproliferative effect of this exogenous cannabinoid.
While only HU210 was used in vivo, in vitro experiments
suggest that the endogenous cannabinoids AEA and 2AG similarly enhanced proliferation (20). Since enhanced
neurogenesis is associated with antidepressant action
(63-65), the authors then applied the drug to an animal
model of anxiety, and saw a significant decrease in
anxiety related behaviors. The authors were careful not to
generalize their effect to all cannabinoids, but
nevertheless this publication received much media
coverage, prompting headlines like Marijuana may
make your brain grow (http://www.nature.com/news/
2005/051010/full/051010-12.html) and Mary Janes
New Brain (http://sciencenow.sciencemag.org/cgi/
content/full/2005/1013/2) and raising questions about
whether marijuana has promise as an antidepressant.
This publication by Jiang et al. certainly suggests the
antianxiety potential of HU210, and this may lead to
important breakthroughs in development of new drugs for
anxiety disorders, or perhaps for some depressive-related
disorders. However, there are two important caveats to this
study. First, HU210 is not equivalent to THC (66, 67). In
fact, HU210 is aversive in animal models (e.g. 68) making
it unclear what conclusions can be drawn from this study
about exposure to marijuana, THC, or even other
cannabinoids. It is certainly intriguing that HU210 has
antianxiety and perhaps antidepressive efficacy in animal
models (23) and this behavioral characterization
encourages closer analysis of HU210s effects on
locomotion, growth factors, and vasculature, all things that
may be central to its effect of enhancing neurogenesis (e.g.
69, 70). Second, the results of this study examine a mixed
population of proliferating and maturing cells, not just
proliferating cells. As animals were sacrificed 24 hours after
the last BrdU injection, all BrdU labeled cells would have
gone through mitosis, and some cells would have reentered
the cell cycle (71, 72). Perhaps the effect shown in this
paper is primarily occurring in maturing cells whose
survival may be enhanced by certain cannabinoids (see
below). The data may also be explained by an HU210induced shortening of the cell cycle, which might mask any
effect on proliferation. This interpretation deserves
consideration, since treatment with the cannabinoid
antagonist AM281 acutely or chronically did not change
proliferation in the SGZ (23). In general, this study by Jiang
et al. urges closer examination of the therapeutic potential
of HU210, and it suggests an interesting diversity in the
action of certain cannabinoids that is distinct from other
drugs of abuse. However, the finding that this cannabinoid
agonist enhances proliferation cannot be generalized to
the in vivo use of cannabinoids, including THC, without
significantly more work.
While it remains unclear what impact the exogenous
cannabinoid HU210 has specifically on the proliferation of
new cells in the adult brain, it is clear that a subpopulation
of proliferating cells destined to be neurons can respond to
either exogenous or endogenous cannabinoids. The
majority of neural stem cells express the CB1 receptor (22,
23), with expression waning during later proliferating
stages, and again detectable as the soon-to-be neuron
nears terminal differentiation (21, 59). Interestingly, broad
neuronal of CB2 expression in the brain was recently
discovered (73), whereas CB2 was previously thought to

be associated with nonneuronal cells or the immune

system (74). This new finding should encourage
exploration of whether stem cells express CB2 as well as
CB1 receptors. Taken together with studies showing the
broad expression of CB1 receptors on mature neurons
(34), these data show that cannabinoids can act at
receptors on stem cells and mature cells that contact
neurogenic regions of the brain, thereby having both
direct and indirect on proliferating cells in the adult brain.
Given the importance of endocannabinoids to myriad
physiological functions (e.g. 7), it is intriguing to consider
whether cannabinoid receptors on neural stem cells play a
role in the regulation of adult neural precursor
proliferation by stimuli unrelated to addictive drugs.
CANNABINOID REGULATION OF SURVIVAL
Up to 9,000 new cells are born each day in the adult rat
brain, but many of these cells are destined to die prior to
incorporation into brain circuitry (e.g. 71). Injecting BrdU
and then sacrificing animals several weeks later provides
an appropriate measure of the survival of newborn cells in
the adult brain (15). Using this approach, several groups
have studied the impact of cannabinoids on the survival of
newborn cells. A variety of drugs and species have been
studied, and the results are not clear, presumably
emphasizing the distinct pharmacological profile of each
drug and the different responsiveness of each species. For
example, chronic treatment with the cannabinoid agonist
M-AEA did not significantly change survival in the adult
rat SGZ, although there was a trend to an increase (19). In
contrast, the more potent cannabinoid agonist HU210
administered chronically increased survival in the rat SGZ
(23). While these studies generally suggest that
cannabinoids enhance survival of new neurons in the adult
brain, it is curious that chronic treatment with the
cannabinoid antagonist AM281 did not change survival in
the SGZ (23). Even more problematic is that while the
agonist HU210 enhanced survival, the cannabinoid
antagonist SR141716A also increased survival in CD1
mice and C57BL/6 mice (22). Nonspecific inverse agonist
actions of the cannabinoid antagonist SR141716A (22,
67), as well as possible activation of the CB2 receptor by
HU210 (66) may explain the differential effect of
cannabinoids on survival. In sum, these studies suggest
that CB1 activation or inactivation does not change
survival of newly born cells, but activation of CB2 or other
unknown cannabinoid receptors may increase survival.
CANNABINOID REGULATION
OF DIFFERENTIATION
Although most surviving cells in the adult SGZ and SVZ
become hippocampal or olfactory bulb neurons, some
cells can become other cell types, including astrocytes
(75, 76). Therefore, a key component of any
neurogenesis study is to examine whether the dividing
cells achieve a neuronal fate, that is, whether they
actually become neurons. The most rigorous of
neurogenesis studies utilize electrophysiological
recordings to probe for neuronal characteristics (e.g. 77,
78, 79). However, most studies instead
immunohistochemically analyze cells labeled with BrdU
four weeks earlier for proteins of neuronal lineage, such
as neuronal nuclear protein, or astrocytic lineage, such as
glial fibrillary acidic protein (15). Unlike the compoundand species-dependent effects of cannabinoids on
survival, cannabinoids appear to have a clear negative
influence on neuronal differentiation. The cannabinoid

chimica oggi Chemistry Today Vol 24 nr 5 September/October 2006

LESSONS FROM TRANSGENIC KNOCKOUT MICE

Work with exogenous and endogenous cannabinoids
presents a diverse picture of effects on the process of
neurogenesis: unclear effect on proliferation, but clear
potential for stem cells to be regulated; possible
enhancement of survival; possible depression of neuronal
fate and enhancement astrocytic fate. Given the various
results produced by different pharmacological application
of cannabinoids, it is useful to have transgenic mouse
models that are lacking key components of the cannabinoid
signaling pathway in the brain. Two transgenic mouse lines
that have been examined for alterations in adult
neurogenesis include the CB1 knockout (KO) mouse (81),
and the fatty acid amide hydrolase (FAAH) KO mouse,
which lacks the enzyme that breaks down
endocannabinoids (82). Both mice lack expression of their
respective genes from conception. Theoretically,
neurogenesis in the CB1 KO mouse should mimic that seen
in a nontransgenic mouse given a CB1 receptor antagonist
chronically. As discussed above, it appears as if
pharmacological blockade of the CB1 receptor is
insufficient to alter proliferation or survival in the adult
brain. However, adult CB1 KO mice showed decreased
proliferation in the SGZ compared to littermate controls
(21). CB1 KO mice also had decreased survival of newly
born cells in the SGZ and SVZ, as well as decreased
astroglial differentiation and increased neuronal
differentiation (21, 22). This increase in the proportion of
cells that become neurons in the CB1 KO may be a
compensation for the smaller pool of progenitors. In sum,
examination of adult neurogenesis in the CB1 KO mouse
suggests that CB1 receptor activation is necessary for basal
levels of proliferation and the survival of progenitors.
How can we reconcile the altered proliferation and
survival in the CB1 KO with a lack of a clear effect from
cannabinoid antagonists in nontransgenic mice? One
possibility, discussed above, is that the cannabinoid
antagonists examined for neurogenesis effects have a
complicated pharmacological profile. In addition, a major
caveat of the CB1 KO mouse line is that CB1 is missing
during prenatal brain development, a time when CB1
receptors are usually expressed (48). Interference with the
endocannabinoids system during development may cause
changes that are not related to cannabinoid function in the
adult. A conditional CB1 KO was made recently (83), and
this would help address these concerns. In addition, if CB2
plays a redundant or opposite role in neurons, knocking
out CB1 alone will not have the intended of effect of
removing cannabinoid signaling. A double CB1/CB2 KO
mouse may be necessary to answer these questions; one
has been developed, but this mouse line has not been
tested for changes in adult neurogenesis (84).
Turning to the FAAH KO mice, one might expect that
knockout of the critical enzyme to metabolize
endocannabinoids would have similar levels of
neurogenesis as a nontransgenic mouse given a

cannabinoid agonist chronically: possible increased

proliferation, enhanced survival, and decreased neuronal
and enhanced glial differentiation. As was expected,
FAAH KO mice showed increased proliferation and
survival of newly born cells in the SGZ compared to
littermate controls (20, 21), and fewer progenitors
adopted a neuronal fate. Again, this may be a
compensatory mechanism keeping a normal number of
new neurons in the SGZ despite the increase in
proliferation and survival. This model suggests that
increased levels of endocannabinoids result in more glial
cells in the SGZ, but not necessarily more neurons. From
these transgenic studies using the CB1 KO and FAAH KO
mouse lines, it may be that the either the SGZ is adept at
keeping a homeostatic level of new neurons in a chronic
case of overactivation or underactivation of CB receptors,
or that these constituitive knockout lines develop
compensations in other neurotransmitter or growth factor
pathways that keep neurogenesis at a normal level.
Further studies will need to clarify this issue. It is important
to note that these knockout mice are actually testing the
influence of stimulation of (FAAH KO) or interference with
(CB1 KO) the endogenous cannabinoid system, and it is
inappropriate to extend these findings to the potential for
exogenous cannabinoids. If anything, the distinct findings
between manipulations of endogenous cannabinoids
(transgenic mice, antagonist exposure) and exogenous
cannabinoids (agonist exposure, drugs of abuse)
underscore the necessity for further research.

Drug discovery

antagonist SR141716A increases neuronal differentiation

in the adult brain (19), while the cannabinoid agonist MAEA inhibits neuronal differentiation by shifting cells to
an astroglial fate (19). Thus, at least with these
compounds, activation of cannabinoid receptors
decreases neuronal differentiation while inactivation of
cannabinoid receptors increases it. This is a particularly
notable finding, since few treatments have been shown to
alter the neuronal fate of neural progenitors (80). Further
exploration of the ability of these and other cannabinoid
agonists and antagonists to shift cell fate will be very
beneficial for the therapeutic use of stem cells.

FUTURE DIRECTIONS FOR THE CANNABINOID FIELD

In addition to the future directions for research indicated
throughout this review, several points deserve emphasis.
The recent discovery of the CB2 receptor in neurons in the
brain (73) begs the question of whether CB2 is expressed
in neural progenitors. Prior to this finding, CB2 function in
the brain had not received much attention, and therefore
little is known. Until the function of CB2 in the brain is
clarified, it would be wise to use CB1 specific drugs for
further exploration of the role of CB1 in neurogenesis. It
will be intriguing to see how neurogenesis is changed in
the CB2 KO (85), double CB1/CB2 KO (84) and
conditional CB1 KO (83) mouse lines, as such studies
may tease out the complications of the cannabinoid story.
The nonspecific actions of cannabinoids to activate noncannabinoid receptors (e.g. endothelial, vanilloid,
glycine) may force reinterpretation of recent findings, as
well as offer a new avenue of research. Neurogenesis can
be modulated by changes in hippocampal vasculature
(70, 86). Since 2-AG and other cannabinoids can act on
VR1 receptors, which are present on brain endothelial
cells (87, 88), it is possible that cannabinoids could alter
neurogenesis by changing the vascular niche. This is an
area of active interest in regards to other regulators of
neurogenesis (69, 86, 89, 90) and it may be fruitful for
researchers to examine the role of the vasculature in
cannabinoid-induced alterations in neurogenesis.
CONCLUSIONS
Review of the current literature and media articles on
adult neurogenesis and cannabinoids might lead one to
conclude that cannabinoids enhance neurogenesis. This
conclusion is incorrect. It is true that chronic treatment with
certain cannabinoid agonists can increase proliferation of
newly born cells, as well as promote their survival.
However, cannabinoid agonists may also switch a dividing
cells neuronal fate to an astroglial one. Thus, the net result

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may be increased astrogliogenesis, not neurogenesis.

Nonspecific actions of some cannabinoid drugs and even
species-specific effects may explain discrepancies in the
literature, such as increased neurogenesis after chronic
treatment with one cannabinoid agonist and not another.
This underscores the need for more studies with several
cannabinoid agonists to clarify the whether cannabinoids
have a unified influence on neurogenesis, or whether the
impact varies with the pharmacological specificity of the
compound used. If the latter is true, it would be literally and
intellectually profitable for researchers to probe the
differences between cannabinoids that promote astrogenesis,
and cannabinoids that promote neurogenesis.
One point is exceedingly clear: there is not sufficient
evidence to say that cannabinoids as a group have a
unified effect on adult neurogenesis. Additional exogenous
and endogenous cannabinoids must be examined prior to
concluding that, unlike other drugs of abuse, cannabinoids
increase neurogenesis. In fact, it would be interesting to see
if cannabinoids with addictive potential decrease
neurogenesis, while those with aversive properties increase
neurogenesis. Clarification of how cannabinoids
individually, not as a group of compounds impact
neurogenesis has tremendous potential to elucidate not
only the field of addiction, but also of stem cell biology as it
may guide us in future efforts to use these multipotent cells
to repair the brain after injury or disease (e.g. 91). Equally
important, and perhaps more immediate, cannabinoid
agonists and antagonists may in the future be prescribed
for a multitude of health problems (36, 38, 92). A key step
in any potential use of these compounds for medical
purposes will require much deeper knowledge, including
information on how such treatments may modify
neurogenesis. Given the growing links between
neurogenesis, memory and mood (5), it will be essential to
ensure that possible side effects on learning and memory
or mood are minimized.
ACKNOWLEDGMENTS
AJE is supported by a NIDA R01 grant DA016765 and a
Young Investigator Award from the National Alliance for
Research on Schizophrenia and Depression.
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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.

MICHELE A. NOONAN, AMELIA J. EISCH*

*Department of Psychiatry
University of Texas Southwestern Medical Center
5323 Harry Hines Blvd.
Dallas, TX 75390-9070

chimica oggi Chemistry Today Vol 24 nr 5 September/October 2006