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Pharmacological exploitation of the endocannabinoid
system: new perspectives for the treatment of depression
and anxiety disorders?
Exploração farmacológica do sistema endocanabinoide: novas
perspectivas para o tratamento de transtornos de ansiedade e
depressão?
Correspondence
Fabrício A. Moreira
Departamrnt of Pharmacology, Institute of Biological Sciences,
Universidade Federal de Minas Gerais (UFMG)
Av. Antônio Carlos, 6627
31270-901 Belo Horizonte, MG, Brazil
Phone.: (+55 31) 3409-2720
E-mail: fabriciomoreira@icb.ufmg.br
Viviane M. Saito,1 Carsten T. Wotjak,2 Fabrício A. Moreira1,3
Abstract
Objective: The present review provides a brief introduction into the
endocannabinoid system and discusses main strategies of pharmacological
interventions. Method: We have reviewed the literature relating to the
endocannabinoid system and its pharmacology; both original and review
articles written in English were considered. Discussion: Cannabinoids
are a group of compounds present in Cannabis sativa (hemp), such as
D9-tetrahydrocannabinol, and their synthetic analogues. Research on
their pharmacological profile led to the discovery of the endocannabinoid
system in the mammalian brain. This system comprises at least two
G-protein coupled receptors, CB1 and CB2, their endogenous ligands
(endocannabinoids; e.g. the fatty acid derivatives anandamide and
2-arachydonoyl glycerol), and the enzymes responsible for endocannabinoid
synthesis and catabolism. Endocannabinoids represent a class of
neuromessengers, which are synthesized on demand and released from
post-synaptic neurons to restrain the release of classical neurotransmitters
from pre-synaptic terminals. This retrograde signalling modulates a variety
of brain functions, including anxiety, fear and mood, whereby activation of
CB1 receptors was shown to exert anxiolytic- and antidepressant-like effects
in preclinical studies. Conclusion: Animal experiments suggest that drugs
promoting endocannabinoid action may represent a novel strategy for the
treatment of depression and anxiety disorders.
Descriptors: Cannabis sativa; Cannabinoids; Endocannabinoids; Anxiety;
Depression
original article
1 Graduate Program in Neurosciences, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
2 Max Planck Institute of Psychiatry, Research Group Neuronal Plasticity, Munich, Germany
3 Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
Resumo
Objetivo: Este artigo revisa o sistema endocanabinoide e as respectivas
estratégias de intervenções farmacológicas. Método: Realizou-se uma
revisão da literatura sobre o sistema endocanabinoide e a sua farmacologia,
considerando-se artigos originais ou de revisão escritos em inglês. Discussão:
Canabinoides são um grupo de compostos presentes na Cannabis sativa
(maconha), a exemplo do D9-tetraidrocanabinol e seus análogos sintéticos.
Estudos sobre o seu perfil farmacológico levaram à descoberta do sistema
endocanabinoide do cérebro de mamíferos. Este sistema é composto por
pelo menos dois receptores acoplados a uma proteína G, CB1 e CB2, pelos
seus ligantes endógenos (endocanabinoides; a exemplo da anandamida e
do 2-araquidonoil glicerol) e pelas enzimas responsáveis por sintetizá-los e
metabolizá-los. Os endocanabinoides representam uma classe de mensageiros
neurais que são sintetizados sob demanda e liberados de neurônios pós-
sinápticos para restringir a liberação de neurotransmissores clássicos de
terminais pré-sinápticos. Esta sinalização retrógrada modula uma diversidade
de funções cerebrais, incluindo ansiedade, medo e humor, em que a ativação
de receptores CB1 pode exercer efeitos dos tipos ansiolítico e antidepressivo em
estudos pré-clínicos. Conclusão: Experimentos com modelos animais sugerem
que drogas que facilitam a ação dos endocanabinoides podem representar uma
nova estratégia para o tratamento de transtornos de ansiedade e depressão.
Descritores: Cannabis sativa; Canabinoides; Endocanabinoides; Ansiedade;
Depressão
Introduction
Because of its analgesic, antiemetic and tranquilizing effects,
the herb Cannabis sativa has been used for medical purposes for
centuries. In addition, preparations of cannabis, such as marijuana,
hashish or skunk, have a long history as drugs of abuse.1 Typical
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Endocannabinoids, depression and anxiety
Revista Brasileira de Psiquiatria • vol 32 • Suppl I • may2010 • S8
pepper substance capsaicin.9 Within the central nervous system,
TRPV1 is expressed in postsynaptic nerve terminals and might be
activated intracellularly by anandamide. Other endocannabinoid
receptors are the formerly “orphan” G-protein coupled receptor
55 (GPR55) and the peroxisome proliferator activated receptors
(PPAR). Furthermore, an allosteric site at the CB1 receptor has
been identified, which may provide an interesting target for
pharmacological intervention.10
2. Modes of endocannabinoid action
Classical neurotransmitters such as acetylcholine, amino
acids (e.g. glutamate, GABA) or monoamines (e.g. dopamine,
serotonin) fulfil the following criteria: 1) The transmitters are
synthesized in pre-synaptic terminals from specific precursors and
stored in synaptic vesicles. 2) They are released into the synaptic
cleft after calcium influx. 3) There are specific mechanisms
to terminate their actions, including uptake and enzymatic
degradation.11,12 These criteria render endocannabinoids atypical
messengers, which mediate information transfer from post- to pre-
synaptic terminals in a retrograde manner: Endocannabinoids are
synthesized on-demand and not stored in vesicles. The synthesis
occurs in post-synaptic neurons following calcium influx and
subsequent activation of phospholipases (phospholipase D in the
case of anandamide and diacyglycerol lipase in the case of 2-AG),
which convert membrane phospholipids into endocannabinoids.13
They seem to immediately reach the synaptic cleft by free or
assisted diffusion and to bind to presynaptically localized CB1
receptors.14 Via a complex network of intracellular signalling
processes, activation of CB1 receptors finally results in decreased
calcium influx into the axon terminals and, thus, to down-
regulation of transmitter release. Other than CB1, activation of
TRPV1 receptors by anandamide leads to increased depolarisation
of postsynaptic membranes. Therefore, activation of CB1 and
TRPV1 seem to exert opposing effects.
As is the case for some classical neurotransmitters, the actions of
endocannabinoids are limited by a two-step process: internalization
followed by catabolism.15 The first step remains elusive, since it is
still a matter of debate whether internalization of endocannabinoids
occurs passively via diffusion or by specific transporters.16-19
After internalization, endocannabinoids undergo enzymatic
hydrolysis. The primary enzymes responsible for anandamide and
2-AG hydrolysis are fatty acid amide hydrolase (FAAH)20 and
monoacylglyceride lipase (MGL),21 respectively. Intriguingly, the
two endocannabinoids are degraded either pre- (2-AG) or post-
synaptically (anandamide). Both FAAH and MGL have emerged
as important pharmacological targets with promising therapeutic
potential. Figure 1 summarizes our current knowledge about the
major “players” of the endocannabinoid system.
3. Pharmacological manipulation of the endocan-
nabinoid system
Several pharmacological tools have been developed that interfere
with the endocannabinoid system. Some may act directly at CB1
or CB2 receptors (i.e., agonists or antagonist). Others may act in
effects of cannabis abuse are amnesia, sedation and a feeling of well-
being described as “bliss”.2 In the middle of the last century, Raphael
Mechoulam and colleagues identified D9-tetrahydrocannabinol
(D9-THC) as the main psychoactive ingredient of this herb. Today,
it is known that Cannabis sativa contains more than 60 substances,
such as cannabidiol, cannabinol and cannabicromene, which are
referred to as phytocannabinoids.3 Their lipid nature posed a
significant obstacle to chemical experiments, which might explain
why the discovery of phytocannabinoids occurred late compared to
other natural compounds (e.g. morphine was isolated from opium
in the XIX century). The molecular structure rendered it likely that
D9-THC exerts its effects primarily by changing physico-chemical
characteristics of cell membranes. Therefore it came as a surprise
that specific binding sites could be identified within the mammalian
brain,4 followed by isolation and characterization of endogenous
binding substances, named endocannabinoids.5 The development
of novel pharmacological compounds targeting receptors or ligand
synthesis and degradation revealed a number of complex brain
functions, which are tightly controlled by the endocannabinoid
system. The aim of the present review is to briefly introduce
this system and its pharmacology, to discuss its involvement in
psychopathology and to illustrate its therapeutic potential.
Method
We have reviewed the literature relating to the endocannabinoid
system and the possibilities of pharmacological interventions
in this system. Original studies employing animals or humans
subjects and review articles written in English were considered.
Discussion
1. The endocannabinoid system of the brain
The endocannabinoid system comprises the receptors, the
endogenous agonists and the related biochemical machinery
responsible for synthesizing these substances and terminating
their actions. The receptors were named by the International
Union of Basic and Clinical Pharmacology (IUPHAR) according
to their order of discovery as CB1 and CB2 receptors.6 Both
are G-protein coupled receptors. Within the central nervous
systems, CB1 is primarily localized at presynaptic nerve terminals
and accounts for the majority of neurobehavioural effects of
cannabinoids. CB2, in contrast, is the major cannabinoid receptor
in the immune system, but may also be expressed in neurons.
The main endogenous agonists of CB1 and CB2 are arachidonic
acid derivates. Arachidonoyl ethanolamine was the first
endocannabinoid characterized and nicknamed anandamide, after
the Sanskrit ananda, meaning “bliss”.5 Later on, 2-arachydonoyl
glycerol (2-AG) was also identified,7 followed by N-arachidonoyl
dopamine (NADA), 2-arachidonoyl-glycerol ether (noladine)
and O-arachidonoyl ethanolamine, also termed virodhamine.8
Endocannabinoids may bind to receptors other than CB1 and
CB2, for instance to the transient receptor potential vanilloid
type-1 (TRPV1), formerly the “capsaicin receptor” or “vanilloid
receptor” (VR1), an ion channel. In the peripheral nervous
system, TRPV1 is activated by heat, low pH and the red chilli
Saito VM et al.
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a more indirect manner, e.g. by interfering with mechanisms that
terminate endocannabinoid action. Table 1 lists representative
examples for each of the intervention strategies, which will be
introduced in the following paragraphs.
1) Cannabinoid receptor agonists
Based on the chemical structure of D9-THC, several synthetic
agonists have been developed with diverse intrinsic activities
and affinities for cannabinoid receptors.6,22 In this context the
mouse tetrad emerged as a valuable tool for characterization of
CB1 receptor agonists. The tetrad stands for four main effects of
systemic cannabinoid treatment: hypolocomotion, catalepsia,
hypothermia and analgesia.23,24 Studies in conditional knockout
mice with cell type-specific deletion of CB1 revealed that the tetrad
effects are mediated by different neuronal populations.25
Some agonists show the same affinity for CB1 and CB2 receptors,
such as D9-THC, nabilone, WIN-55,212-2, CP-55940 or HU-
210. Others bind rather selectively to CB1 (e.g. ACEA) or CB2,
(e.g. AM-1241, JWH-133). In addition, compounds acting on
the allosteric site of CB1 have been developed (e.g. Org275796,
Org29647 and PSNCBAM).10 Apart from D9-THC, other
phytocannabinoids with low affinity for CB1 receptor (e.g.
cannabidiol) may act through complex mechanisms, targeting
receptors not related to the endocannabinoid system.26-28
2) Enhancement of endocannabinoid action
Drugs that enhance endocannabinoid action may provide a
more subtle strategy for pharmacological interventions than direct
activation of cannabinoid receptors. Given that endocannabinoids
are produced and released on-demand, compounds interfering
with endocannabinoid uptake and degradation could increase
CB1 signalling with temporal and neuroanatomical specificity.
Such drugs are expected to induce fewer side-effects compared to
direct agonists, as will be discussed later. A number of drugs have
been developed that seemingly increase endocannabinoid action
by blocking endocannabinoid uptake.17,29 Examples are AM404,
VDM11, UCM707, OMDM and AM1172. Drawbacks of these
compounds are that they may lack pharmacological selectivity, in
addition to targeting, with the endocannabinoid transporter a still
elusive biochemical entity.
Another strategy to increase endocannabinoid signalling is to
inhibit catabolic processes. This approach appears to be the most
promising, since the enzymes responsible for endocannabinoid
hydrolysis are well characterized. Among the FAAH-inhibitors,
URB-597 has been most widely studied so far.30,31 This compound
irreversibly blocks FAAH with good target selectively, leading to
increased anandamide levels. More recently, inhibitors of MGL
have been developed as well (e.g. URB602 or JZL184), which
cause increased bioavailability of 2-AG.32,33 Inhibition of 2-AG,
but not anandamide, hydrolysis exerts tetrad effects similar to CB1
agonists.33 This underscores the functional dissociation of 2-AG
and anandamide action.
3) Inhibition of endocannabinoid action
Several antagonists have been synthesized with different
affinities for CB1 and CB2 receptors. The first and prototype
compound that binds to the CB1 receptor and blocks the effects
of its endogenous ligands is SR141716A (SR1; rimonabant).34
Another widely employed CB1 antagonist is AM25.6,22 CB2
receptors, in turn, can be blocked by SR1414528 and AM630
in a selective manner.6,22
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An alternative strategy to reduce endocannabinoid signalling
would be by inhibiting anabolic enzymes. So far, this strategy
has not been widely explored, possibly because of the diversity
of mechanisms responsible for anandamide and 2-AG synthesis.
First compounds which may inhibit 2-AG synthesis are O-3640
and O-3841.35
4. Role of the endocannabinoid system in psychiatric
disorders
Rimonabant was the first pharmacological compound which
interfered with the endocannabinoid system to be approved
for the treatment of metabolic syndrome. Today we know that
the drug exerts its beneficial effects primarily by blocking CB1
receptors in the periphery. However, because of its lipophilic
nature, rimonabant could cross the blood-brain barrier and get
into the central nervous system. Here it had devastating side effects
in patients, such as increase in depression, suicidality and anxiety
disorder.36 After being turned down by the FDA, rimonabant (also
known as AccompliaTM) has been retracted from market by Sanofi-
Aventis. The rimonabant saga illustrates how clinicians learnt by
“accident” that the plethora of anxiogenic effects described for
the compound in animal models also applied to human beings.
They might have been “warned” before by the dramatic effects
of cannabis abuse on the regulation of emotional states: cannabis
consumption may induce anxiolytic, euphoric and rewarding
effects, in addition to improving mood.2 However, in addition,
psychotic symptoms, panic attacks and mood disturbances were
frequently encountered after chronic cannabis consumption.2
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Animal studies have provided more direct evidence for
involvement of the endocannabinoid system in anxiety and
depression. They revealed that the endocannabinoid system is
functional in several brain regions, such as the prefrontal cortex,
hippocampus, amygdala and midbrain periaqueductal gray,37
that are involved in diverse psychiatric disorders. Moreover,
mutant mice lacking expression of CB1 receptors exhibit a
plethora of behavioural changes that resemble stress-related
psychopathology.38 For instance, they show an anxiety-like
phenotype in exploration based tests,39,40 sustained fear responses,41
impaired stress-coping40,42 and impaired extinction of aversive,43
but not appetitive,44 memories. Treatment of wild-type mice with
CB1 receptor antagonists revealed essentially the same phenotypes.
Changes in endocannabinoid levels were consonant with
the behavioural data. For instance, a variety of stressors caused
an increase in endocannabinoid levels in the amygdala43 or
periaqueductal gray.32 At the same time they reduced them
in other structures, such as the hippocampus.45 Divergent
regulation of anandamide vs. 2-AG synthesis and tonic vs. phasic
changes illustrate the complexity of those processes. Changes
in endocannabinoid signalling within the hypothalamus46 may
contribute to the modulatory consequences of the endocannabinoid
system on regulation of hormonal stress responses.47
Few studies have measured the levels of endocannabinoids
in psychiatric disorders so far: basal serum concentrations of
AEA and 2-AG were significantly reduced in women with
major depression,48 suggesting a role for this system in this
disorder. Furthermore, schizophrenic patients show increased
anandamide levels in the cerebrospinal fluid.49 However, because
of the complexity of intracerebral endocannabinoid signalling
mentioned before, endocannabinoid measurements in blood and
even cerebrospinal fluid samples might be of limited value for our
understanding of the involvement of the endocannabinoid system
in mood disturbances.
Taken together, with a few exceptions,50,51 the majority of the
preclinical and clinical data support a scenario, where attenuated
endocannabinoid signalling promotes the occurrence of anxiety-
and depression-like symptoms.
5. Pharmacological and therapeutic perspectives
The diverse substances that interfere with the endocannabinoid
system and CB1 signalling have been extensively studied in animals
in terms of efficacy and side-effects in mood and anxiety regulation.
The following paragraphs discuss the advantages and limitations
of each of the treatment strategies (for summary see Table 1).
1) Cannabinoid receptor agonists
Low doses of D9-THC and its synthetic analogues exerted
anxiolytic-like effects in animal models of generalized anxiety
disorder.52 Furthermore, cannabinoids impaired the formation
but facilitated the extinction of contextual fear.53,54 Apart from
anxiolytic-like activities, cannabinoids showed antidepressant-
like properties. At the behavioural level, they alleviated the
consequences of inescapable stressors in animal models of
depression.55,56 Moreover, cannabinoids increased the levels of
neurotrophins, induced hippocampal neurogenesis and suppressed
stress hormone secretion.38,42,48
Although one could envisage therapeutic applications for these
substances, there are major obstacles that limit their applicability
in clinical practice. For instance, cannabinoid treatment may
cause addiction and tolerance, induce sedative effects, and impair
learning and memory. In general, low doses tend to induce
anxiolysis, whereas higher doses may induce opposite effects.57,58
The reasons for these differences remain to be determined. They
might be attributed to dose-dependent actions upon different brain
regions and neural populations.58 Moreover, high cannabinoid
concentrations may lead to desensitization/ internalization of
CB1 receptors, thus resulting in decreased endocannabinoid
signalling. It is tempting to assume that such processes account
for the paradoxical effects of cannabis consumption on emotional
responses such as episodes of anxiety and panic.2 To circumvent
these problems, future studies may try to target the allosteric site
of the CB1 receptor.10
2) Compounds that enhance endocannabinoid action
The major difference between the action of endogenous and
exogenous cannabinoids is the on-demand activation of the
endocannabinoid system in a temporally and spatially restricted
manner. Drugs that enhance endocannabinoid action have been
extensively studied in animal models of anxiety and depression.
For instance, blockade of endocannabinoid up-take by AM404
induced anxiolytic-like effects59,60 and facilitated the extinction
of conditioned fear.61,62 Also the treatment with the anandamide-
hydrolysis inhibitor URB597 exerted anxiolytic-like effects similar
to benzodiazepines.30,60,63-65 URB597 showed also antidepressant-
like actions in animal models of stress-related psychopathology.66,67
Noteworthy, URB597 increased the activity of monoaminergic
neurons projecting from the brain stem to the prefrontal cortex,
an effect similar to those observed after chronic treatment with
antidepressant drugs.67
It is of note that some well-established pharmacological
compounds, such as aspirin or paracetamol, depend for their
action at least partially on endocannabinoid signalling.68 This
may contribute their mood-lifting effects.69
In summary, anandamide uptake and/or hydrolysis represent
promising pharmacological targets for the development of novel
therapeutic strategies of depression and anxiety disorders. The
effects induced by these “endocannabinoid-enhancers” differ from
those of direct CB1 agonists in several aspects: first, they avoid
ubiquitous receptor activation, but promote endocannabinoid
action in a temporally and spatially restricted manner. Second, they
show a broader therapeutic window. Third, pre-clinical studies
point to a significantly lower risk of addiction, abuse liability and
tolerance. Fourth, the occurrence of biphasic paradoxical effects
on emotional responses was less evident.
The applicability of “endocannabinoid-enhancers” is limited by
promiscuous binding capabilities of anandamide, For instance,
binding to TRPV1 seems to exert opposing effects to those
Endocannabinoids, depression and anxiety
Revista Brasileira de Psiquiatria • vol 32 • Suppl I • may2010 • S12
mediated via CB1.57,70 Hence, the simultaneous blockade of
FAAH and TRPV1 may represent a reasonable approach to obtain
more effective anxiolytic and/or antidepressant drugs. In fact, the
compound arachidonoyl serotonin (AA-5HT), which meets those
objectives, induced anxiolytic-like effects in mice with higher
efficacy than URB597.64
3) Cannabinoid receptors antagonists
The development of novel generations of CB1 receptor
antagonists with restricted access to the brain may enable the
exploitation of the beneficial effects of blocked endocannabinoid
signalling in peripheral tissues (e.g. hepatocytes or adipocytes) on
diabetes and metabolic syndrome in absence of the devastating
side effects on mood and cognition.36
Conclusion
Malfunctions in the endocannabinoid system may promote
the development and maintenance of psychiatric disorders such
as depression, phobias and panic disorder. Thus, CB1 agonists
or inhibitors of anandamide hydrolysis are expected to exert
antidepressant and anxiolytic effects. Future studies should
consider 1) the development of CB1 antagonists that cannot
readily cross the blood-brain barrier, 2) shifts in the balance of
CB1 vs. TRPV1 signalling, 3) the allosteric site of CB1 receptor
and 4) the potential involvement of CB2 receptor in mood
regulation. Striking similarities in (endo)cannabinoid action in
animals and men render it likely that the new pharmacological
principle outlined in the present article may find their way into
clinical practice.
Acknowledgments
F.A.M. is a recipient of a research grant from Fundação de Apoio à Pesquisa
do Estado de Minas Gerais (FAPEMIG). C.T.W. is recipient of research
grants from the Max Planck Society.
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References
1. Zuardi AW. History of cannabis as a medicine: a review. Rev Bras Psiquiatr.
2006;28(2):153-7.
2. Hall W, Solowij N. Adverse effects of cannabis. Lancet. 1998;352(9140):1611-6.
3. Mechoulam R. Marihuana chemistry. Science. 1970;168(936):1159-66.
4. Devane WA, Dysarz FA 3rd, Johnson MR, Melvin LS, Howlett AC.
Determination and characterization of a cannabinoid receptor in rat
brain. Mol Pharmacol. 1988;34(5):605-13.
5. Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson
D, Mandelbaum A, Etinger A, Mechoulam R. Isolation and structure
of a brain constituent that binds to the cannabinoid receptor. Science.
1992;258(5090):1946-9.
6. Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder
CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee
RG. International Union of Pharmacology. XXVII. Classification of
cannabinoid receptors. Pharmacol Rev. 2002;54(2):161-202.
7. Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz
AR, Gopher A, Almog S, Martin BR, Compton DR, Pertwee RG, Griffin
G, Bayewitch M, Barg J, Vogel Z. Identification of an endogenous
2-monoglyceride, present in canine gut, that binds to cannabinoid
receptors. Biochem Pharmacol. 1995;50(1):83-90.
8. De Petrocellis L, Di Marzo V. An introduction to the endocannabinoid system:
from the early to the latest concepts. Best Pract Res Clin Endocrinol Metab.
2009;23(1):1-15.
9. Ross RA. Anandamide and vanilloid TRPV1 receptors. Br J Pharmacol.
2003;140(5):790-801.
10. Ross RA. Allosterism and cannabinoid CB(1) receptors: the shape of things
to come. Trends Pharmacol Sci. 2007;28(11):567-72.
11. Burnstock G. Autonomic neurotransmission: 60 years since sir Henry Dale.
Annu Rev Pharmacol Toxicol. 2009;49:1-30.
12. Wotjak CT, Landgraf R, Engelmann M. Listening to neuropeptides by
microdialysis: echoes and new sounds? Pharmacol Biochem Behav.
2008;90(2):125-34.
13. Piomelli D. The molecular logic of endocannabinoid signalling. Nat Rev
Neurosci. 2003;4(11):873-84.
14. Egertová M, Giang DK, Cravatt BF, Elphick MR. A new perspective on
cannabinoid signalling: complementary localization of fatty acid
amide hydrolase and the CB1 receptor in rat brain. Proc Biol Sci.
1998;265(1410):2081-5.
15. Di Marzo V, Fontana A, Cadas H, Schinelli S, Cimino G, Schwartz JC, Piomelli
D. Formation and inactivation of endogenous cannabinoid anandamide
in central neurons. Nature. 1994;372(6507):686-91.
16. Beltramo M, Stella N, Calignano A, Lin SY, Makriyannis A, Piomelli D.
Functional role of high-affinity anandamide transport, as revealed by
selective inhibition. Science. 1997;277(5329):1094-7.
17. Giuffrida A, Beltramo M, Piomelli D. Mechanisms of endocannabinoid
inactivation: biochemistry and pharmacology. J Pharmacol Exp Ther.
2001;298(1):7-14.
18. Glaser ST, Abumrad NA, Fatade F, Kaczocha M, Studholme KM, Deutsch
DG. Evidence against the presence of an anandamide transporter. Proc
Natl Acad Sci U S A. 2003;100(7):4269-74.
19. Glaser ST, Kaczocha M, Deutsch DG. Anandamide transport: a critical review.
Life Sci. 2005;77(14):1584-604.
20. Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB.
Molecular characterization of an enzyme that degrades neuromodulatory
fatty-acid amides. Nature. 1996;384(6604):83-7.
21. Dinh TP, Carpenter D, Leslie FM, Freund TF, Katona I, Sensi SL,
Kathuria S, Piomelli D. Brain monoglyceride lipase participating
in endocannabinoid inactivation. Proc Natl Acad Sci U S A.
2002;99(16):10819-24.
22. Pertwee RG. Ligands that target cannabinoid receptors in the brain: from THC
to anandamide and beyond. Addict Biol. 2008;13(2):147-59.
23. Compton DR, Johnson MR, Melvin LS, Martin BR. Pharmacological profile of
a series of bicyclic cannabinoid analogs: classification as cannabimimetic
agents. J Pharmacol Exp Ther. 1992;260(1):201-9.
24. Martin BR, Compton DR, Thomas BF, Prescott WR, Little PJ, Razdan
RK, Johnson MR, Melvin LS, Mechoulam R, Ward SJ. Behavioral,
biochemical, and molecular modeling evaluations of cannabinoid analogs.
Pharmacol Biochem Behav. 1991;40(3):471-8.
25. Monory K, Blaudzun H, Massa F, Kaiser N, Lemberger T, Schütz G, Wotjak
CT, Lutz B, Marsicano G. Genetic dissection of behavioural and
autonomic effects of Delta(9)-tetrahydrocannabinol in mice. PLoS Biol.
2007;5(10):e269.
26. Izzo AA, Borrelli F, Capasso R, Di Marzo V, Mechoulam R. Non-psychotropic
plant cannabinoids: new therapeutic opportunities from an ancient herb.
Trends Pharmacol Sci. 2009;30(10):515-27.
27. Zuardi AW. Cannabidiol: from an inactive cannabinoid to a drug with wide
spectrum of action. Rev Bras Psiquiatr. 2008;30(3):271-80.
28. Zuardi AW, Crippa JA, Hallak JE, Moreira FA, Guimarães FS. Cannabidiol,
a Cannabis sativa constituent, as an antipsychotic drug. Braz J Med Biol
Res. 2006;39(4):421-9.
29. Beltramo M, Stella N, Calignano A, Lin SY, Makriyannis A, Piomelli D.
Functional role of high-affinity anandamide transport, as revealed by
selective inhibition. Science. 1997;277(5329):1094-7.
30. Kathuria S, Gaetani S, Fegley D, Valiño 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. 2003;9(1):76-81.
31. Piomelli D, Tarzia G, Duranti A, Tontini A, Mor M, Compton TR, Dasse
O, Monaghan EP, Parrott JA, Putman D. Pharmacological profile of
the selective FAAH inhibitor KDS-4103 (URB597). CNS Drug Rev.
2006;12(1):21-38.
32. Hohmann AG, Suplita RL, Bolton NM, Neely MH, Fegley D, Mangieri R,
Krey JF, Walker JM, Holmes PV, Crystal JD, Duranti A, Tontini A, Mor
M, Tarzia G, Piomelli D. An endocannabinoid mechanism for stress-
induced analgesia. Nature. 2005;435(7045):1108-12.
33. Long JZ, Li W, Booker L, Burston JJ, Kinsey SG, Schlosburg JE, Pavón FJ,
Serrano AM, Selley DE, Parsons LH, Lichtman AH, Cravatt BF. Selective
blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid
behavioral effects. Nat Chem Biol. 2009;5(1):37-44.
34. Rinaldi-Carmona M, Barth F, Héaulme M, Shire D, Calandra B, Congy C,
Martinez S, Maruani J, Néliat G, Caput D, et al. SR141716A, a potent
and selective antagonist of the brain cannabinoid receptor. FEBS Lett.
1994;350(2-3):240-4.
35. Bisogno T, Cascio MG, Saha B, Mahadevan A, Urbani P, Minassi A, Appendino
G, Saturnino C, Martin B, Razdan R, Di Marzo V. Development of the
first potent and specific inhibitors of endocannabinoid biosynthesis.
Biochim Biophys Acta. 2006;1761(2):205-12.
36. Moreira FA, Crippa JA. The psychiatric side-effects of rimonabant. Rev Bras
Psiquiatr. 2009;31(2):145-53.
37. Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, de Costa BR,
Rice KC. Cannabinoid receptor localization in brain. Proc Natl Acad Sci
U S A. 1990;87(5):1932-6.
38. Hill MN, Gorzalka BB. Is there a role for the endocannabinoid system in the
etiology and treatment of melancholic depression? Behav Pharmacol.
2005;16(5-6):333-52.
39. Haller J, Varga B, Ledent C, Barna I, Freund TF. Context-dependent effects of
CB1 cannabinoid gene disruption on anxiety-like and social behaviour
in mice. Eur J Neurosci. 2004;19(7):1906-12.
40. Martin M, Ledent C, Parmentier M, Maldonado R, Valverde O. Involvement of
CB1 cannabinoid receptors in emotional behaviour. Psychopharmacology
(Berl). 2002;159(4):379-87.
41. Kamprath K, Marsicano G, Tang J, Monory K, Bisogno T, Di Marzo V, Lutz
B, Wotjak CT. Cannabinoid CB1 receptor mediates fear extinction via
habituation-like processes. J Neurosci. 2006;26(25):6677-86.
42. Steiner MA, Wanisch K, Monory K, Marsicano G, Borroni E, Bächli H,
Holsboer F, Lutz B, Wotjak CT. Impaired cannabinoid receptor type 1
signaling interferes with stress-coping behavior in mice. Pharmacogenomics
J. 2008;8(3):196-208.
43. Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, Cascio MG,
Hermann H, Tang J, Hofmann C, Zieglgänsberger W, Di Marzo V, Lutz
B. The endogenous cannabinoid system controls extinction of aversive
memories. Nature. 2002;418(6897):530-4.
44. Hölter SM, Kallnik M, Wurst W, Marsicano G, Lutz B, Wotjak CT.
Cannabinoid CB1 receptor is dispensable for memory extinction in
an appetitively-motivated learning task. Eur J Pharmacol. 2005;510(1-
2):69-74.
45. Hill MN, Patel S, Carrier EJ, Rademacher DJ, Ormerod BK, Hillard CJ, Gorzalka
BB. Downregulation of endocannabinoid signaling in the hippocampus
following chronic unpredictable stress. Neuropsychopharmacology.
2005;30(3):508-15.
46. Patel S, Roelke CT, Rademacher DJ, Cullinan WE, Hillard CJ. Endocannabinoid
signaling negatively modulates stress-induced activation of the
hypothalamic-pituitary-adrenal axis. Endocrinology. 2004;145(12):5431-8.
Endocannabinoids, depression and anxiety
Revista Brasileira de Psiquiatria • vol 32 • Suppl I • may2010 • S14
47. Steiner MA, Wotjak CT. Role of the endocannabinoid system in regulation
of the hypothalamic-pituitary-adrenocortical axis. Prog Brain Res.
2008;170:397-432.
48. Hill MN, Hillard CJ, Bambico FR, Patel S, Gorzalka BB, Gobbi G. The
therapeutic potential of the endocannabinoid system for the development
of a novel class of antidepressants. Trends Pharmacol Sci. 2009;30(9):484-
93.
49. Giuffrida A, Leweke FM, Gerth CW, Schreiber D, Koethe D, Faulhaber
J, Klosterkötter J, Piomelli D. Cerebrospinal anandamide levels are
elevated in acute schizophrenia and are inversely correlated with psychotic
symptoms. Neuropsychopharmacology. 2004;29(11):2108-14.
50. Griebel G, Stemmelin J, Scatton B. Effects of the cannabinoid CB1 receptor
antagonist rimonabant in models of emotional reactivity in rodents. Biol
Psychiatry. 2005;57(3):261-7.
51. Witkin JM, Tzavara ET, Davis RJ, Li X, Nomikos GG. A therapeutic role for
cannabinoid CB1 receptor antagonists in major depressive disorders.
Trends Pharmacol Sci. 2005;26(12):609-17.
52. Moreira FA, Lutz B. The endocannabinoid system: emotion, learning and
addiction. Addict Biol. 2008;13(2):196-212.
53. Pamplona FA, Prediger RD, Pandolfo P, Takahashi RN. The cannabinoid
receptor agonist WIN 55,212-2 facilitates the extinction of contextual
fear memory and spatial memory in rats. Psychopharmacology (Berl).
2006;188(4):641-9.
54. Pamplona FA, Takahashi RN. WIN 55212-2 impairs contextual fear
conditioning through the activation of CB1 cannabinoid receptors.
Neurosci Lett. 2006;397(1-2):88-92.
55. Bambico FR, Katz N, Debonnel G, Gobbi G. Cannabinoids elicit
antidepressant-like behavior and activate serotonergic neurons through
the medial prefrontal cortex. J Neurosci. 2007;27(43):11700-11.
56. Hill MN, Gorzalka BB. Pharmacological enhancement of cannabinoid CB1
receptor activity elicits an antidepressant-like response in the rat forced
swim test. Eur Neuropsychopharmacol. 2005;15(6):593-9.
57. Moreira FA, Aguiar DC, Campos AC, Lisboa SF, Terzian AL, Resstel LB,
Guimarães FS. Antiaversive effects of cannabinoids: is the periaqueductal
gray involved? Neural Plast. 2009;2009:625469.
58. Moreira FA, Wotjak CT. Cannabinoids and anxiety. In: Current Topics in
Behavioral Neuroscience: Behavioral Neurobiology of Anxiety and its
Treatment. Berlin: Springer; In press 2010.
59. Bortolato M, Campolongo P, Mangieri RA, Scattoni ML, Frau R, Trezza V,
La Rana G, Russo R, Calignano A, Gessa GL, Cuomo V, Piomelli D.
Anxiolytic-like properties of the anandamide transport inhibitor AM404.
Neuropsychopharmacology. 2006;31(12):2652-9.
60. Patel S, Hillard CJ. Pharmacological evaluation of cannabinoid receptor
ligands in a mouse model of anxiety: further evidence for an anxiolytic
role for endogenous cannabinoid signaling. J Pharmacol Exp Ther.
2006;318(1):304-11.
61. Bitencourt RM, Pamplona FA, Takahashi RN. Facilitation of contextual fear
memory extinction and anti-anxiogenic effects of AM404 and cannabidiol
in conditioned rats. Eur Neuropsychopharmacol. 2008;18(12):849-59.
62. Chhatwal JP, Davis M, Maguschak KA, Ressler KJ. Enhancing cannabinoid
neurotransmission augments the extinction of conditioned fear.
Neuropsychopharmacology. 2005;30(3):516-24.
63. Haller J, Barna I, Barsvari B, Gyimesi Pelczer K, Yasar S, Panlilio LV, Goldberg
S. Interactions between environmental aversiveness and the anxiolytic
effects of enhanced cannabinoid signaling by FAAH inhibition in rats.
Psychopharmacology (Berl). 2009;204(4):607-16.
64. Micale V, Cristino L, Tamburella A, Petrosino S, Leggio GM, Drago F, Di
Marzo V. Anxiolytic effects in mice of a dual blocker of fatty acid amide
hydrolase and transient receptor potential vanilloid type-1 channels.
Neuropsychopharmacology. 2009;34(3):593-606.
65. More ir a FA, Ka is er N, Monor y K, Lut z B. Red uce d an xiety -like
behaviour induced by genetic and pharmacological inhibition of the
endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH)
is mediated by CB1 receptors. Neuropharmacology. 2008;54(1):141-50.
66. Bortolato M, Mangieri RA, Fu J, Kim JH, Arguello O, Duranti A, Tontini A,
Mor M, Tarzia G, Piomelli D. Antidepressant-like activity of the fatty
acid amide hydrolase inhibitor URB597 in a rat model of chronic mild
stress. Biol Psychiatry. 2007;62(10):1103-10.
67. Gobbi G, Bambico FR, Mangieri R, Bortolato M, Campolongo P, Solinas
M, Cassano T, Morgese MG, Debonnel G, Duranti A, Tontini A,
Tarzia G, Mor M, Trezza V, Goldberg SR, Cuomo V, Piomelli D.
Antidepressant-like activity and modulation of brain monoaminergic
transmission by blockade of anandamide hydrolysis. Proc Natl Acad Sci
U S A. 2005;102(51):18620-5.
68. Högestätt ED, Jönsson BA, Ermund A, Andersson DA, Björk H, Alexander JP,
Cravatt BF, Basbaum AI, Zygmunt PM. Conversion of acetaminophen to
the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-
dependent arachidonic acid conjugation in the nervous system. J Biol
Chem. 2005;280(36):31405-12.
69. Umathe SN, Manna SS, Utturwar KS, Jain NS. Endocannabinoids mediate
anxiolytic-like effect of acetaminophen via CB1 receptors. Prog
Neuropsychopharmacol Biol Psychiatry. 2009;33(7):1191-9.
70. Marsch R, Foeller E, Rammes G, Bunck M, Kössl M, Holsboer F,
Zieglgänsberger W, Landgraf R, Lutz B, Wotjak CT. Reduced anxiety,
conditioned fear, and hippocampal long-term potentiation in transient
receptor potential vanilloid type 1 receptor-deficient mice. J Neurosci.
2007;27(4):832-9.
