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Exploração farmacológica do sistema endocanabinoide: novas perspectivas para o tratamento de transtornos de ansiedade e depressão?

Authors:

Abstract

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 Δ9-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 préclínicos. 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.
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
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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.
... The CB2 receptor, on the other hand, was initially linked to lymphoid tissue, mycroglia, and the immune system (RANG et al., 2016). After AEA and 2-AG are taken up from the extracellular space, the enzymes responsible for metabolizing them are fatty acid amide hydrolase and monoacyl glycerol lipase, respectively (SAITO et al., 2010;RANG et al., 2016). ...
... The importance of the endocannabinoid system has been reported in studies, since the malfunction of this system has been associated with psychiatric disorders and mood disorders. The endocannabinoid system is also involved in pain, inflammation, and metabolic dysfunctions (SAITO et al., 2010;MELO REIS et al., 2021). One of the proposals for strengthening the endocannabinoid system, according to Melo Reis and collaborators (2021), is an active life through a healthy diet and physical exercise. ...
... The CB2 receptor, on the other hand, was initially linked to lymphoid tissue, mycroglia, and the immune system (RANG et al., 2016). After AEA and 2-AG are taken up from the extracellular space, the enzymes responsible for metabolizing them are fatty acid amide hydrolase and monoacyl glycerol lipase, respectively (SAITO et al., 2010;RANG et al., 2016). ...
... The importance of the endocannabinoid system has been reported in studies, since the malfunction of this system has been associated with psychiatric disorders and mood disorders. The endocannabinoid system is also involved in pain, inflammation, and metabolic dysfunctions (SAITO et al., 2010;MELO REIS et al., 2021). One of the proposals for strengthening the endocannabinoid system, according to Melo Reis and collaborators (2021), is an active life through a healthy diet and physical exercise. ...
... (Dravet & Bureau, 2008, citado em Chiron & Dulac, 2011 Como já foi apontada a existência do sistema endocanabinóides no cérebro de mamíferos, concluiu-se que ele é um complexo com dois receptores interligados a proteína G, que é o CB1 e CB2. (Saito, et al., 2010). ...
... Formando assim um grupo de mensageiros neurais que são produzidos sob demanda e liberados por neurônios póssinápticos para inibir a liberação de neurotransmissores clássicos de terminais pré-sinápticos. Essa regulação controla uma variedade de funções neuronais como a ansiedade, medo e humor (Saito, et al., 2010). ...
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The endocannabinoid system is a neuromodulatory system which is known to regulate emotional, cognitive, neurovegetative and motivational processes. Substantial evidence has accumulated implicating a deficit in endocannabinoid in the etiology of depression; accordingly, pharmacological augmentation of endocannabinoid signaling could be a novel target for the pharmacotherapy of depression. Within preclinical models, facilitation of endocannabinoid neurotransmission evokes both antidepressant and anxiolytic effects. Similar to the actions of conventional antidepressants, enhancement of endocannabinoid signaling can enhance serotonergic and noradrenergic transmission; increase cellular plasticity and neurotrophin expression within the hippocampus; and dampen activity within the neuroendocrine stress axis. Furthermore, limbic endocannabinoid activity is increased by both pharmacological and somatic treatments for depression, and, in turn, appears to contribute to some of the neuroadaptive alterations elicited by these treatments. These preclinical findings support the rationale for the clinical development of agents which inhibit the cellular uptake and/or metabolism of endocannabinoids in the treatment of mood disorders.
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Delta(9)-tetrahydrocannabinol binds cannabinoid (CB(1) and CB(2)) receptors, which are activated by endogenous compounds (endocannabinoids) and are involved in a wide range of physiopathological processes (e.g. modulation of neurotransmitter release, regulation of pain perception, and of cardiovascular, gastrointestinal and liver functions). The well-known psychotropic effects of Delta(9)-tetra hydrocannabinol, which are mediated by activation of brain CB(1) receptors, have greatly limited its clinical use. However, the plant Cannabis contains many cannabinoids with weak or no psychoactivity that, therapeutically, might be more promising than Delta(9)-tetra hydrocannabinol. Here, we provide an overview of the recent pharmacological advances, novel mechanisms of action, and potential therapeutic applications of such non-psychotropic plant-derived cannabinoids. Special emphasis is given to cannabidiol, the possible applications of which have recently emerged in inflammation, diabetes, cancer, affective and neurodegenerative diseases, and to Delta(9)-tetrahydrocannabivarin, a novel CB(1) antagonist which exerts potentially useful actions in the treatment of epilepsy and obesity.
Article
Although anecdotal reports suggest that cannabis may be used to alleviate symptoms of depression, the psychotropic effects and abuse liability of this drug prevent its therapeutic application. The active constituent of cannabis, Delta(9)-tetrahydrocannabinol, acts by binding to brain CB, cannabinoid receptors, but an alternative approach might be to develop agents that amplify the actions of endogenous cannabinoids by blocking their deactivation. Here, we show that URB597, a selective inhibitor of the enzyme fatty-acid amide hydrolase, which catalyzes the intracellular hydrolysis of the endocannabinoid anandamide, exerts potent antidepressant-like effects in the mouse tail-suspension test and the rat forced-swim test. Moreover, URB597 increases firing activity of serotonergic neurons in the dorsal raphe nucleus and noradrenergic neurons in the nucleus locus ceruleus. These actions are prevented by the CB, antagonist rimonabant, are accompanied by increased brain anandamide levels, and are maintained upon repeated URB597 administration. Unlike direct CB, agonists, URB597 does not exert rewarding effects in the conditioned place preference test or produce generalization to the discriminative effects of Delta(9)-tetrahydrocannabinol in rats. The findings support a role for anandamide in mood regulation and point to fatty-acid amide hydrolase as a previously uncharacterized target for antidepressant drugs.
Article
Numerous cannabinoids have been synthesized that are extremely potent in all of the behavioral assays conducted in our laboratory. An important feature in increasing potency has been the substitution of a dimethylheptyl (DMH) side chain for the pentyl side chain. Our previous studies have shown that (−)-11-OH-Δ8-THC-dimethylheptyl was 80–1150 times more potent than Δ9-THC. Stereospecificity was demonstrated by its (+)- enantiomer which was more than 1400–7500 times less potent. A related series of DMH cannabinoid analogs has recently been synthesized and preliminary evaluations reported here. (−)-11-OH-Δ9-THC-DMH was found to be equipotent with (−)-11-OH-Δ8-THC-DMH. The aldehyde (−)-11-oxo-Δ9-THC-DMH was 15–50 times more potent than Δ9-THC. Surprisingly, (−)-11-carboxy-Δ9-THC-DMH was also active, being slightly more potent than Δ9-THC. In the bicyclic cannabinoid series, the length and bulk of the side chain were found to be equally important. Aminoalkylindoles, which are structurally dissimilar from classical cannabinoids, have been found to exhibit a pharmacological profile similar to Δ9-THC. Though not extremely potent in vivo, they appear to represent an entirely new approach to studying the actions of the cannabinoids. The structural diversity and wide-ranging potencies of the analogs described herein provide the opportunity to develop a pharmacophore for the cannabinoids using molecular modeling techniques.
Article
In this study, we report the isolation from canine intestines of 2-arachidonyl glycerol (2-Ara-Gl). Its structure was determined by mass spectrometry and by direct comparison with a synthetic sample. 2-Ara-Gl bound to membranes from cells transiently transfected with expression plasmids carrying DNA of either CB1 or CB2—the two cannabinoid receptors identified thus far—with Ki values of 472 ± 55 and 1400 ± 172 nM, respectively. In the presence of forskolin, 2-Ara-Gl inhibited adenylate cyclase in isolated mouse spleen cells, at the potency level of Δ9-tetrahydrocannabinol (Δ9-THC). Upon intravenous administration to mice, 2-Ara-Gl caused the typical tetrad of effects produced by THC: antinociception, immobility, reduction of spontaneous activity, and lowering of the rectal temperature. 2-Ara-Gl also shares the ability of Δ9-THC to inhibit electrically evoked contractions of mouse isolated vasa deferentia; however, it was less potent than Δ9-THC.
Article
The endocannabinoid system has been recognized as a major neuromodulatory system, which functions to maintain brain homoeostasis. Endocannabinoids are synthesized and released from the postsynapse and act as retrograde neuronal messengers, which bind to cannabinoid type 1 receptors at the presynapse. Here, they inhibit the release of neurotransmitters, including glutamate and GABA. By these means, endocannabinoids control the activation of various neuronal circuits including those involved in neuroendocrine stress processing. Accordingly, exogenous cannabinoids such as the major active component of marijuana, Delta(9)-tetrahydrocannabinol, have long been known to activate the major neuroendocrine stress response system of mammals, the hypothalamic-pituitary-adrenocortical (HPA) axis. However, the function of the endocannabinoid system in the regulation of stress hormone secretion has only recently begun to be understood. It is the focus of the present review to provide the reader with an overview of our current knowledge of the role of endocannabinoid signalling in HPA axis regulation under basal as well as under stressful conditions. This includes the specific sites of action, potential underlying neuronal pathways and interactions between behavioural and neuroendocrine stress coping. Furthermore, the potential role of HPA axis activity dysregulations, caused by deficits in the endocannabinoid system, for the pathophysiology of psychiatric diseases is discussed.
Article
The term cannabinoids encompasses compounds produced by the plant Cannabis sativa, such as Δ 9-tetrahydrocannabinol, and synthetic counterparts. Their actions occur mainly through activation of cannabinoid type 1 (CB1) receptors. Arachidonoyl ethanolamide (anandamide) and 2-arachidonoyl glycerol (2-AG) serve as major endogenous ligands (endocannabinoids) of CB1 receptors. Hence, the cannabinoid receptors, the endocannabinoids, and their metabolizing enzymes comprise the endocannabinoid system. Cannabinoids induce diverse responses on anxiety- and fear-related behaviors. Generally, low doses tend to induce anxiolytic-like effects, whereas high doses often cause the opposite. Inhibition of endocannabinoid degradation seems to circumvent these biphasic effects by enhancing CB1 receptor signaling in a temporarily and spatially restricted manner, thus reducing anxiety-like behaviors. Pharmacological blockade or genetic deletion of CB1 receptors, in turn, primarily exerts anxiogenic-like effects and impairments in extinction of aversive memories. Interestingly, pharmacological blockade of Transient Receptor Potential Vanilloid Type-1 (TRPV1) channel, which can be activated by anandamide as well, has diametrically opposite consequences. This book chapter summarizes and conceptualizes our current knowledge about the role of (endo)cannabinoids in fear and anxiety and outlines implications for an exploitation of the endocannabinoid system as a target for new anxiolytic drugs.
Article
Acetaminophen (Paracetamol), a most commonly used antipyretic/analgesic agent, is metabolized to AM404 (N-arachidonoylphenolamine) that inhibits uptake and degradation of anandamide which is reported to mediate the analgesic action of acetaminophen via CB1 receptor. AM404 and anandamide are also reported to produce anxiolytic-like behavior. In view of the implication of endocannabinoids in the effect of acetaminophen, we contemplated that acetaminophen may have anxiolytic-like effect. Therefore, this possibility was tested by observing the effects of various doses of acetaminophen in mice on anxiety-related indices of Vogel conflict test and social interaction test. The results from both the tests indicated that acetaminophen (50, 100, or 200 mg/kg, i.p.) or anandamide (10 or 20 microg/mouse, i.c.v.) dose dependently elicited anxiolytic-like effect, that was comparable to diazepam (2 mg/kg, i.p.). Moreover, co-administration of sub-effective dose of acetaminophen (25 mg/kg, i.p.) and anandamide (5 microg/mouse, i.c.v) produced similar anxiolytic effect. Further, pre-treatment with AM251 (a CB1 receptor antagonist; 1 mg/kg, i.p.) antagonized the effects of acetaminophen and anandamide with no per se effect at 1 mg/kg dose, while anxiogenic effect was evident at a higher dose (5 mg/kg, i.p.). None of the treatment/s was found to induce any antinociceptive or locomotor impairment effects. In conclusion, the findings suggested that acetaminophen (50, 100, or 200 mg/kg, i.p.) exhibited dose dependent anxiolytic effect in mice and probably involved endocannabinoid-mediated mechanism in its effect.