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Role of the Endocannabinoid System in Depression: from Preclinical to Clinical Evidence

Katarina Tabiova
Katarina Tabiova
Katarina Tabiova

Abstract and Figures

The endogenous cannabinoid system (ECS) works as pro-homeostatic and pleiotropic signaling system activated in a time-and tissue-specific way during physiological conditions, which include cognitive, emotional and motivational processes. It is composed of two G protein-coupled receptors (the cannabinoid receptors types 1 and 2 [CB1 and CB2] for marijuana's psychoactive ingredient Δ9-tetrahydrocannabinol [Δ9-THC]), their endogenous small lipid ligands (anan-damide [AEA] and 2-arachidonoylglycerol [2-AG], also known as endocannabi-noids), and the proteins for endocannabinoid biosynthesis and deactivation. Data from preclinical and clinical studies have reported that a hypofunction of the endo-cannabinoid signaling could induce a depressive-like phenotype; consequently, enhancement of endocannabinoid signaling could be a novel therapeutic avenue for the treatment of depression. To this aim there have been proposed cannabinoid receptor agonists or synthetic molecules that inhibit endocannabinoid degradation. The latter ones do not induce the psychotropic side effects by direct CB1 receptor activation, but rather elicit antidepressant-like effects by enhancing the monoami-nergic neurotransmission, promoting hippocampal neurogenesis and normalizing the hyperactivity of hypothalamic-pituitary-adrenal axis, similarly as the standard antidepressants. The dysfunction of elements belonging to the ECS and the possible therapeutic use of endocannabinoid deactivation inhibitors and phytocannabinoids in depression is discussed in this chapter.
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Chapter 5
Role of the Endocannabinoid System in
Depression: from Preclinical to Clinical
Vincenzo Micale, Katarina Tabiova, Jana Kucerova and Filippo Drago
V. Micale () · K. Tabiova · J. Kucerova
Department of Pharmacology, CEITEC (Central European Institute of Technology)
Masaryk University, Brno, Czech Republic
F. Drago
Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry,
Medical School, University of Catania, Catania, Italy
Abstract The endogenous cannabinoid system (ECS) works as pro-homeostatic
and pleiotropic signaling system activated in a time- and tissue-specific way dur-
ing physiological conditions, which include cognitive, emotional and motivational
processes. It is composed of two G protein-coupled receptors (the cannabinoid
receptors types 1 and 2 [CB1 and CB2] for marijuana’s psychoactive ingredient
Δ9-tetrahydrocannabinol [Δ9-THC]), their endogenous small lipid ligands (anan-
damide [AEA] and 2-arachidonoylglycerol [2-AG], also known as endocannabi-
noids), and the proteins for endocannabinoid biosynthesis and deactivation. Data
from preclinical and clinical studies have reported that a hypofunction of the endo-
cannabinoid signaling could induce a depressive-like phenotype; consequently,
enhancement of endocannabinoid signaling could be a novel therapeutic avenue
for the treatment of depression. To this aim there have been proposed cannabinoid
receptor agonists or synthetic molecules that inhibit endocannabinoid degradation.
The latter ones do not induce the psychotropic side effects by direct CB1 receptor
activation, but rather elicit antidepressant-like effects by enhancing the monoami-
nergic neurotransmission, promoting hippocampal neurogenesis and normalizing
the hyperactivity of hypothalamic-pituitary-adrenal axis, similarly as the standard
antidepressants. The dysfunction of elements belonging to the ECS and the possible
therapeutic use of endocannabinoid deactivation inhibitors and phytocannabinoids
in depression is discussed in this chapter.
Keywords Endocannabinoid system · CB1 and CB2 receptors · TRPV1 channels ·
Animal models · Depression · Antidepressants · ∆9-THC · Cannabidiol
© Springer Science+Business Media New York 2015
P. Campolongo, L. Fattore (eds.), Cannabinoids and Modulation of Emotion,
Memory, and Motivation, DOI 10.1007/978-1-4939-2294-9_5
98 V. Micale et al.
Current Pharmacological Approach for the Treatment of
Depression is one of the most common mental illness with a lifetime prevalence
of about 15–20 %, resulting in enormous personal suffering, as well as social and
economic burden [1]. The major depressive disorder is characterized by episodes
of depressed mood lasting for more than 2 weeks often associated with feelings of
guilt, decreased interest in pleasurable activities and inability to experience plea-
sure (named anhedonia), low self-esteem and worthlessness, high anxiety, disturbed
sleep patterns and appetite, impairment in memory and suicidal ideation [2].
The treatment of depression was revolutionized in the 1950s with the introduc-
tion of two classes of pharmacological agents to the clinical practice: the mono-
amine oxidase inhibitors “MAOIs” and the tricyclic antidepressants “TCAs”. The
discovery was based on the serendipitous finding that enhancement of the synaptic
levels of monoamines improves the symptoms of depression, leading to the mono-
amine hypothesis of depression [3]. Thus, the introduction of antidepressant drugs
had a profound impact on the way depression was viewed: if chemicals can reverse
most depressive symptomatologies, then depression itself may be caused by chemi-
cal abnormalities in the brain. However first generation antidepressants, due to their
toxic and poorly tolerated profile, were largely replaced by the selective serotonin
reuptake inhibitors (SSRIs), norepinephrine reuptake inhibitors and serotonin nor-
epinephrine reuptake inhibitors and by atypical antidepressants (i.e. nefazodone and
mirtazapine), which are not more effective than MAOIs or TCAs but show an im-
proved safety profile [4].
Recently, some atypical antipsychotics such as olanzapine, quetiapine or aripip-
razole, used either as monotherapy or in combination with venlafaxine or sertra-
line, have also shown efficacy at ameliorating symptoms of bipolar disorder and
treatment-resistant major depression and received approval from the FDA (US Food
and Drug Administration) for these indications [5]. Since disruptions of circadian
and sleep-wake cycles have been recognized as major contributor to mood distur-
bance, and agomelatine (a melatonergic agonist and a serotonin 5-HT2C receptor
antagonist) was found to be very effective in ameliorating depressive symptoms
with a good tolerability and safety profile, a new concept for the treatment of mood
disorders has recently emerged [6].
However, the past decade has witnessed a driven focus on the rational discovery
of highly selective drugs, acting at novel non monoamine based targets such as GA-
BAergic and glutamatergic neurotransmission, neuroendocrine system or neuropep-
tide signaling, which in turn could affect intracellular signal transduction pathways.
Yet, except for the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine
[7], none of these drugs has reached the market [811]. Thus, the dominant hypoth-
esis of depression is still based on the monoamine model, which comprises the pri-
mary target for current antidepressants. Although today’s treatments are generally
995 Role of the Endocannabinoid System in Depression
safe and effective, 30 % of depressed patients treated with the conventional antide-
pressants are pharmacoresistant. In addition, the medication has to be administered
for weeks or months to see appreciable clinical benefit [12]. Therefore, there is still
a great need to update the current level of knowledge with regard to the pathophysi-
ological mechanisms underlying depressive disorders in order to develop safer,
more effective, and faster acting pharmacotherapies. The partial efficacy of current
drugs raises the central question to be addressed in this chapter: Does the alteration
of the endocannabinoid system (ECS) have a crucial role in the pathophysiology
of depressive disorders and is the ECS consequently able to provide a promising
therapeutic approach for their treatment?
The Endocannabinoid System (ECS)
The ECS is a neuromodulatory system, which plays a role in a variety of physiologi-
cal processes both in the central nervous system (CNS) and in the periphery, mediat-
ing the effects of the psychoactive constituent of Cannabis Δ9-tetrahydrocannabinol
(∆9-THC) [13]. Multiple lines of evidence have shown that its dysregulation is
associated with several pathological conditions such as pain and inflammation [14,
15], obesity, metabolic [16, 17], gastrointestinal [18], hepatic [19], neurodegen-
erative [2022] and psychiatric disorders [2325]. However, the exact pathophysi-
ological mechanisms through which the ECS controls these functions are not fully
elucidated yet. The ECS is comprised of: (1) the cannabinoid receptors type CB1
and CB2 [2628], (2) their endogenous ligands anandamide (N-arachidonoyl-etha-
nolamine, AEA) and 2-arachidonylglycerol (2-AG) [29, 30], (3) a specific and not
yet identified cellular uptake mechanism [31, 32], and (4) the enzymes for endocan-
nabinoid biosynthesis, N-acyl-phosphatidylethanolamine-selective phosphodiester-
ase or glycerophosphodiesterase E1 and diacylglycerol lipase α or β [33, 34], or
their inactivation, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase
(MAGL) [35, 36], respectively for AEA and 2-AG. However, additional “players”
which are described as potential members of the ECS include the TRPV1 channels,
the putative CB1 receptor antagonist peptides like hemopressins, peroxisome pro-
liferator-activated receptor-α (PPAR-α) and γ (PPAR-γ) ligands, such as oleoyletha-
nolamide (OEA) or palmitoylethanolamide (PEA), and N-arachidonoyl-dopamine
(NADA), which activates both TRPV1 and CB1 receptors. Although the existence
of a third cannabinoid receptor subtype has also been suggested [37], to date only
CB1 and CB2 receptors are recognized as G protein-coupled receptors for endocan-
nabinoids [38].
The cannabinoid CB1 and CB2 receptors are established as mediators of the bio-
logical effects induced by cannabinoids, either plant derived, synthetic, or endog-
enously produced. These receptors are encoded by two different genes on human
chromosomes: 6q14-q15 (CNR1) and 1p36.11 (CNR2). They are 7 transmembrane
Gi/o coupled receptors that share 44 % protein identity and display different phar-
macological profiles and patterns of expression, a dichotomy that provides a unique
opportunity to develop pharmaceutical approaches.
100 V. Micale et al.
The CB1 receptors are ubiquitously expressed in the CNS where they are pre-
dominantly found at high densities in the basal ganglia, frontal cortex, hippocampus
and cerebellum. They are present at a moderate/low densities in the periaqueduc-
tal gray, amygdala, nucleus accumbens, thalamus and medulla. However, the CB1
receptors are also found in non-neuronal cells of the brain such as microglia, oli-
godendrocytes and astrocytes [39]. Within these cortical areas there are two major
neuronal subpopulations expressing the CB1 receptors: the GABAergic interneu-
rons (with high CB1 receptor levels) and glutamatergic neurons (with relatively low
CB1 receptor levels) [40], which represent the two major opposing players regulat-
ing the excitation state of the brain, GABAergic interneurons being inhibitory and
glutamatergic neurons being excitatory. CB1 receptors are also located in neurons
of the dorsal raphe nucleus (DRN) and in the locus coeruleus (LC) which are the
major sources of serotonin (5-HT) and noradrenalin (NE) in the brain [41, 42].
Thus, the direct or indirect modulation of monoamine activity or of GABA and glu-
tamate neurons, respectively, could underlie the psychotropic and non-psychotropic
effects of CB1 receptor activation.
The cannabinoid CB2 receptors, which are also activated by AEA and 2-AG,
are mainly distributed in immune tissues and inflammatory cells, although they
are also detected in glial cells, and to a much lesser extent, in neurons of several
brain regions such as cerebral cortex, hippocampus, amygdala, hypothalamus and
cerebellum [43, 44]. While their role in pain and inflammation has been extensively
reported, recently their involvement in emotional processes has been suggested
[45]. The observation that the elements belonging to the ECS are prevalent through-
out the neuroanatomical structures and circuits implicated in emotionality, includ-
ing prefrontal cortex (PFC), hippocampus, amygdala, hypothalamus and forebrain
monoaminergic circuits, provides a rationale for the preclinical development of
agents targeting this system to treat affective diseases.
Cannabis, Endocannabinoid System and Depression: Clinical and
Preclinical Evidence
Cannabis sativa is the most commonly used illicit “recreational” drug worldwide,
its popularity being due to its capacity to increase sociability, to induce euphoria
and to alter sensory perception. Although the association between Cannabis sativa
and psychopathologic conditions has been known for thousands of years, only in the
last 50 years the identification of the chemical structure of marijuana components,
the cloning of specific cannabinoid receptors and the discovery of the ECS in the
brain have triggered an exponential growth of studies to explore its real effects on
mental health [46].
The Cannabis plant contains over 100 terpenophenolic pharmacologically active
compounds, known as cannabinoids. Of these, ∆9-THC, characterized in 1964 by
Mechoulam’s team [47], was identified as the primary psychoactive component of
Cannabis, and later shown to act as a direct agonist of CB1 and CB2 receptors. Oth-
1015 Role of the Endocannabinoid System in Depression
er cannabinoids include cannabichromene, cannabigerol and cannabidiol (CBD),
which do not seem to induce the psychotropic side effects of ∆9-THC. They act on
several levels in the CNS, including modulation of endocannabinoid tone [4850],
interaction with transient receptor potential vanilloid 1 (TRPV1) channels [48] and
serotonin 5-HT1A receptors [51], and enhancement of adenosine signaling [52, 53].
The above mentioned mechanisms could underlie the positive effects induced by
CBD treatment in preclinical studies of several psychiatric as well as other disor-
ders [54, 55].
Although elevation of mood is one of the commonly cited motivations for the
use of Cannabis, in addition to its recreational actions, data from clinical trials in the
1970’s failed to show any antidepressant effects of ∆9-THC [56, 57]. Additionally,
the hypothesis that depressed individuals use Cannabis as a mean of self-medication
proposed by preclinical studies [58] has not been fully supported by clinical data
yet [59, 60]. By contrast, some data support the hypothesis that Cannabis use pre-
cipitates depression [6165], where genetic and environmental factors could play a
pivotal role [6668]. However, a recent study has shown that depressive symptoms
are indirectly related to Cannabis use through positive, but not negative, expectan-
cies [69]. It is not to be excluded that other factors such as the dose, route of admin-
istration, baseline emotional states, personality, environment and the setting, during
which the drug is used, could be involved in ∆9-THC effects on mood.
Despite preclinical data supporting an altered endocannabinoid signaling as a
molecular underpinning of several psychiatric disorders [70], to date only few di-
rect investigations have assessed endocannabinoid activity in depressed patients,
as reviewed in Table 5.1. A significant increase of CB1 receptor density has been
found in the dorsolateral prefrontal cortex (dlPFC) of depressed suicide victims,
possibly suggesting a hyperfunctionality of the ECS in this population [71]. By
contrast, a down-regulation of the ECS activity was suggested by Koethe et al. [72]
and Hill et al. [73, 74], showing a decreased CB1 receptor density in grey matter
glial cells and lower serum concentration of 2-AG in patients with major depres-
sion. However, an increase of endocannabinoid tissue content in the dlPFC of alco-
holic depressed patients as well as a significantly enhanced serum level of AEA in
patients suffering of minor depression were also reported [73, 75]. Furthermore, in
two recent clinical studies, a positive correlation was found among high blood pres-
sure and serum contents of endocannabinoids in depressed females [76] and among
intense physical exercise, AEA and brain-derived neurotrophic factor (BDNF) lev-
els [77], suggesting that an interrelationship among endocannabinoids, depression
and cardiovascular risk factors in women and an increase in peripheral BDNF levels
could be a mechanism by which AEA intervenes in the neuroplastic and antidepres-
sant effects of exercise.
Thus, considering the recent preclinical evidence relating the effects of enhanced
endocannabinoid signaling to the promotion of neurogenesis, it is not to exclude
that its activation exerts antidepressant properties through mechanisms that re-
semble the ones triggered by conventional antidepressants on synaptic plasticity
[78, 79]. However, the increasing interest concerning ECS dysfunction in depres-
sive disorders was engendered after the clinical use of the CB1 receptor antagonist
102 V. Micale et al.
rimonabant for the treatment of obesity was interrupted. In line with the theory that
a deficiency in CB1 receptor signaling could be involved in depression, rimonabant
was withdrawn from the market because of undesirable psychiatric side effects such
as anxiety, depression and suicidal ideations [80]. Although no controlled clinical
trials concerning endocannabinoid signaling in depression are available, opposite
changes in endocannabinoid activity could underlie the different forms of depres-
sive illness.
As recently suggested, genetic variations in CB1 receptor function could also
facilitate the development of mood disorders in humans [81]. The human CB1 re-
ceptor gene (CNR1), which is located on the chromosome 6q14–15, seems to play a
role in a broad spectrum of psychiatric disorders such as substance abuse disorders,
schizophrenia and autism spectrum conditions [8284]. With regard to depression,
while Barrero et al. [85] showed a significant association between polymorphisms
in CNR1 and depression only in Parkinson’s disease patients, recent studies support
that genetic variations in CB1 receptor function and in FAAH could influence both
Table 5.1  Schematic representation of the changes of the endocannabinoid system (ECS) elements
in clinical studies of depression
ECS elements Sex (number
of cases)
Diagnosis Tissue sampleaMolecular
CB1 ♂♀ ( n = 10) Major depression dlPFC ↑ density [71]
♂♀ ( n = 11) Alcohol
tal cortex
↑ density
♂♀ ( n = 1 5 ) Major depression Anterior-cin-
gulate cortex
↓ density [72]
AEA ♂♀ ( n = 11) Alcohol
dlPFC ↑ level [75]
♀ ( n = 1 6 ) Major depression Serum No effect [73]
♀ ( n = 12) Minor depression Serum ↑ level [73]
♀ ( n = 1 5 ) Major depression Serum ↓ level [74]
♀ ( n = 28) Major/Minor
Serum ↑ level [76]
2-AG ♂♀ ( n = 11) Alcohol
dlPFC ↑ level [75]
♀ ( n = 1 6 ) Major depression Serum ↓ level [73]
♀ ( n = 12) Minor depression Serum No effect [73]
♀ ( n = 1 5 ) Major depression Serum ↓ level [74]
♀ ( n = 28) Major/Minor
Serum ↑ level [76]
♀ ( n = 1 5 ) Major depression Serum No effect [74]
amide (OEA)
♀ ( n = 1 5 ) Major depression Serum No effect [74]
a dlPFC dorsolateral prefrontal cortex
1035 Role of the Endocannabinoid System in Depression
the development of depressive symptoms and the antidepressant treatment response
[8688]. However, a significant genetic interaction among the polymorphism in the
serotonin transporter gene 5-HTTLPR, variants in the CNR1 gene, anxiety or stress
adaptation have also been found [89, 90]. Thus, the identification of individuals
with a high-risk of psychiatric disorders through genetic testing could be a promis-
ing strategy for the development of safer drugs [91].
The putative role of the ECS in depression is supported by evidence showing
that the majority of available antidepressants also modify CB1 receptor expression
and endocannabinoid content in brain regions related to mood disorders (Table 5.2).
While fluoxetine increased CB1 receptor binding and/or signaling in the limbic
region [92, 93], citalopram reduced CB1 receptor signaling in the hippocampus
and hypothalamic paraventricular nucleus [94], suggesting a region-specific effect
of SSRI on CB1 receptor-mediated signaling. Similarly, TCAs elicited different ef-
fects based on various brain regions: desipramine increased hippocampal and hypo-
thalamic CB1 receptor binding [95], while imipramine reduced it within the hypo-
thalamus, midbrain and ventral striatum and increased it within the amygdala [96].
However, no difference has been found in the AEA content. The MAOI tranylcy-
promine enhanced CB1 receptor binding and 2-AG level in PFC and hippocampus,
while reducing AEA content within the PFC, hippocampus and hypothalamus [92].
Despite the conflicting panorama, these findings suggest that the antidepressants
modify the endocannabinoid tone in different ways, depending both on the class of
drugs and on the different brain regions considered.
Changes in ECS elements have also been reported in several stress related ani-
mal models (Table 5.3), in accordance with the clinical data described above. In
Table 5.2  Schematic representation of the antidepressants effects on the endocannabinoid system
(ECS) elements
Drug class Effective
Brain regionaMolecular readout References
Tricyclic anti-
Desipramine Hippocampus,
↑ CB1 receptor binding [95]
Imipramine Hypothalamus,
↓ CB1 receptor binding
(Hypothalamus, Midbrain,
↑ CB1 receptor binding
Tranylcypromine PFC, Hip-
↑ CB1 receptor binding
↑ 2-AG content (PFC)
↓ AEA content
Fluoxetine PFC ↑ CB1 receptor binding [92, 93]
Citalopram Hippocampus,
↓ CB1 receptor binding [94]
a PFC prefrontal cortex, vStriatum ventral striatum
104 V. Micale et al.
ECS elements Experimental
Animals Behavioural responseaBrain regionaMolecular
Positive control References
CB1 CMS Wistar rats ↓ sucrose preference
↓ body weight
↑ expression
↓ expression
Imipramine [97]
↓ body weight ♂♀
↓ sucrose preference ♂
Hippocampus ↓ expression ♂
↑ expression ♀
ND [102]
Chronic unpre-
dictable stress
Long-Evans rats Cognitive deficit in the
Limbic forebrain
↓ expression
No effects
ND [101]
↓ sexual motivation PFC
↑ binding
↓ binding
↓ binding
↓ binding
Imipramine [96]
↑ immobility time in the FST vmPFC
↑ binding
ND [100]
↑ immobility time in the FST
↓ sucrose preference
↓ locomotor activity in the
Hippocampus ↓ expression Transcranial
OBX Sprague-Dawley
↑ locomotor activity in the
PFC ↑ binding Fluoxetine [98]
Restraint stress Sprague-Dawley
ND Amygdala
↑ binding
↓ binding (adult)
↑ binding
ND [99]
CB2 Chronic unpre-
dictable mild
Wild type mice of
CB2 overexpress-
ing mice
↑ immobility time in the FST
↓ sucrose preference
Hippocampus ↓ expression ND [106]
Table 5.3  Schematic representation of the changes of the endocannabinoid system (ECS) elements in preclinical studies of depression
1055 Role of the Endocannabinoid System in Depression
ECS elements Experimental
Animals Behavioural responseaBrain regionaMolecular
Positive control References
TRPV1 Restraint stress Wistar rats ↑ immobility time in the FST Hippocampus ↑ expression Clomipramine [158]
FAAH Restraint stress Wistar rats ↑ immobility time in the FST Hippocampus ↑ expression Clomipramine [158]
AEA CMS Wistar rats ↓ sucrose preference
↓ body weight
PFC, Midbrain,
pus, Striatum,
No effect Imipramine [97]
Restraint stress ICR mice ND Amygdala ↓ content ND [108]
↓ content
(Amygdala and
↑ content
ND [111]
ND PFC, Hippocam-
pus, Hypothala-
mus, Amygdala
↓ content ND [109]
Bl6 mice ND Amygdala ↓ content ND [110]
Wistar rats ↑ immobility time in the FST PFC,
No effect Clomipramine [158]
Chronic unpre-
dictable stress
Long-Evans rats ↓ sexual motivation PFC, Hip-
↓ content Imipramine [96]
Table 5.3  (continued)
106 V. Micale et al.
ECS elements Experimental
Animals Behavioural responseaBrain regionaMolecular
Positive control References
2-AG Chronic unpre-
dictable stress
Long-Evans rats Cognitive deficit in the
Limbic forebrain
↓ content
No effect
ND [101]
↓ sexual motivation PFC, Hippocam-
pus, Hypothala-
mus, vStriatum,
↑ content
Imipramine [96]
Restraint stress ICR mice ND Amygdala,
↑ content ND [108]
CMS Wistar rats ↓sucrose preference
↓ body weight
PFC, Hippocam-
pus, Striatum,
↑ content
Imipramine [97]
Restraint stress ICR mice ND Amygdala,
↑ content
↓ content
ND [111]
Amygdala ↑ content ND [112]
ND Amygdala ↑ content ND [109]
Bl6 mice ND Amygdala No effect ND [110]
Wistar rats ↑ immobility time in the FST PFC,
No effect Clomipramine [158]
a FST forced swim test, CMS chronic mild stress, MWM Morris water maze, ND not determined, OBX bilateral olfactory bulbectomy, OFT open field test, PFC
prefrontal cortex, mPFC medial prefrontal cortex, dmPFC dorsomedial prefrontal cortex, vmPFC ventromedial prefrontal cortex, vStriatum ventral striatum
Table 5.3  (continued)
1075 Role of the Endocannabinoid System in Depression
well validated animal models of depression such as the chronic mild stress (CMS)
paradigm or the bilateral olfactory bulbectomy (OBX) model, which produce be-
havioural and neurochemical changes similar to those in human depression, a sig-
nificant increase of CB1 receptor density and binding has been found in the PFC
[96100], together with a significant decrease in the ventral striatum, hypothalamus
[96], midbrain [97] and hippocampus [99, 101103]. This latter seems to be asso-
ciated with a significant alteration of the hippocampal endocannabinoid-mediated
neurotransmission and synaptic plasticity [104]. Collectively, the effects of experi-
mental stress procedures on brain CB1 receptor expression seem to be region de-
Although the presence of CB2 receptors in stress responsive brain regions sug-
gests their involvement in the regulation of mood, to date there is no evidence con-
cerning their modification in the brain of depressed patients. More data come from
preclinical studies, which reported a reduction of CB2 receptors in the hippocam-
pus, striatum and midbrain in animal models of depression. Similarly, an increase of
CB2 receptor expression counteracts behavioural and neurochemical features relat-
ed to a depressive-like state [105107]. Other controversial data about the endocan-
nabinoid brain content in depression have also been recorded. While Bortolato et al.
[97] did not find a change in AEA levels in different brain regions of rats subjected
to CMS, others reported a significant reduction of AEA content following different
chronic stress paradigms [96, 108111]. The effects of stress procedure on 2-AG
levels are confusing as well, since a reduction in the hippocampus and an increase
in thalamus, hypothalamus and amygdala has been shown [96, 97, 101, 109, 112],
or no such effects [97, 110]. Although the discrepancy may be due to numerous fac-
tors, such as the nature and duration of the stress, the species (rats vs. mice) or strain
(Wistar vs. Sprague-Dawley rats), differences in response to stress procedure, or the
time and tissue of extraction, the data described above supports the general hypoth-
esis that a deficiency in the functioning of the endocannabinoid signaling, both in
depressed patients and in animal models of depression, may directly lead to a vul-
nerability in development of the illness. Thus, it seems reasonable to hypothesize
that its pharmacological facilitation would produce certain antidepressant effects.
Current Status of Animal Models of Depression
and Antidepressant Responsive Tests
Due to the limited efficacy of antidepressant treatments, a better understanding of
the pathophysiology of mental health disorders and the development of novel, im-
proved therapeutic treatments would fill a considerable unmet medical need [113].
Due to the enormous cost of clinical trials, pharmaceutical companies make all ef-
forts at testing new chemicals designed to alter the function of a specific target of
disease in a predictable and safe manner [114]. Thus, of central importance to this
approach is the availability of valid preclinical animal models for the evaluation of
108 V. Micale et al.
the potential efficacy of novel compounds and the further understanding of the neu-
ropathology that underlies the idiopathic disease state of depression [115].
Ideally, an experimental animal model should reflect the human psychiatric dis-
ease in terms of face validity (i.e. reproduce the symptoms of depression observed
in humans), construct validity (the same neurochemical mechanisms in humans as
in the animal model) and predictive validity (chronic antidepressant treatment must
reverse the phenotype of the animal model) [116]. In the case of depression, an
animal model which perfectly includes the etiology, the pathophysiology and the
symptoms of depression whilst allowing evaluating the responses to treatments re-
mains impossible to fully envisage. However, different models, each with specific
limitations, are able to reproduce most of the etiological factors and many symp-
toms of depression or possess a satisfactory predictive value for identifying new
compounds. For this purpose, the forced swim test (FST) or the tail suspension
test (TST) and the CMS or the OBX seem to be good experimental approaches for
screening potential new antidepressants and shape the underlying disease etiology
The most widely used paradigm to assess antidepressant-like behaviour is the
FST also known as Porsolt’s test [118]. In the FST rodents are forced to swim in
an inescapable cylinder filled with water and eventually adopt a characteristic im-
mobile posture which is interpreted as a passive stress-coping strategy or depres-
sive-like behaviour (behavioural despair). The FST has shown its ability to detect a
broad spectrum of substances with antidepressant efficacy, as these drugs shift from
passive stress-coping towards active coping, which is detected as reduced immobil-
ity. Furthermore, the quantity of different movements such as climbing and swim-
ming behaviour has predictive value to differentiate between NEergic and 5-HTer-
gic activity. Some of the most representative potential antidepressants with different
mechanisms of action have been submitted to this test [23, 119].
Similar assumptions and interpretations as the FST is the TST [120]. In this test,
mice are suspended by their tails for a defined period of time and their immobility
is decreased by several antidepressants. A major drawback of the TST is that its
application is restricted to mice and limited to strains which do not tend to climb
their tail, a behaviour that would otherwise confuse the interpretations of the results
[121]. The test however is sensitive to acute treatment only and its validity for non-
monoamine antidepressants is uncertain [119, 122].
A different model is the CMS paradigm, which is based on reduced sweet fluid
intake as an index of anhedonia, induced by repeated (at least 2 weeks) exposure
to unpredictable stressors (i.e. wet bedding, disruption of dark-light cycle and food
or water deprivation) [123]. This model induces various long-term behavioural
and neurochemical alterations resembling some of the dysfunctions observed in
depressed patients, which are reversed only by chronic treatment with a broad spec-
trum of antidepressants. As compared to other experimental models of depression,
it has been evaluated as a high perspective research approach, despite its procedural
complexity and poor inter-laboratory reliability.
The OBX, a lesion model of depression is based on surgical removal of olfactory
bulbs by aspiration [124] and results in a disruption of the limbic hypothalamic axis
1095 Role of the Endocannabinoid System in Depression
followed by neurochemical (i.e. changes in all major neurotransmitter systems) and
behavioural (e.g. hyperactive response in the open field paradigm and anhedonia)
alterations, which resemble changes seen in depressed patients and are reversed
only by chronic administration of antidepressants [125, 126]. In most of the models
described above, locomotor activity in the open field test must be also monitored
to ensure that motor depression rather than emotional behaviour is not influencing
animal responses [126].
Although none of the available experimental paradigms are able to model all
aspects of depression disorders in terms of etiological factors and symptoms, and
most likely never will, the paradigms described above have proven extremely use-
ful both in the identification of potential new antidepressants and in the validation
of neurobiological concepts. More specifically, they have been extensively used for
assessing the potential antidepressant-like activity of compounds modulating the
endocannabinoid signaling in rodents.
Effects of Pharmacological Manipulation of the
Endocannabinoid Signaling in Preclinical Studies
of Depression
After discovering the ECS members (CB1 and CB2 receptors, endocannabinoids
AEA and 2-AG and enzymes for their degradation, FAAH and MAGL) several
pharmacological tools, which vary from direct agonists or antagonists (Fig. 5.1)
to endocannabinoid enhancers have been evaluated in several in vitro and in vivo
studies to assess their therapeutic potential in stress-related neuropsychiatric disor-
ders [23] (Table 5.4). Based on the hypothesis that a reduction of endocannabinoid
signaling could underlie depressive disorders, it has been seen that acute or repeated
treatment with different compounds which activate directly cannabinoid receptors,
such as the main pharmacologically active principle of Cannabis sativa ∆9-THC
[98, 127130], the endogenous cannabinoid AEA [131, 132], the synthetic nonspe-
cific CB1/CB2 receptor agonists CP55,940 [133], WIN55,212–2 [134, 135] and
HU-210 [136139] or the selective CB1 receptor agonist arachidonoyl 2’-chloro-
ethylamide (ACEA) [140, 141] elicited antidepressant-like effects through CB1 and
5-HTergic or NEergic receptor-mediated mechanisms.
However, chronic exposure to Δ9-THC or WIN55,212–2 in adolescence led to a
depressive-like phenotype in adulthood, further supporting the fact that adolescence
is a critical period in which protracted direct CB1 receptor activation may influence
mood control [142146] (see also Chap. 12). Although the CB1 receptor antago-
nist rimonabant, which was introduced into clinical practice as antiobesity agent,
was withdrawn from the market due to the higher incidence of psychiatric side
effects [147], preclinical studies have reported an antidepressant-like activity of
rimonabant in rodents [129, 130, 148151]. Using a genetic approach controversial
results regarding the effects of CB1 receptor signaling inhibition on stress coping
110 V. Micale et al.
behaviour have been obtained indicating that they could depend on specific deletion
of CB1 receptors in some neuronal subpopulations [129, 152, 153]. However, com-
pensatory mechanisms which develop in mutant mice could underlie the discrepan-
cies between pharmacological and genetic inhibition of CB1 receptor signaling.
Although CB2 receptor ligands might be potentially safer due to the lack of
psychoactive effects, controversial evidence concerning the effects of CB2 recep-
tor signaling modulation on depressive-like behaviour has been recently described
[23]. Thus, further clinical and preclinical investigations are required to define the
role of CB2 receptors in the pathophysiology and treatment of depression. Despite
the fact that vanilloid TRPV1 channels, due to their co-localization with CB1 recep-
tors in several brain regions [154], seem to represent “the other side of the coin” in
the regulation of anxiety, a similar function in depression is still ambiguous, since
both TRPV1 agonists [155, 156] and pharmacological [155158] or genetic TRPV1
blockade [159] elicited antidepressant-like effects. Thus, further studies are neces-
sary to assess the role of TRPV1 channels as additional ECS “players” in mood
regulation. Based on the assumption that direct activation of CB1 receptors elicited
psychotropic side effects, several compounds have been developed that reinforce
the effects of AEA and 2-AG by inhibiting their degradative enzymes FAAH and
MAGL, or by blocking their cellular reuptake. Since CB1 receptors, FAAH and
MAGL are not equally distributed in the brain; the indirect stimulation of CB1
receptors by endocannabinoid breakdown blockers could modulate the endocan-
nabinoid signaling in selected brain areas which control mood [160].
Fig. 5.1  Schematic illustration of the pharmacological modulation (i.e. agonists, antagonists and
endocannabinoid enhancers) of the endocannabinoid system in preclinical studies of depression.
For details about the different drugs see the main text and Table 5.4
1115 Role of the Endocannabinoid System in Depression
Drugs Mechanism of action Experimental
Animals Behavioural responseaPositive control References
∆9-THC Non selective CB1/CB2
receptor agonist
OBX Sprague-Dawley rats ↓ locomotor activity Fluoxetine [98]
Lister hooded rats ↓ locomotor activity ND [130]
FST/TST Swiss-DBA/2 mice ↓ immobility time Fluoxetine, Desipramine [127]
Sprague-Dawley rats ↓ immobility time Citalopram [128]
Bl6N mice ↓ immobility time ND [129]
AEA Non selective CB1/CB2
receptor agonist
FST/TST/CMS ICR mice No effect on immo-
bility time/↑ sucrose
Clomipramine [131]
FST Swiss mice ↓ immobility time Fluoxetine [132]
CP,55940 Non selective CB1/CB2
receptor agonist
FST Wistar rats ↓ immobility time ND [133]
WIN55,212–2 Non selective CB1/CB2
receptor agonist
FST Sprague-Dawley rats ↓ immobility time Citalopram, Desipramine [134]
CMS Sprague-Dawley rats ↓ immobility time/↑
extinction of avoidance
No effect on sucrose
ND [135]
HU-210 Non selective CB1/CB2
receptor agonist
FST Long-Evans rats ↓ immobility time Desipramine [136]
ND [137]
Sprague-Dawley rats ↓ immobility time ND [138]
Desipramine [139]
Selective CB1 receptor
FST BALB/c mice ↓ immobility time Fluoxetine [140]
CMS Sprague-Dawley rats ↑ extinction of aversive
ND [141]
Table 5.4  Schematic representation of the effects of the pharmacological modulation of the endocannabinoid system (ECS) in preclinical studies of depression
112 V. Micale et al.
Drugs Mechanism of action Experimental
Animals Behavioural responseaPositive control References
JWH015 Selective CB2 receptor
CMS BALB/c mice ↑ sucrose consumption ND [105]
GW405833 Selective CB2 receptor
FST Wistar rats ↓ immobility time Desipramine [224]
Olvanil Selective TRPV1 agonist FST/TST ICR mice ↓ immobility time ND [156]
Capsaicin Selective TRPV1 agonist FST/TST ICR mice ↓ immobility time ND [156]
Swiss mice ↓ immobility time Fluoxetine [155]
Arvanil Nonselective TRPV1/
CB1 receptor agonist
FST/TST ICR mice ↓ immobility time ND [156]
Selective CB1 receptor
antagonist/inverse agonist
FST Swiss mice ↓ immobility time ND [148]
CMS/FST Wistar rats/
BALB/c mice
↓ immobility time Fluoxetine [149]
FST Bl6 N mice ↓ immobility time ND [129]
Desipramine [150]
ICR mice ↓ immobility time Imipramine [151]
OBX Lister hooded rats ↓ locomotor activity ND [130]
Capsazepine selective TRPV1
FST/TST Swiss mice ↓ immobility time Fluoxetine [155]
Resiniferatoxin selective TRPV1
FST Swiss mice ↓ immobility time
(26 °C)
↑ immobility time
(41 °C)
SB366791 selective TRPV1
FST Wistar rats ↓ immobility time in
STR rats
Clomipramine [158]
Table 5.4  (continued)
1135 Role of the Endocannabinoid System in Depression
Drugs Mechanism of action Experimental
Animals Behavioural responseaPositive control References
URB597 FAAH inhibitor FST Long-Evans rats ↓ immobility time ND [161]
Wistar rats ↓ immobility time ND [133]
Swiss mice ↓ immobility time Fluoxetine [132]
Sprague-Dawley rats ↓ immobility time ND [162]
TST Bl6J mice ↓ immobility time Desipramine [163]
CMS Wistar rats ↑ sucrose consumption Imipramine [97]
ICR mice ↑ sucrose consumption ND [164]
Oleamide FAAH inhibitor FST Long-Evans rats ↓ immobility time Desipramine [136]
Albino mice ↓ immobility time ND [166]
AA-5-HT FAAH inhibitor/TRPV1
FST Wistar rats ↓ immobility time in
STR rats
Clomipramine [158]
AM404 AEA uptake inhibitor FST Long-Evans rats ↓ immobility time Desipramine [136]
Wistar rats ↓ immobility time Imipramine [133]
Swiss mice ↓ immobility time ND [172]
Swiss mice ↓ immobility time Fluoxetine [132]
JZL184 MAGL inhibitor Chronic unpre-
dictable mild
Bl6J mice ↑ sucrose consumption
↓ immobility time
ND [176]
Cannabidiol CB1-CB2 receptor antag-
onist/inverse agonist,
5-HT1 A receptor agonist,
TRPV1 agonist,
AEA uptake inhibitor,
FAAH inhibitor
FST Swiss mice ↓ immobility time Fluoxetine, Desipramine [127]
Swiss mice ↓ immobility time Imipramine [180]
TRPV1 agonist,
AEA uptake inhibitor
FST/TST Swiss-DBA/2 mice ↓ immobility time Fluoxetine, Desipramine [127]
a CMS chronic mild stress, FST forced swim test, ND not determined, OBX bilateral olfactory bulbectomy, TST tail suspension test, STR stressed group
Table 5.4  (continued)
114 V. Micale et al.
The FAAH inhibitor URB597 has shown CB1 receptor-mediated antidepressant-
like effects by enhancing AEA signaling in several experimental models such as
FST [132, 133, 161, 162], TST [163], CMS paradigm [97, 164], adolescent Δ9-THC
exposure [146] and tail-pinch test [165]. Another FAAH inhibitor, oleamide, elic-
ited antidepressant-like effects through a CB1 receptor-mediated mechanism [136,
166]. In agreement with the pharmacological approach, transgenic mice lacking
FAAH, which exhibit more than 10-fold higher levels of AEA as compared to wild-
type mice, have shown a less depressive-like phenotype [145].
A particularly innovative approach in the treatment of mood disorders could be
the use of compounds with the capability to combine inhibition of AEA hydroly-
sis with antagonism of TRPV1 channels. One such dual FAAH/TRPV1 blocker is
N-arachidonoyl-serotonin (AA-5-HT) [167, 168], which elicited anxiolytic- [169
171] and antidepressant-like activity [158], suggesting the potential therapeutic use
of dual FAAH/TRPV1 inhibitors in stress-related disorders. A different strategy to
enhance AEA signaling at the receptor is to block its uptake into pre- and/or post-
synaptic terminals, thereby promoting the indirect activation of CB1 receptors. The
prototypical endocannabinoid transport inhibitor AM404 has improved the behav-
ioural performance of rodents in the FST, through a CB1 receptor-mediated mecha-
nism [132, 133, 136, 172]. However, the exact mechanism of action of endocan-
nabinoid uptake inhibitors as well as the molecular identity of the transporter itself
still remains to be characterized. Therefore, further biomolecular studies will have
to be performed in this direction.
Collectively, this evidence supports the clinical potential of endocannabinoid
level modulators as new therapeutic tools for the treatment of mood disorders. Re-
cent data have suggested that 2-AG could act in the brain modulating behavioural
responses in stress-related conditions [173175]. In this context the prototypical
MAGL inhibitor JZL184, by inducing an 8-fold increase in 2-AG, but not AEA,
brain content reversed the depressive-like behaviour via activation of both CB1
receptor and mTor signaling [176]. However, contrary to FAAH blockade, a po-
tential drawback in the use of MAGL inhibitors could be the development of tetrad
effects which are typical of CB1 receptor agonists [177] as well as of tolerance with
chronic use [178, 179].
In conclusion, while endocannabinoids are rapidly metabolized in vivo, limiting
the potential efficacy of their exogenous administration, the data described above
supports more FAAH than MAGL as a potential therapeutic target for the identifica-
tion of new pharmacotherapies for affective disorders [160]. In addition to the phar-
macological modulation of the endocannabinoid signaling, a different approach to
reduce the psychotropic side effects of Cannabis is the use of plant-derived canna-
binoids with very weak or no psychotropic effects such as CBD, cannabichromene,
cannabigerol, cannabidivarin and ∆9-Tetrahydrocannabinol, some of which show
potential as therapeutic agents in preclinical models of CNS disorders [55]. Special
emphasis is given to CBD, which exerts several positive pharmacological effects
in preclinical and clinical studies to the point of making it a highly attractive thera-
peutic entity in several diseases. We still do not know the exact mechanism(s) of
action underlying the mood-elevating effect of CBD, as it may act not only through
1155 Role of the Endocannabinoid System in Depression
the ECS, but also by directly or indirectly activating the metabotropic receptors for
5-HT or adenosine or by targeting nuclear receptors of the PPAR family as well as
modulating ion channels including TRPV1 [18]. Contrary to the extensive research
done regarding the potential therapeutic effects of CBD in anxiety [23] or schizo-
phrenia [24], only few studies have examined its antidepressant-like effects. In the
FST, which represents a standard preclinical test to assess the effects of potential
antidepressants, cannabichromene and CBD decreased the immobility time, the lat-
ter acting through a 5-HT1 A receptor–mediated mechanism [127, 180]. However,
further studies are necessary to establish the efficacy and safety profile of phytocan-
nabinoids for the treatment of stress-related disorders.
Endocannabinoid Signaling and Antidepressant-Like
Effects: Potential Molecular Underpinning
As described above, based on the monoaminergic hypothesis of depression, the
actual antidepressants act by enhancing the central 5-HTergic and/or NEergic neu-
rotransmission through the inhibition of the synaptic re-uptake or enzymatic deg-
radation, and the desensitization or sensitization of specific receptors [4]. Several
lines of evidence suggest that modulation of endocannabinoid signaling could fa-
cilitate 5-HTergic neurotransmission through an enhancement of 5-HT neuronal ac-
tivity, an increased 5-HT efflux or modulation of 5-HT receptors (i.e. 5-HT1A and
5-HT2A/C). Both direct and indirect activation of CB1 receptors (the latter acting
through pharmacological or genetic inhibition of FAAH activity) increased firing
activity of 5-HTergic neurons in the DRN [128, 134, 162, 181], and enhanced basal
5-HT efflux in several brain regions such as nucleus accumbens, striatum, hippo-
campus and PFC [181183]. However, chronic exposure to the CB1 receptor ago-
nist WIN55,212–2 during adolescence attenuated 5-HTergic activity and elicited a
depressive-like phenotype in adulthood, further supporting the importance of ado-
lescence as a highly sensitive developmental window within which the disruptive
effects of cannabinoid exposure increase the risk for developing psychiatric disor-
ders [145]. Interestingly, inhibition of CB1 receptor signaling induced a depressive-
like phenotype in mice, which was mediated by an impairment of 5-HTergic neural
activity [152, 153, 184186], strenghening the role of the endocannabinoid tone in
emotional behaviour through the modulation of the 5-HTergic neurotransmission.
As described for conventional antidepressants, which induce a desensitization of the
5-HT2A/C autoreceptors and/or an enhancement of the tonic activity of 5-HT1A re-
ceptors [187], the antidepressant-like effects elicited by cannabinoids could be due
to changes in the expression and function of these receptors [128, 188]. However,
further 5-HT receptor subtypes (i.e. 5-HT3 or 5-HT4) could also be involved in the
emotional responses induced by the endocannabinoid tone modulation [189192].
A dysregulation of NEergic system seems to be implicated in the pathophysiol-
ogy of depression, as supported by the primary action of antidepressants to en-
hance central NEergic transmission. In this context, a strong interaction between
116 V. Micale et al.
the endocannabinoid and NEergic systems could participate in the antidepressant
effects of endocannabinoid signaling enhancement, based on the expression of CB1
receptors in the LC (the major NEergic nucleus). More specifically, CB1 receptor
activation could directly or indirectly, by modulating inhibitory and/or excitatory
inputs to LC, increase the firing activity of NEergic neurons and consequently the
release of NE in the forebrain. This indicates the existence of a functional interac-
tion between these two systems in the action of antidepressants [181, 193, 194].
However, in vitro studies have shown the capacity of cannabinoids to inhibit mono-
amine reuptake and metabolism, sharing some pharmacological properties with an-
tidepressants [195198].
Increasing evidence links stress to depression and antidepressant action, and sug-
gests that stressors act by inducing a disruption in cellular mechanisms governing
neuronal plasticity and disturbances in the hypothalamic-pituitary adrenal (HPA)
axis [199, 200]. Hence, current and potential antidepressants exert neurotrophic
activity, by increasing the hippocampal expression of factors such as cyclic adenos-
ine monophosphate-response element binding protein (CREB) and BDNF, and also
affect HPA axis hyperactivity [201205]. The endogenous cannabinoids AEA and
2-AG [206] and the synthetic nonspecific cannabinoid CB1/CB2 receptor agonists
HU-210 [137] or WIN55,212–2 [207, 208] stimulate neurogenesis, which is inhibit-
ed by pharmacological [151, 206] or genetic [209212] CB1 receptor blockade. The
enhanced AEA signaling also stimulates hippocampal cell proliferation, through a
CB1 receptor-mediated mechanism [158, 213, 214]
Based on the recent detection of CB2 receptors in the brain [43], their potential
mechanisms underlying emotional responses are under investigation. So far, it has
been seen that pharmacological activation or genetic inactivation of CB2 recep-
tors enhanced or reduced hippocampal neuronal plasticity, respectively [215, 216].
Similarly, the CMS procedure did not alter BDNF expression in mice overexpress-
ing CB2 receptors [106], suggesting their potential protective role. On one hand the
controversial in vivo data does not give us a coherent picture concerning the role of
CB2 receptors in depression, on the other hand, however, the molecular data further
strengthens the rationale for the development of selective CB2 receptor agonists as
promising candidates to target neurogenesis, thus bypassing the undesired psycho-
active effects of central CB1 receptor activation.
Taken together the data presented herein suggests that facilitation of the en-
docannabinoid signaling through CB1 and/or CB2 receptors activation seems to
mimic the effects of current antidepressants on hippocampal neuroplasticity. The
HPA axis acts as a neuroendocrine bridge, regulating the stress response by con-
trolling the secretion of corticotrophin-releasing hormone, adrenocorticotropic and
glucocorticoidhormones. Additionally, it is controlled by a negative feedback inhi-
bition loop which involves mineralocorticoid and glucocorticoid receptors [217].
Depressive disorders are also characterized by an inability of glucocorticoids to
bind their receptors, which in turn can lead to HPA axis hyperactivity and increased
levels of circulating glucocorticoids. Treatment with the current antidepressants re-
sults in reduction of glucocorticoid release, suggesting that the attenuation of HPA
axis hyper-responsivity could be one of the long-term adaptations in response to
1175 Role of the Endocannabinoid System in Depression
antidepressants that contributes to their therapeutic efficacy [218]. Several evidence
highlights the role of the endocannabinoid signaling to regulate the HPA axis both
during basal conditions and after stress exposure [133, 219] (see also Chap. 1).
While CB1 receptor activation inhibits HPA axis activity, as a part of the HPA axis
negative feedback inhibition loop, impairment in the CB1 receptor signaling in-
creases HPA axis activity under both basal conditions and following stress exposure
[152, 220222]. Collectively the data described above suggests that the antidepres-
sant-like effects of different classes of cannabinoids may in part be due to molecular
mechanisms which resemble the ones triggered by antidepressants.
Future Perspective and Conclusive Remarks
In conclusion, the current evidence suggests a strong link between ECS and depres-
sive disorders. A deficiency in the endocannabinoid tone leads to a depressive-like
phenotype in experimental animal models of depression (Table 5.3), which is in
line with clinical findings where depressed patients have reduced levels of endog-
enous cannabinoids (Table 5.1). Hence, facilitation of the endocannabinoid signal-
ing could be the target for developing potential new antidepressants. Supporting
this hypothesis is preclinical data which has shown that elevated endocannabinoid
signaling is able to produce behavioural and biochemical effects as the conventional
antidepressant treatment (Table 5.4), and that many antidepressants alter endoge-
nous cannabinoid tone (Table 5.2). However, whilst the direct activation of CB1 re-
ceptors is hampered by unwanted psychotropic effects, and the possibly safer direct
modulation of CB2 receptors still lacks sufficient experimental evidence to justify
its use, the indirect activation of cannabinoid receptors with agents that inhibit en-
docannabinoids deactivation has produced very promising results in experimental
animal models of depression. Yet, this approach is not devoid of intrinsic problems,
mostly due to the fact that endocannabinoid-deactivating proteins also recognize
other non-endocannabinoid mediators as substrates which then activate different
receptors—a property also shared to some extent by endocannabinoids like AEA
and NADA. Thus, inhibition of enzymes like FAAH or of the putative endocan-
nabinoid transporter might lead to the activation of these alternative receptors. This
complication and the possible compensatory action of co-occurring deactivation
routes and enzymes for endocannabinoids [223] may render this approach not suf-
ficiently efficacious or safe. In view of these potential problems and of the fact
that genetic studies have revealed a relationship between depression and polymor-
phisms of cannabinoid receptors and/or degradative enzymes, only time will tell if
targeting the ECS may result in effective pharmacotherapies for major depression
and other affective-related disorders.
Acknowledgments The research of the authors is supported by the project “CEITEC—Central
European Institute of Technology” (CZ.1.05/1.1.00/02.0068) from European Regional Develop-
ment Fund. We thank Caitlin Riebe (independent scientific illustrator, Vancouver, Canada) for the
artwork and Vanessa Raileanu (Toronto, Canada) for the proof-reading.
118 V. Micale et al.
1. Wittchen HU, Jacobi F, Rehm J, Gustavsson A, Svensson M, Jönsson B, Olesen J, Allguland-
er C, Alonso J, Faravelli C, Fratiglioni L, Jennum P, Lieb R, Maercker A, van Os J, Preisig M,
Salvador-Carulla L, Simon R, Steinhausen H-C. The size and burden of mental disorders and
other disorders of the brain in Europe 2010. Eur Neuropsychopharmacol. 2011;21(9):655–
2. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th
ed. A.P. Publishing: Arlington;2013.
3. Schildkraut JJ. The catecholamine hypothesis of affective disorders: a review of supporting
evidence. Am J Psychiatry. 1965;122(5):509–22.
4. Li X, Frye MA, Shelton RC. Review of pharmacological treatment in mood disorders and
future directions for drug development. Neuropsychopharmacology. 2012;37(1):77–101.
5. Han C, Wang S-M, Kato M, Lee S-J, Patkar AA, Masand PS, Pae C-U. Second-generation
antipsychotics in the treatment of major depressive disorder: current evidence. Expert Rev
Neurother. 2013;13(7):851–70.
6. Srinivasan V, De Berardis D, Shillcutt SD, Brzezinski A. Role of melatonin in mood
disorders and the antidepressant effects of agomelatine. Expert Opin Investig Drugs.
7. Krystal JH, Sanacora G, Duman RS. Rapid-acting glutamatergic antidepressants: the path to
ketamine and beyond. Biol Psychiatry. 2013;73(12):1133–41.
8. Machado-Vieira R, Salvadore G, Diazgranados N, Zarate CA Jr. Ketamine and the next gen-
eration of antidepressants with a rapid onset of action. Pharmacol Ther. 2009;123(2):143–50.
9. Kehne JH, Cain CK. Therapeutic utility of non-peptidic CRF1 receptor antagonists in anxi-
ety, depression, and stress-related disorders: evidence from animal models. Pharmacol Ther.
10. Wong EHF, Tarazi FI, Shahid M. The effectiveness of multi-target agents in schizophre-
nia and mood disorders: Relevance of receptor signature to clinical action. Pharmacol Ther.
11. Engin E, Liu J, Rudolph U. α2-containing GABA(A) receptors: a target for the development
of novel treatment strategies for CNS disorders. Pharmacol Ther. 2012;136(2):142–52.
12. Connolly KR, Thase ME. Emerging drugs for major depressive disorder. Expert Opin Emerg
Drugs. 2012;17(1):105–26.
13. Isbell H, Gorodetzsky CW, Jasinski D, Clausseln U, von Spulak F, Korte F. Effects of (—)
delta-9-trans-tetrahydrocannabinol in man. Psychopharmacologia. 1967;11(2):184–8.
14. Luongo L, Maione S, Di Marzo V. Endocannabinoids and neuropathic pain: focus on neuron-
glia and endocannabinoid-neurotrophin interactions. Eur J Neurosci. 2014;39(3):401–8.
15. Starowicz K, Makuch W, Korostynski M, Malek N, Slezak M, Zychowska M, Petrosino S,
De Petrocellis L, Cristino L, Przewlocka B, Di Marzo V. Full inhibition of spinal FAAH
leads to TRPV1-mediated analgesic effects in neuropathic rats and possible lipoxygenase-
mediated remodeling of anandamide metabolism. PLoS ONE. 2013;8(4):e60040.
16. Di Marzo V. “De-liver-ance” from CB(1): a way to counteract insulin resistance? Gastroen-
terology. 2012;142(5):1063–6.
17. Silvestri C, Di Marzo V. The endocannabinoid system in energy homeostasis and the etiopa-
thology of metabolic disorders. Cell Metab. 2013;17(4):475–90.
18. Izzo AA, Sharkey KA. Cannabinoids and the gut: new developments and emerging concepts.
Pharmacol Ther. 2010;126(1):21–38.
19. Silvestri C, Ligresti A, Di Marzo V. Peripheral effects of the endocannabinoid system in
energy homeostasis: adipose tissue, liver and skeletal muscle. Rev Endocr Metab Disord.
20. Mazzola C, Micale V, Drago F. Amnesia induced by beta-amyloid fragments is counteracted
by cannabinoid CB1 receptor blockade. Eur J Pharmacol. 2003;477(3):219–25.
21. Micale V, Mazzola C, Drago F. Endocannabinoids and neurodegenerative diseases. Pharma-
col Res. 2007;56(5):382–92.
1195 Role of the Endocannabinoid System in Depression
22. Micale V, Cristino L, Tamburella A, Petrosino S, Leggio GM, Di Marzo V, Drago F. Enhanced
cognitive performance of dopamine D3 receptor “knock-out” mice in the step-through pas-
sive-avoidance test: assessing the role of the endocannabinoid/endovanilloid systems. Phar-
macol Res. 2010;61(6):531–6.
23. Micale V, Di Marzo V, Sulcova A, Wotjak CT, Drago F. Endocannabinoid system and mood
disorders: priming a target for new therapies. Pharmacol Ther. 2013;138(1):18–37.
24. Kucerova J, Tabiova K, Drago F, Micale V. Therapeutic potential of cannabinoids in schizo-
phrenia. Recent Pat CNS Drug Discov. 2014;9(1):13–25.
25. Terzian ALB, Micale V, Wotjak CT. Cannabinoid receptor type 1 receptors on GABAergic
vs. glutamatergic neurons differentially gate sex-dependent social interest in mice. Eur J
Neurosci. 2014;40(1):2293–8.
26. Howlett AC, Bidaut-Russell M, Devane WA, Melvin LS, Johnson MR, Herkenham M. The
cannabinoid receptor: biochemical, anatomical and behavioral characterization. Trends Neu-
rosci. 1990;13(10):420–3.
27. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI. Structure of a cannabinoid
receptor and functional expression of the cloned cDNA. Nature. 1990;346(6284):561–4.
28. Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for
cannabinoids. Nature. 1993;365(6441):61–5.
29. Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandel-
baum A, Etinger A, Mechoulam R. Isolation and structure of a brain constituent that binds to
the cannabinoid receptor. Science. 1992;258(5090):1946–9.
30. Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, Gopher A,
Almog S, Martin BR, Compton DR. Identification of an endogenous 2-monoglyceride, pres-
ent in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol. 1995;50(1):83–
31. Lovinger DM. Endocannabinoid liberation from neurons in transsynaptic signaling. J Mol
Neurosci. 2007;33(1):87–93.
32. Marnett LJ. Decoding endocannabinoid signaling. Nat Chem Biol. 2009;5(1):8–9.
33. Di Marzo V Petrosino S. Endocannabinoids and the regulation of their levels in health and
disease. Curr Opin Lipidol. 2007;18(2):129–40.
34. Liu J, Wang L, Harvey-White J, Huang BX, Kim H-Y, Luquet S, Palmiter RD, Krystal G, Rai
R, Mahadevan A, Razdan RK, Kunos G. Multiple pathways involved in the biosynthesis of
anandamide. Neuropharmacology. 2008;54(1):1–7.
35. Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB. Molecular char-
acterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature.
36. 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 USA. 2002;99(16):10819–24.
37. Begg M, Pacher P, Bátkai S, Osei-Hyiaman D, Offertáler L, Mo FM, Liu J, Kunos G. Evi-
dence for novel cannabinoid receptors. Pharmacol Ther. 2005;106(2):133–45.
38. Pertwee RG. Receptors and channels targeted by synthetic cannabinoid receptor agonists and
antagonists. Curr Med Chem. 2010;17(14):1360–81.
39. Mackie K. Distribution of cannabinoid receptors in the central and peripheral nervous sys-
tem. Handb Exp Pharmacol. 2005;(168):299–325.
40. Marsicano G, Lutz B. Expression of the cannabinoid receptor CB1 in distinct neuronal sub-
populations in the adult mouse forebrain. Eur J Neurosci. 1999;11(12):4213–25.
41. Häring M, Marsicano G, Lutz B, Monory K. Identification of the cannabinoid receptor type
1 in serotonergic cells of raphe nuclei in mice. Neuroscience. 2007;146(3):1212–9.
42. Oropeza VC, Mackie K, Van Bockstaele EJ. Cannabinoid receptors are localized to noradren-
ergic axon terminals in the rat frontal cortex. Brain Res. 2007;1127(1):36–44.
43. Van Sickle MD Duncan M Kingsley PJ Mouihate A Urbani P Mackie K Stella N Makriyannis
A Piomelli D Davison JS Marnett LJ Di Marzo V Pittman QJ Patel KD Sharkey KA. Iden-
tification and functional characterization of brainstem cannabinoid CB2 receptors. Science.
120 V. Micale et al.
44. Gong JP, Onaivi ES, Ishiguro H, Liu QR, Tagliaferro PA, Brusco A, Uhl GR. Cannabinoid
CB2 receptors: immunohistochemical localization in rat brain. Brain Res. 2006;1071(1):10–
45. Marco EM, García-Gutiérrez MS, Bermúdez-Silva F-J, Moreira FA, Guimarães F, Man-
zanares J, Viveros M-P. Endocannabinoid system and psychiatry: in search of a neurobiologi-
cal basis for detrimental and potential therapeutic effects. Front Behav Neurosci. 2011;5:63.
46. Pacher P, Bátkai S, Kunos G. The endocannabinoid system as an emerging target of pharma-
cotherapy. Pharmacol Rev. 2006;58(3):389–462.
47. Gaoni Y, Mechoulam R. Isolation, structure, and partial synthesis of an active constituent of
hashish. J Am Chem Soc. 1964;86(8):1646–7.
48. Bisogno T, Hanus L, De Petrocellis L, Tchilibon S, Ponde DE, Brandi I, Moriello AS, Davis
JB, Mechoulam R, Di Marzo V. Molecular targets for cannabidiol and its synthetic ana-
logues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis
of anandamide. Br J Pharmacol. 2001;134(4):845–52.
49. Carrier EJ, Auchampach JA, Hillard CJ. Inhibition of an equilibrative nucleoside transporter
by cannabidiol: a mechanism of cannabinoid immunosuppression. Proc Natl Acad Sci USA.
50. De Petrocellis L Ligresti A Moriello AS Allarà M Bisogno T Petrosino S Stott CG Di Marzo
V. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and
endocannabinoid metabolic enzymes. Br J Pharmacol. 2011;163(7):1479–94.
51. Russo EB, Burnett A, Hall B, Parker KK. Agonistic properties of cannabidiol at 5-HT1a
receptors. Neurochem Res. 2005;30(8):1037–43.
52. Magen I, Avraham Y, Ackerman Z, Vorobiev L, Mechoulam R, Berry EM. Cannabidiol
ameliorates cognitive and motor impairments in mice with bile duct ligation. J Hepatol.
53. Cascio MG, Gauson LA, Stevenson LA, Ross RA, Pertwee RG. Evidence that the plant can-
nabinoid cannabigerol is a highly potent alpha2-adrenoceptor agonist and moderately potent
5HT1 A receptor antagonist. Br J Pharmacol. 2010;159(1):129–41.
54. Izzo AA, Borrelli F, Capasso R, Di Marzo V, Mechoulam R. Non-psychotropic plant can-
nabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol Sci.
55. Hill AJ, Williams CM, Whalley BJ, Stephens GJ. Phytocannabinoids as novel therapeutic
agents in CNS disorders. Pharmacol Ther. 2012;133(1):79–97.
56. Ablon SL, Goodwin FK. High frequency of dysphoric reactions to tetrahydrocannabinol
among depressed patients. Am J Psychiatry. 1974;131(4):448–53.
57. Kotin J, Post RM, Goodwin FK. 9-Tetrahydrocannabinol in depressed patients. Arch Gen
Psychiatry. 1973;28(3):345–8.
58. Amchova P, Kucerova J, Giugliano V, Babinska Z, Zanda MT, Scherma M, Dusek L, Fadda P,
Micale V, Sulcova A, Fratta W, Fattore L. Enhanced self-administration of the CB1 receptor
agonist WIN55, 212–2 in olfactory bulbectomized rats: evaluation of possible serotonergic
and dopaminergic underlying mechanisms. Front Pharmacol. 2014;5:44.
59. Patton GC, Coffey C, Carlin JB, Degenhardt L, Lynskey M, Hall W. Cannabis use and mental
health in young people: cohort study. BMJ. 2002;325(7374):1195–8.
60. Arendt M, Rosenberg R, Fjordback L, Brandholdt J, Foldager L, Sher L, Munk-Jørgensen P.
Testing the self-medication hypothesis of depression and aggression in cannabis-dependent
subjects. Psychol Med. 2007;37(7):935–45.
61. Bovasso GB. Cannabis abuse as a risk factor for depressive symptoms. Am J Psychiatry.
62. Rey JM, Sawyer MG, Raphael B, Patton GC, Lynskey M. Mental health of teenagers who use
cannabis. Results of an Australian survey. Br J Psychiatry. 2002;180:216–21.
63. Degenhardt L, Hall W, Lynskey M. Exploring the association between cannabis use and
depression. Addiction. 2003;98(11):1493–504.
64. Harder VS, Morral AR, Arkes J. Marijuana use and depression among adults: testing for
causal associations. Addiction. 2006;101(10):1463–72.
1215 Role of the Endocannabinoid System in Depression
65. Tziraki S. [Mental disorders and neuropsychological impairment related to chronic use of
cannabis]. Rev Neurol. 2012;54(12):750–60.
66. Fu Q, Heath AC, Bucholz KK, Nelson E, Goldberg J, Lyons MJ, True WR, Jacob T, Tsuang
MT, Eisen SA. Shared genetic risk of major depression, alcohol dependence, and marijuana
dependence: contribution of antisocial personality disorder in men. Arch Gen Psychiatry.
67. Lynskey MT, Heath AC, Nelson EC, Bucholz KK, Madden PAF, Slutske WS, Statham DJ,
Martin NG. Genetic and environmental contributions to cannabis dependence in a national
young adult twin sample. Psychol Med. 2002;32(2):195–207.
68. Lynskey MT, Glowinski AL, Todorov AA, Bucholz KK, Madden PAF, Nelson EC, Statham
DJ, Martin NG, Heath AC. Major depressive disorder, suicidal ideation, and suicide attempt
in twins discordant for cannabis dependence and early-onset cannabis use. Arch Gen Psy-
chiatry. 2004;61(10):1026–32.
69. Farris SG, Zvolensky MJ, Boden MT, Bonn-Miller MO. Cannabis use expectancies medi-
ate the relation between depressive symptoms and cannabis use among cannabis-dependent
veterans. J Addict Med. 2014;8(2):130–6.
70. Parolaro D, Realini N, Vigano D, Guidali C, Rubino T. The endocannabinoid system and
psychiatric disorders. Exp Neurol. 2010;224(1):3–14.
71. Hungund BL, Vinod KY, Kassir SA, Basavarajappa BS, Yalamanchili R, Cooper TB, Mann
JJ, Arango V. Upregulation of CB1 receptors and agonist-stimulated [35S]GTPgammaS bind-
ing in the prefrontal cortex of depressed suicide victims. Mol Psychiatry. 2004;9(2):184–90.
72. Koethe D, Llenos IC, Dulay JR, Hoyer C, Torrey EF, Leweke FM, Weis S. Expression of
CB1 cannabinoid receptor in the anterior cingulate cortex in schizophrenia, bipolar disorder,
and major depression. J Neural Transm. 2007;114(8):1055–63.
73. Hill MN, Miller GE, Ho W-SV, Gorzalka BB, Hillard CJ. Serum endocannabinoid content
is altered in females with depressive disorders: a preliminary report. Pharmacopsychiatry.
74. Hill MN, Miller GE, Carrier EJ, Gorzalka BB, Hillard CJ. Circulating endocannabinoids and
N-acyl ethanolamines are differentially regulated in major depression and following expo-
sure to social stress. Psychoneuroendocrinology. 2009;34(8):1257–62.
75. Vinod KY, Arango V, Xie S, Kassir SA, Mann JJ, Cooper TB, Hungund BL. Elevated levels
of endocannabinoids and CB1 receptor-mediated G-protein signaling in the prefrontal cortex
of alcoholic suicide victims. Biol Psychiatry. 2005;57(5):480–6.
76. Ho WS, Hill MN, Miller GE, Gorzalka BB, Hillard CJ. Serum contents of endocannabinoids
are correlated with blood pressure in depressed women. Lipids Health Dis. 2012;11:32.
77. Heyman E, Gamelin F-X, Goekint M, Piscitelli F, Roelands B, Leclair E, Di Marzo V,
Meeusen R. Intense exercise increases circulating endocannabinoid and BDNF levels in
humans—possible implications for reward and depression. Psychoneuroendocrinology.
78. Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol
Psychiatry. 2006;59(12):1116–27.
79. Hill MN, Hillard CJ, Bambico FR, Patel S, Gorzalka BB, Gobbi G. The therapeutic poten-
tial of the endocannabinoid system for the development of a novel class of antidepressants.
Trends Pharmacol Sci. 2009;30(9):484–93.
80. Moreira FA, Crippa JAS. The psychiatric side-effects of rimonabant. Rev Bras Psiquiatr.
81. Lazary J, Juhasz G, Hunyady L, Bagdy G. Personalized medicine can pave the way for the
safe use of CBâ receptor antagonists. Trends Pharmacol Sci. 2011;32(5):270–80.
82. Levinson DF, Holmans P, Straub RE, Owen MJ, Wildenauer DB, Gejman PV, Pulver AE,
Laurent C, Kendler KS, Walsh D, Norton N, Williams NM, Schwab SG, Lerer B, Mowry BJ,
Sanders AR, Antonarakis SE, Blouin JL, DeLeuze JF, Mallet J. Multicenter linkage study of
schizophrenia candidate regions on chromosomes 5q, 6q, 10p, and 13q: schizophrenia link-
age collaborative group III. Am J Hum Genet. 2000;67(3):652–63.
122 V. Micale et al.
83. Chen X, Williamson VS, An S-S, Hettema JM, Aggen SH, Neale MC, Kendler KS. Can-
nabinoid receptor 1 gene association with nicotine dependence. Arch Gen Psychiatry.
84. Chakrabarti B, Baron-Cohen S. Variation in the human cannabinoid receptor CNR1 gene
modulates gaze duration for happy faces. Mol Autism. 2011;2(1):10.
85. Barrero FJ, Ampuero I, Morales B, Vives F, de Dios Luna Del Castillo J, Hoenicka J, García
Yébenes J. Depression in Parkinson’s disease is related to a genetic polymorphism of the
cannabinoid receptor gene (CNR1). Pharmacogenomics J. 2005;5(2):135–41.
86. Domschke K, Dannlowski U, Ohrmann P, Lawford B, Bauer J, Kugel H, Heindel W, Young
R, Morris P, Arolt V, Deckert J, Suslow T, Baune BT. Cannabinoid receptor 1 (CNR1) gene:
impact on antidepressant treatment response and emotion processing in major depression.
Eur Neuropsychopharmacol. 2008;18(10):751–9.
87. Juhasz G, Chase D, Pegg E, Downey D, Toth ZG, Stones K, Platt H, Mekli K, Payton A,
Elliott R, Anderson IM, Deakin JFW. CNR1 gene is associated with high neuroticism and
low agreeableness and interacts with recent negative life events to predict current depressive
symptoms. Neuropsychopharmacology. 2009;34(8):2019–27.
88. Monteleone P, Bifulco M, Maina G, Tortorella A, Gazzerro P, Proto MC, Di Filippo C, Mon-
teleone F, Canestrelli B, Buonerba G, Bogetto F, Maj M. Investigation of CNR1 and FAAH
endocannabinoid gene polymorphisms in bipolar disorder and major depression. Pharmacol
Res. 2010;61(5):400–4.
89. Lazary J, Lazary A, Gonda X, Benko A, Molnar E, Hunyady L, Juhasz G, Bagdy G. Promoter
variants of the cannabinoid receptor 1 gene (CNR1) in interaction with 5-HTTLPR affect the
anxious phenotype. Am J Med Genet B Neuropsychiatr Genet. 2009;150B(8):1118–27.
90. Agrawal A, Nelson EC, Littlefield AK, Bucholz KK, Degenhardt L, Henders AK, Madden
PAF, Martin NG, Montgomery GW, Pergadia ML, Sher KJ, Heath AC, Lynskey MT. Canna-
binoid receptor genotype moderation of the effects of childhood physical abuse on anhedonia
and depression. Arch Gen Psychiatry. 2012;69(7):732–40.
91. Mitjans M, Gastó C, Catalán R, Fañanás L, Arias B. Genetic variability in the endocannabi-
noid system and 12-week clinical response to citalopram treatment: the role of the CNR1,
CNR2 and FAAH genes. J Psychopharmacol. 2012;26(10):1391–8.
92. Hill MN, Ho W-SV, Hillard CJ, Gorzalka BB. Differential effects of the antidepressants tran-
ylcypromine and fluoxetine on limbic cannabinoid receptor binding and endocannabinoid
contents. J Neural Transm. 2008;115(12):1673–9.
93. Mato S, Vidal R, Castro E, Díaz A, Pazos A, Valdizán EM. Long-term fluoxetine treatment
modulates cannabinoid type 1 receptor-mediated inhibition of adenylyl cyclase in the rat
prefrontal cortex through 5-hydroxytryptamine 1 A receptor-dependent mechanisms. Mol
Pharmacol. 2010;77(3):424–34.
94. Hesketh SA, Brennan AK, Jessop DS, Finn DP. Effects of chronic treatment with citalopram
on cannabinoid and opioid receptor-mediated G-protein coupling in discrete rat brain re-
gions. Psychopharmacology (Berl). 2008;198(1):29–36.
95. Hill MN, Ho W-SV, Sinopoli KJ, Viau V, Hillard CJ, Gorzalka BB. Involvement of the endo-
cannabinoid system in the ability of long-term tricyclic antidepressant treatment to suppress
stress-induced activation of the hypothalamic-pituitary-adrenal axis. Neuropsychopharma-
cology. 2006;31(12):2591–9.
96. Hill MN, Carrier EJ, McLaughlin RJ, Morrish AC, Meier SE, Hillard CJ, Gorzalka BB. Re-
gional alterations in the endocannabinoid system in an animal model of depression: effects of
concurrent antidepressant treatment. J Neurochem. 2008;106(6):2322–36.
97. Bortolato M, Mangieri RA, Fu J, Kim JH, Arguello O, Duranti A, Tontini A, Mor M, Tar-
zia 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.
98. Rodríguez-Gaztelumendi A, Rojo ML, Pazos A, Díaz A. Altered CB receptor-signaling in
prefrontal cortex from an animal model of depression is reversed by chronic fluoxetine. J
Neurochem. 2009;108(6):1423–33.
99. Lee TTY, Hill MN. Age of stress exposure modulates the immediate and sustained effects of
repeated stress on corticolimbic cannabinoid CBâ receptor binding in male rats. Neurosci-
ence. 2013;249:106–14.
1235 Role of the Endocannabinoid System in Depression
100. McLaughlin RJ, Hill MN, Dang SS, Wainwright SR, Galea LAM, Hillard CJ, Gorzalka
BB. Upregulation of CBâ receptor binding in the ventromedial prefrontal cortex promotes
proactive stress-coping strategies following chronic stress exposure. Behav Brain Res.
101. Hill MN, Patel S, Carrier EJ, Rademacher DJ, Ormerod BK, Hillard CJ, Gorzalka BB.
Downregulation of endocannabinoid signaling in the hippocampus following chronic un-
predictable stress. Neuropsychopharmacology. 2005;30(3):508–15.
102. Reich CG, Taylor ME, McCarthy MM. Differential effects of chronic unpredictable stress
on hippocampal CB1 receptors in male and female rats. Behav Brain Res. 2009;203(2):264–
103. Wang H, Wang L, Zhang R, Chen Y, Liu L, Gao F, Nie H, Hou W, Peng Z, Tan Q. Anti-
depressive mechanism of repetitive transcranial magnetic stimulation in rat: the role of the
endocannabinoid system. J Psychiatr Res. 2014;51:79–87.
104. Reich CG, Mihalik GR, Iskander AN, Seckler JC, Weiss MS. Adolescent chronic mild
stress alters hippocampal CB1 receptor-mediated excitatory neurotransmission and plastic-
ity. Neuroscience. 2013;253:444–54.
105. Onaivi ES, Ishiguro H, Gong JP, Patel S, Meozzi PA, Myers L, Perchuk A, Mora Z, Ta-
gliaferro PA, Gardner E, Brusco A, Akinshola BE, Liu Q-R, Chirwa SS, Hope B, Lujilde J,
Inada T, Iwasaki S, Macharia D, Teasenfitz L, Arinami T, Uhl GR. Functional expression of
brain neuronal CB2 cannabinoid receptors are involved in the effects of drugs of abuse and
in depression. Ann N Y Acad Sci. 2008;1139:434–49.
106. García-Gutiérrez MS, Pérez-Ortiz JM, Gutiérrez-Adán A, Manzanares J. Depression-resis-
tant endophenotype in mice overexpressing cannabinoid CB(2) receptors. Br J Pharmacol.
107. Zoppi S, Madrigal JL, Caso JR, García-Gutiérrez MS, Manzanares J, Leza JC, García-
Bueno B. Regulatory role of the cannabinoid CB2 receptor in stress-induced neuroinflam-
mation in mice. Br J Pharmacol. 2014;171(11):2814–26.
108. Patel S, Roelke CT, Rademacher DJ, Hillard CJ. Inhibition of restraint stress-induced
neural and behavioural activation by endogenous cannabinoid signalling. Eur J Neurosci.
109. Hill MN, McLaughlin RJ, Bingham B, Shrestha L, Lee TTY, Gray JM, Hillard CJ, Gor-
zalka BB, Viau V. Endogenous cannabinoid signaling is essential for stress adaptation. Proc
Natl Acad Sci USA. 2010;107(20):9406–11.
110. Hill MN, Kumar SA, Filipski SB, Iverson M, Stuhr KL, Keith JM, Cravatt BF, Hillard
CJ, Chattarji S, McEwen BS. Disruption of fatty acid amide hydrolase activity prevents
the effects of chronic stress on anxiety and amygdalar microstructure. Mol Psychiatry.
111. Rademacher DJ, Meier SE, Shi L, Ho WV, Jarrahian A, Hillard CJ. Effects of acute and
repeated restraint stress on endocannabinoid content in the amygdala, ventral striatum, and
medial prefrontal cortex in mice. Neuropharmacology. 2008;54(1):108–16.
112. Patel S, Kingsley PJ, Mackie K, Marnett LJ, Winder DG. Repeated homotypic stress elevates
2-arachidonoylglycerol levels and enhances short-term endocannabinoid signaling at in-
hibitory synapses in basolateral amygdala. Neuropsychopharmacology. 2009;34(13):2699–
113. Millan MJ. Dual- and triple-acting agents for treating core and co-morbid symptoms of
major depression: novel concepts, new drugs. Neurotherapeutics. 2009;6(1):53–77.
114. DiMasi JA, Hansen RW, Grabowski HG. The price of innovation: new estimates of drug
development costs. J Health Econ. 2003;22(2):151–85.
115. Micale V, Kucerova J, Sulcova A. Leading compounds for the validation of animal models
of psychopathology. Cell Tissue Res. 2013;354(1):309–30.
116. McKinney WT Jr, Bunney WE Jr. Animal model of depression. I. Review of evidence:
implications for research. Arch Gen Psychiatry. 1969;21(2):240–8.
117. Nestler EJ, Gould E, Manji H, Buncan M, Duman RS, Greshenfeld HK, Hen R, Koester S,
Lederhendler I, Meaney M, Robbins T, Winsky L, Zalcman S. Preclinical models: status of
basic research in depression. Biol Psychiatry. 2002;52(6):503–28.
124 V. Micale et al.
118. Porsolt RD, Le Pichon M, Jalfre M. Depression: a new animal model sensitive to antide-
pressant treatments. Nature. 1977;266(5604):730–2.
119. Cryan JF, Valentino RJ, Lucki I. Assessing substrates underlying the behavioral effects
of antidepressants using the modified rat forced swimming test. Neurosci Biobehav Rev.
120. Steru L, Chermat R, Thierry B, Simon P. The tail suspension test: a new method for screen-
ing antidepressants in mice. Psychopharmacology (Berl). 1985;85(3):367–70.
121. Cryan JF, Mombereau C, Vassout A. The tail suspension test as a model for assessing an-
tidepressant activity: review of pharmacological and genetic studies in mice. Neurosci
Biobehav Rev. 2005;29(4–5):571–625.
122. Berrocoso E, Ikeda K, Sora I, Uhl GR, Sánchez-Blázquez P, Mico JA. Active behaviours
produced by antidepressants and opioids in the mouse tail suspension test. Int J Neuropsy-
chopharmacol. 2013;16(1):151–62.
123. Willner P, Towell A, Sampson D, Sophokleous S, Muscat R. Reduction of sucrose prefer-
ence by chronic unpredictable mild stress, and its restoration by a tricyclic antidepressant.
Psychopharmacology (Berl). 1987;93(3):358–64.
124. Kelly JP, Wrynn AS, Leonard BE. The olfactory bulbectomized rat as a model of depres-
sion: an update. Pharmacol Ther. 1997;74(3):299–316.
125. Song C, Leonard BE. The olfactory bulbectomised rat as a model of depression. Neurosci
Biobehav Rev. 2005;29(4–5):627–47.
126. Cryan JF, Markou A, Lucki I. Assessing antidepressant activity in rodents: recent develop-
ments and future needs. Trends Pharmacol Sci. 2002;23(5):238–45.
127. El-Alfy AT, Ivey K, Robinson K, Ahmed S, Radwan M, Slade D, Khan I, ElSohly M, Ross
S. Antidepressant-like effect of delta9-tetrahydrocannabinol and other cannabinoids iso-
lated from Cannabis sativa L. Pharmacol Biochem Behav. 2010;95(4):434–42.
128. Bambico FR, Hattan PR, Garant JP, Gobbi G. Effect of delta-9-tetrahydrocannabinol on
behavioral despair and on pre- and postsynaptic serotonergic transmission. Prog Neuropsy-
chopharmacol Biol Psychiatry. 2012;38(1):88–96.
129. Häring M, Grieb M, Monory K, Lutz B, Moreira FA. Cannabinoid CBâ receptor in the
modulation of stress coping behavior in mice: the role of serotonin and different forebrain
neuronal subpopulations. Neuropharmacology. 2013;65:83–9.
130. Elbatsh MM, Moklas MAA, Marsden CA, Kendall DA. Antidepressant-like effects of Δ9-
tetrahydrocannabinol and rimonabant in the olfactory bulbectomised rat model of depres-
sion. Pharmacol Biochem Behav. 2012;102(2):357–65.
131. Hayase T. Depression-related anhedonic behaviors caused by immobilization stress: a com-
parison with nicotine-induced depression-like behavioral alterations and effects of nicotine
and/or “antidepressant” drugs. J Toxicol Sci. 2011;36(1):31–41.
132. Umathe SN, Manna SS, Jain NS. Involvement of endocannabinoids in antidepressant and
anti-compulsive effect of fluoxetine in mice. Behav Brain Res. 2011;223(1):125–34.
133. Adamczyk P, Gołda A, McCreary AC, Filip M, Przegaliński E. Activation of endocan-
nabinoid transmission induces antidepressant-like effects in rats. J Physiol Pharmacol.
134. Bambico FR, Katz N, Debonnel G, Gobbi G. Cannabinoids elicit antidepressant-like be-
havior and activate serotonergic neurons through the medial prefrontal cortex. J Neurosci.
135. Segev A, Rubin AS, Abush H, Richter-Levin G, Akirav I. Cannabinoid receptor activation
prevents the effects of chronic mild stress on emotional learning and LTP in a rat model of
depression. Neuropsychopharmacology. 2014;39(4):919–33.
136. Hill MN, Gorzalka BB. Pharmacological enhancement of cannabinoid CB1 receptor activ-
ity elicits an antidepressant-like response in the rat forced swim test. Eur Neuropsychophar-
macol. 2005;15(6):593–9.
137. Jiang W, Zhang Y, Xiao L, Van Cleemput J, Ji SP, Bai G, Zhang X. Cannabinoids promote
embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepres-
sant-like effects. J Clin Invest. 2005;115(11):3104–16.
1255 Role of the Endocannabinoid System in Depression
138. McLaughlin RJ, Hill MN, Morrish AC, Gorzalka BB. Local enhancement of cannabinoid
CB1 receptor signalling in the dorsal hippocampus elicits an antidepressant-like effect.
Behav Pharmacol. 2007;18(5–6):431–8.
139. Morrish AC, Hill MN, Riebe CJN, Gorzalka BB. Protracted cannabinoid administration
elicits antidepressant behavioral responses in rats: role of gender and noradrenergic trans-
mission. Physiol Behav. 2009 Aug 4;98(1–2):118–24.
140. Rutkowska M, Jachimczuk O. Antidepressant—like properties of ACEA (arachid-
onyl-2-chloroethylamide), the selective agonist of CB1 receptors. Acta Pol Pharm.
141. Reich CG, Iskander AN, Weiss MS. Cannabinoid modulation of chronic mild stress-in-
duced selective enhancement of trace fear conditioning in adolescent rats. J Psychopharma-
col. 2013;27(10):947–55.
142. Rubino T, Vigano’ D, Realini N, Guidali C, Braida D, Capurro V, Castiglioni C, Cherubino
F, Romualdi P, Candeletti S, Sala M, Parolaro D. Chronic delta9-tetrahydrocannabinol dur-
ing adolescence provokes sex-dependent changes in the emotional profile in adult rats:
behavioral and biochemical correlates. Neuropsychopharmacology. 2008;33(11):2760–71.
143. Rubino T, Realini N, Braida D, Alberio T, Capurro V, Viganò D, Guidali C, Sala M, Fa-
sano M, Parolaro D. The depressive phenotype induced in adult female rats by adolescent
exposure to THC is associated with cognitive impairment and altered neuroplasticity in the
prefrontal cortex. Neurotox Res. 2009;15(4):291–302.
144. Rubino T, Zamberletti E, Parolaro D. Adolescent exposure to cannabis as a risk factor for
psychiatric disorders. J Psychopharmacol. 2012;26(1):177–88.
145. Bambico FR, Nguyen N-T, Katz N, Gobbi G. Chronic exposure to cannabinoids during
adolescence but not during adulthood impairs emotional behaviour and monoaminergic
neurotransmission. Neurobiol Dis. 2010;37(3):641–55.
146. Realini N, Vigano’ D, Guidali C, Zamberletti E, Rubino T, Parolaro D. Chronic URB597
treatment at adulthood reverted most depressive-like symptoms induced by adolescent ex-
posure to THC in female rats. Neuropharmacology. 2011;60(2–3):235–43.
147. Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rössner S, RIO-Europe Study Group.
Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardio-
vascular risk factors in overweight patients: 1-year experience from the RIO-Europe study.
Lancet. 2005;365(9468):1389–97.
148. Tzavara ET, Davis RJ, Perry KW, Li X, Salhoff C, Bymaster FP, Witkin JM, Nomikos
GG. The CB1 receptor antagonist SR141716 A selectively increases monoaminergic neu-
rotransmission in the medial prefrontal cortex: implications for therapeutic actions. Br J
Pharmacol. 2003;138(4):544–53.
149. 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–
150. Steiner MA, Marsicano G, Nestler EJ, Holsboer F, Lutz B, Wotjak CT. Antidepressant-like
behavioral effects of impaired cannabinoid receptor type 1 signaling coincide with exagger-
ated corticosterone secretion in mice. Psychoneuroendocrinology. 2008;33(1):54–67.
151. Lee S, Kim DH, Yoon SH, Ryu JH. Sub-chronic administration of rimonabant causes loss
of antidepressive activity and decreases doublecortin immunoreactivity in the mouse hip-
pocampus. Neurosci Lett. 2009;467(2):111–6.
152. Steiner MA, Marsicano G, Wotjak CT, Lutz B. Conditional cannabinoid receptor type 1
mutants reveal neuron subpopulation-specific effects on behavioral and neuroendocrine
stress responses. Psychoneuroendocrinology. 2008;33(8):1165–70.
153. 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.
154. Cristino L, de Petrocellis L, Pryce G, Baker D, Guglielmotti V, Di Marzo V. Immunohis-
tochemical localization of cannabinoid type 1 and vanilloid transient receptor potential
vanilloid type 1 receptors in the mouse brain. Neuroscience. 2006;139(4):1405–15.
126 V. Micale et al.
155. Manna SS, Umathe SN. A possible participation of transient receptor potential vanilloid
type 1 channels in the antidepressant effect of fluoxetine. Eur J Pharmacol. 2012;685
15. Hayase T. Differential effects of TRPV1 receptor ligands against nicotine-induced depres-
sion-like behaviors. BMC Pharmacol. 2011;11:6.
157. Abdelhamid RE, Kovács KJ, Nunez MG, Larson AA. Depressive behavior in the forced
swim test can be induced by TRPV1 receptor activity and is dependent on NMDA recep-
tors. Pharmacol Res. 2014;79:21–7.
158. Navarria A, Tamburella A, Iannotti FA, Micale V, Camillieri G, Gozzo L, Verde R, Impera-
tore R, Leggio GM, Drago F, Di Marzo V. The dual blocker of FAAH/TRPV1 N-arachi-
donoylserotonin reverses the behavioral despair induced by stress in rats and modulates the
HPA-axis. Pharmacol Res. 2014;87:151–9.
159. You IJ, Jung YH, Kim MJ, Kwon SH, Hong SI, Lee SY, Jang CG. Alterations in the emo-
tional and memory behavioral phenotypes of transient receptor potential vanilloid type
1-deficient mice are mediated by changes in expression of 5-HTâA, GABA(A), and NMDA
receptors. Neuropharmacology. 2012;62(2):1034–43.
160. Petrosino S, Di Marzo V. FAAH and MAGL inhibitors: therapeutic opportunities from
regulating endocannabinoid levels. Curr Opin Investig Drugs. 2010;11(1):51–62.
161. Hill MN, Karacabeyli ES, Gorzalka BB. Estrogen recruits the endocannabinoid system to
modulate emotionality. Psychoneuroendocrinology. 2007;32(4):350–7.
162. McLaughlin RJ, Hill MN, Bambico FR, Stuhr KL, Gobbi G, Hillard CJ, Gorzalka BB.
Prefrontal cortical anandamide signaling coordinates coping responses to stress through a
serotonergic pathway. Eur Neuropsychopharmacol. 2012;22(9):664–71.
163. Naidu PS, Varvel SA, Ahn K, Cravatt BF, Martin BR, Lichtman AH. Evaluation of fatty
acid amide hydrolase inhibition in murine models of emotionality. Psychopharmacology
(Berl). 2007;192(1):61–70.
164. Rademacher DJ, Hillard CJ. Interactions between endocannabinoids and stress-induced
decreased sensitivity to natural reward. Prog Neuropsychopharmacol Biol Psychiatry.
165. Haller J, Goldberg SR, Pelczer KG, Aliczki M, Panlilio LV. The effects of anandamide
signaling enhanced by the FAAH inhibitor URB597 on coping styles in rats. Psychophar-
macology (Berl). 2013;230(3):353–62.
166. Akanmu MA, Adeosun SO, Ilesanmi OR. Neuropharmacological effects of oleamide in
male and female mice. Behav Brain Res. 2007;182(1):88–94.
167. Bisogno T, Melck D, De Petrocellis L, Bobrov MYu, Gretskaya NM, Bezuglov VV, Sit-
achitta N, Gerwick WH, Di Marzo V. Arachidonoylserotonin and other novel inhibitors of
fatty acid amide hydrolase. Biochem Biophys Res Commun. 1998;248(3):515–22.
168. Maione S, De Petrocellis L, de Novellis V, Moriello AS, Petrosino S, Palazzo E, Rossi FS,
Woodward DF, Di Marzo V. Analgesic actions of N-arachidonoyl-serotonin, a fatty acid
amide hydrolase inhibitor with antagonistic activity at vanilloid TRPV1 receptors. Br J
Pharmacol. 2007;150(6):766–81.
169. Micale V, Cristino L, Tamburella A, Petrosino S, Leggio GM, Drago F, Di Marzo V. Anx-
iolytic 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.
170. Micale V, Cristino L, Tamburella A, Petrosino S, Leggio GM, Drago F, Di Marzo V. Al-
tered responses of dopamine D3 receptor null mice to excitotoxic or anxiogenic stimuli:
Possible involvement of the endocannabinoid and endovanilloid systems. Neurobiol Dis.
171. John CS, Currie PJ. N-arachidonoyl-serotonin in the basolateral amygdala increases anxio-
lytic behavior in the elevated plus maze. Behav Brain Res. 2012;233(2):382–8.
172. Mannucci C, Navarra M, Pieratti A, Russo GA, Caputi AP, Calapai G. Interactions between
endocannabinoid and serotonergic systems in mood disorders caused by nicotine withdraw-
al. Nicotine Tob Res. 2011;13(4):239–47.
1275 Role of the Endocannabinoid System in Depression
173. Sütt S, Raud S, Areda T, Reimets A, Kõks S, Vasar E. Cat odour-induced anxiety—a study of
the involvement of the endocannabinoid system. Psychopharmacology. 2008;198(4):509–
174. Suárez J, Rivera P, Llorente R, Romero-Zerbo SY, Bermúdez-Silva FJ, de Fonseca FR, Vi-
veros M-P. Early maternal deprivation induces changes on the expression of 2-AG biosyn-
thesis and degradation enzymes in neonatal rat hippocampus. Brain Res. 2010;1349:162–
175. Eisenstein SA, Clapper JR, Holmes PV, Piomelli D, Hohmann AG. A role for 2-arachidon-
oylglycerol and endocannabinoid signaling in the locomotor response to novelty induced
by olfactory bulbectomy. Pharmacol Res. 2010;61(5):419–29.
176. Zhong P, Wang W, Pan B, Liu X, Zhang Z, Long JZ, Zhang H, Cravatt BF, Liu Q. Mono-
acylglycerol lipase inhibition blocks chronic stress-induced depressive-like behaviors via
activation of mTOR signaling. Neuropsychopharmacology. 2014;39(7):1763–76.
177. 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-arachidonoylg-
lycerol hydrolysis produces cannabinoid behavioral effects. Nat Chem Biol. 2009;5(1):37–
178. Schlosburg JE, Blankman JL, Long JZ, Nomura DK, Pan B, Kinsey SG, Nguyen PT, Ra-
mesh D, Booker L, Burston JJ, Thomas EA, Selley DE, Sim-Selley LJ, Liu Q, Lichtman
AH, Cravatt BF. Chronic monoacylglycerol lipase blockade causes functional antagonism
of the endocannabinoid system. Nat Neurosci. 2010;13(9):1113–9.
179. Busquets-Garcia A, Puighermanal E, Pastor A, de la Torre R, Maldonado R, Ozaita A.
Differential role of anandamide and 2-arachidonoylglycerol in memory and anxiety-like
responses. Biol Psychiatry. 2011;70(5):479–86.
180. Zanelati TV, Biojone C, Moreira FA, Guimarães FS, Joca SRL. Antidepressant-like ef-
fects of cannabidiol in mice: possible involvement of 5-HT1 A receptors. Br J Pharmacol.
181. 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 mono-
aminergic transmission by blockade of anandamide hydrolysis. Proc Natl Acad Sci USA.
182. Bambico FR, Duranti A, Tontini A, Tarzia G, Gobbi G. Endocannabinoids in the treatment
of mood disorders: evidence from animal models. Curr Pharm Des. 2009;15(14):1623–46.
183. Cassano T, Gaetani S, Macheda T, Laconca L, Romano A, Morgese MG, Cimmino CS,
Chiarotti F, Bambico FR, Gobbi G, Cuomo V, Piomelli D. Evaluation of the emotional phe-
notype and serotonergic neurotransmission of fatty acid amide hydrolase-deficient mice.
Psychopharmacology (Berl). 2011;214(2):465–76.
184. Martin M, Ledent C, Parmentier M, Maldonado R, Valverde O. Involvement of CB1 can-
nabinoid receptors in emotional behaviour. Psychopharmacology (Berl). 2002;159(4):379–
185. Aso E, Renoir T, Mengod G, Ledent C, Hamon M, Maldonado R, Lanfumey L, Valverde
O. Lack of CB1 receptor activity impairs serotonergic negative feedback. J Neurochem.
186. Burokas A, Martín-García E, Gutiérrez-Cuesta J, Rojas S, Herance JR, Gispert JD, Serra
MÁ, Maldonado R. Relationships between serotonergic and cannabinoid system in depres-
sive-like behavior: a PET study with [(11) C]-DASB. J Neurochem. 2014;130(1):126–35.
187. Mahar I, Bambico FR, Mechawar N, Nobrega JN. Stress, serotonin, and hippocampal
neurogenesis in relation to depression and antidepressant effects. Neurosci Biobehav Rev.
188. Bambico FR, Nguyen NT, Gobbi G. Decline in serotonergic firing activity and desensitiza-
tion of 5-HT1 A autoreceptors after chronic unpredictable stress. Eur Neuropsychopharma-
col. 2009;19(3):215–28.
128 V. Micale et al.
189. Höfelmann D, di Benedetto B, Azad SC, Micale V, Wotjak CT, Rammes G. Lack of inter-
action of endocannabinoids and 5-HT(3) neurotransmission in associative fear circuits of
the amygdala: evidence from electrophysiological and behavioural experiments. Brain Res.
190. Walstab J, Rappold G, Niesler B. 5-HT(3) receptors: role in disease and target of drugs.
Pharmacol Ther. 2010;128(1):146–69.
191. Chegini HR, Nasehi M, Zarrindast MR. Differential role of the basolateral amygdala 5-HT3
and 5-HT4 serotonin receptors upon ACPA-induced anxiolytic-like behaviors and emo-
tional memory deficit in mice. Behav Brain Res. 2014;261:114–26.
192. Xiong W, Koo B, Morton R, Zhang L. Psychotropic and nonpsychotropic cannabis de-
rivatives inhibit human 5-HT(3A) receptors through a receptor desensitization-dependent
mechanism. Neuroscience. 2011;184:28–37.
193. Muntoni AL, Pillolla G, Melis M, Perra S, Gessa GL, Pistis M. Cannabinoids modulate
spontaneous neuronal activity and evoked inhibition of locus coeruleus noradrenergic neu-
rons. Eur J Neurosci. 2006;23(9):2385–94.
194. Esteban S, García-Sevilla JA. Effects induced by cannabinoids on monoaminergic systems
in the brain and their implications for psychiatric disorders. Prog Neuropsychopharmacol
Biol Psychiatry. 2012;38(1):78–87.
195. Steffens M, Feuerstein TJ. Receptor-independent depression of DA and 5-HT uptake by
cannabinoids in rat neocortex—involvement of Na( + )/K( + )-ATPase. Neurochem Int.
196. Velenovská M, Fisar Z. Effect of cannabinoids on platelet serotonin uptake. Addict Biol.
197. Fisar Z, Hroudová J, Raboch J. Inhibition of monoamine oxidase activity by antidepres-
sants and mood stabilizers. Neuro Endocrinol Lett. 2010;31(5):645–56.
198. Fišar Z. Cannabinoids and monoamine neurotransmission with focus on monoamine oxi-
dase. Prog Neuropsychopharmacol Biol Psychiatry. 2012;38(1):68–77.
199. Kunugi H, Hori H, Adachi N, Numakawa T. Interface between hypothalamic-pituitary-
adrenal axis and brain-derived neurotrophic factor in depression. Psychiatry Clin Neurosci.
200. Schmidt HD, Duman RS. The role of neurotrophic factors in adult hippocampal neuro-
genesis, antidepressant treatments and animal models of depressive-like behavior. Behav
Pharmacol. 2007;18(5–6):391–418.
201. Pittenger C, Duman RS. Stress, depression, and neuroplasticity: a convergence of mecha-
nisms. Neuropsychopharmacology. 2008;33(1):88–109.
202. Grady MM, Stahl SM. Novel agents in development for the treatment of depression. CNS
Spectr. 2013;18(Suppl 1):37–40.
203. Tamburella A, Micale V, Navarria A, Drago F. Antidepressant properties of the 5-HT4 re-
ceptor partial agonist, SL65.0155: behavioral and neurochemical studies in rats. Prog Neu-
ropsychopharmacol Biol Psychiatry. 2009;33(7):1205–10.
204. Tamburella A, Micale V, Leggio GM, Drago F. The beta3 adrenoceptor agonist, amibegron
(SR58611 A) counteracts stress-induced behavioral and neurochemical changes. Eur Neu-
ropsychopharmacol. 2010;20(10):704–13.
205. Tamburella A, Leggio GM, Micale V, Navarria A, Bucolo C, Cicirata V, Drago F, Salomone
S. Behavioural and neurochemical changes induced by stress-related conditions are coun-
teracted by the neurokinin-2 receptor antagonist saredutant. Int J Neuropsychopharmacol.
206. Aguado T, Carracedo A, Julien B, Velasco G, Milman G, Mechoulam R, Alvarez L, Guzmán
M, Galve-Roperh I. Cannabinoids induce glioma stem-like cell differentiation and inhibit
gliomagenesis. J Biol Chem. 2007;282(9):6854–62.
207. Aguado T, Monory K, Palazuelos J, Stella N, Cravatt B, Lutz B, Marsicano G, Kokaia Z,
Guzmán M, Galve-Roperh I. The endocannabinoid system drives neural progenitor prolif-
eration. FASEB J. 2005;19(12):1704–6.
5 Role of the Endocannabinoid System in Depression 129
208. Marchalant Y, Brothers HM, Wenk GL. Cannabinoid agonist WIN-55,212–2 partially re-
stores neurogenesis in the aged rat brain. Mol Psychiatry. 2009;14(12):1068–9.
209. Jin K, Xie L, Kim SH, Parmentier-Batteur S, Sun Y, Mao XO, Childs J, Greenberg DA.
Defective adult neurogenesis in CB1 cannabinoid receptor knockout mice. Mol Pharmacol.
210. Kim SH, Won SJ, Mao XO, Jin K, Greenberg DA. Molecular mechanisms of cannabinoid
protection from neuronal excitotoxicity. Mol Pharmacol. 2006;69(3):691–6.
211. Aso E, Ozaita A, Valdizán EM, Ledent C, Pazos A, Maldonado R, Valverde O. BDNF
impairment in the hippocampus is related to enhanced despair behavior in CB1 knockout
mice. J Neurochem. 2008;105(2):565–72.
212. Beyer CE, Dwyer JM, Piesla MJ, Platt BJ, Shen R, Rahman Z, Chan K, Manners MT,
Samad TA, Kennedy JD, Bingham B, Whiteside GT. Depression-like phenotype following
chronic CB1 receptor antagonism. Neurobiol Dis. 2010;39(2):148–55.
213. Derkinderen P, Valjent E, Toutant M, Corvol JC, Enslen H, Ledent C, Trzaskos J. Regula-
tion of extracellular signal-regulated kinase by cannabinoids in hippocampus. J Neurosci.
214. Ferreira-Vieira TH, Bastos CP, Pereira GS, Moreira FA, Massensini AR. A role for the
endocannabinoid system in exercise-induced spatial memory enhancement in mice. Hip-
pocampus. 2014;24(1):79–88.
215. García-Gutiérrez MS, Ortega-Álvaro A, Busquets-García A, Pérez-Ortiz JM, Caltana L,
Ricatti MJ, Brusco A, Maldonado R, Manzanares J. Synaptic plasticity alterations associ-
ated with memory impairment induced by deletion of CB2 cannabinoid receptors. Neuro-
pharmacology. 2013;73:388–96.
216. Avraham HK, Jiang S, Fu Y, Rockenstein E, Makriyannis A, Zvonok A, Masliah E, Avraham
S. The cannabinoid CBâ receptor agonist AM1241 enhances neurogenesis in GFAP/Gp120
transgenic mice displaying deficits in neurogenesis. Br J Pharmacol. 2014;171(2):468–79.
217. De Kloet ER Sibug RM Helmerhorst FM Schmidt MV Schmidt M. Stress, genes
and the mechanism of programming the brain for later life. Neurosci Biobehav Rev.
218. Pariante CM, Lightman SL. The HPA axis in major depression: classical theories and new
developments. Trends Neurosci. 2008;31(9):464–8.
219. Riebe CJ, Wotjak CT. Endocannabinoids and stress. Stress. 2011;14(4):384–97.
220. 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.
221. Hill MN, Tasker JG. Endocannabinoid signaling, glucocorticoid-mediated negative feed-
back, and regulation of the hypothalamic-pituitary-adrenal axis. Neuroscience. 2012;204:5–
222. Roberts CJ, Stuhr KL, Hutz MJ, Raff H, Hillard CJ. Endocannabinoid signaling in hypo-
thalamic-pituitary-adrenocortical axis recovery following stress: effects of indirect agonists
and comparison of male and female mice. Pharmacol Biochem Behav. 2014;117:17–24.
223. Piscitelli F, Di Marzo V. “Redundancy” of endocannabinoid inactivation: new challenges
and opportunities for pain control. ACS Chem Neurosci. 2012;3(5):356–63.
224. Hu B, Doods H, Treede RD, Ceci A. Depression-like behaviour in rats with mononeuropa-
thy is reduced by the CB2-selective agonist GW405833. Pain. 2009;143(3):206–12.
... Major depression is characterized by depressed mood and anhedonia -a lack of pleasure, including other symptoms like reduced appetite and libido and disturbed sleep. Preclinical and clinical studies showed that the ECS is responsible in modulating depression with reports that there is a negative correlation between the ECS signaling and depression (84). In animal models of depression and depressed patients, changes have been observed in eCB levels. ...
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The endocannabinoid system (ECS) is composed of the two canonical receptor subtypes; type-1 cannabinoid (CB1R) and type 2 receptor (CB2R), endocannabinoids (eCBs) and enzymes responsible for the synthesis and degradation of eCBs. Recently, with the identification of additional lipid mediators, enzymes and receptors, the expanded ECS called the endocannabinoidome (eCBome) has been identified and recognized. Activation of CB1R is associated with a plethora of physiological effects and some central nervous system (CNS) side effects, whereas, CB2R activation is devoid of such effects and hence CB2Rs might be utilized as potential new targets for the treatment of different disorders including neuropsychiatric disorders. Previous studies suggested that CB2Rs were absent in the brain and they were considered as peripheral receptors, however, recent studies confirmed the presence of CB2Rs in different brain regions. Several studies have now focused on the characterization of its physiological and pathological roles. Studies done on the role of CB2Rs as a therapeutic target for treating different disorders revealed important putative role of CB2R in neuropsychiatric disorders that requires further clinical validation. Here we provide current insights and knowledge on the potential role of targeting CB2Rs in neuropsychiatric and neurodegenerative disorders. Its non-psychoactive effect makes the CB2R a potential target for treating CNS disorders; however, a better understanding of the fundamental pharmacology of CB2R activation is essential for the design of novel therapeutic strategies.
... Several studies have demonstrated that the endocannabinoid content in the tissues and serum of patients with depression shows marked variation compared to those of healthy individuals. CB1 receptor expression and 2-AG levels have been found to be significantly reduced in the hippocampus as a result of chronic unpredictable stress, which is thought to mimic the behavioral and endocrine changes that promote the development of human clinical depression [128][129][130]. An interesting study on the changes in the ECS revealed that the serum level of 2-AG is significantly decreased in patients with major depression, while in patients with mild depression, the serum content of AEA and 2-AG showed a tendency to increase [131]. ...
Full-text available
Polypharmacology breaks up the classical paradigm of “one-drug, one target, one disease” electing multitarget compounds as potential therapeutic tools suitable for the treatment of complex diseases, such as metabolic syndrome, psychiatric or degenerative central nervous system (CNS) disorders, and cancer. These diseases often require a combination therapy which may result in positive but also negative synergistic effects. The endocannabinoid system (ECS) is emerging as a particularly attractive therapeutic target in CNS disorders and neurodegenerative diseases including Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), stroke, traumatic brain injury (TBI), pain, and epilepsy. ECS is an organized neuromodulatory network, composed by endogenous cannabinoids, cannabinoid receptors type 1 and type 2 (CB1 and CB2), and the main catabolic enzymes involved in the endocannabinoid inactivation such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). The multiple connections of the ECS with other signaling pathways in the CNS allows the consideration of the ECS as an optimal source of inspiration in the development of innovative polypharmacological compounds. In this review, we focused our attention on the reported polypharmacological examples in which FAAH and MAGL inhibitors are involved.
... While anhedonia can be modeled in rodent studies, a depressed mood is difficult to characterize. However, preclinical and clinical studies showed that the ECS is responsible for modulating depression, with reports that there is a negative correlation between the ECS signaling and depression [76]. The withdrawal of rimonabant, a CB1R antagonist, used for the treatment of obesity due to the risk of suicide and depression, has received increased interest as regards the role of CB1R in affecting mood and affective behavior. ...
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The endocannabinoid system (ECS) is ubiquitous in most human tissues, and involved in the regulation of mental health. Consequently, its dysregulation is associated with neuropsychiatric and neurodegenerative disorders. Together, the ECS and the expanded endocannabinoidome (eCBome) are composed of genes coding for CB1 and CB2 cannabinoid receptors (CB1R, CB2R), endocannabinoids (eCBs), and the metabolic enzyme machinery for their synthesis and catabolism. The activation of CB1R is associated with adverse effects on the central nervous system (CNS), which has limited the therapeutic use of drugs that bind this receptor. The discovery of the functional neuronal CB2R raised new possibilities for the potential and safe targeting of the ECS for the treatment of CNS disorders. Previous studies were not able to detect CB2R mRNA transcripts in brain tissue and suggested that CB2Rs were absent in the brain and were considered peripheral receptors. Studies done on the role of CB2Rs as a potential therapeutic target for treating different disorders revealed the important putative role of CB2Rs in certain CNS disorders, which requires further clinical validation. This review addresses recent advances on the role of CB2Rs in neuropsychiatric and neurodegenerative disorders, including, but not limited to, anxiety, depression, schizophrenia, Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD) and addiction.
... Since cannabis operates on the ECS, the master homeostatic regulatory system that has been implicated in mood disorders and schizophrenia, it may be addressing underlying problems in a way that current psychiatric medications are not (D. Skosnik, 2011;Micale et al., 2015;Saito, Wotjak, & Moreira, 2010). Certainly, many patients think so, and their expanding self-directed use of cannabis to manage mental health disrupts conventional medical control. ...
Medicinal cannabis use is rapidly expanding and gaining acceptance for a variety of conditions, yet most physicians and laypersons hold diametrically different views on the effects of cannabis use on mental health. Among the millions of people using cannabis medicinally, roughly half report they do so to manage a mental disorder. Among medical professionals, there is widespread agreement that increased risk of psychosis and other mental disorders is the central harm associated with cannabis use. This chapter explores that paradox in terms of competing medicalizations of cannabis—one driven by medical professionals enacting social control of users and the other by patients and their advocates seeking legitimacy for that use—which can be understood in terms of the differences between ‘system’ and ‘lifeworld’ standards for evidence and decision making. The authors argue that substantial scientific uncertainty about both cannabis and mental disorders created a vacuum that allowed stigmatizing social constructions of both to dominate the scientific literature, public policy, and lay perceptions. They claim flaws in methods and concepts underlying psychiatric diagnoses related to cannabis use have persisted through five editions of the Diagnostic and Statistical Manual (DSM) and explore in detail problems with the validity and reliability of such diagnoses, particularly in the context of medicinal use. Close attention is given to disputes over how cannabis use affects people diagnosed with schizophrenia, as well as problems with diagnosing problem cannabis use in the context of medicinal use.
... The effect of the endocannabinoid system can be summarized as promoting a cool, calm, collected, fat, and happy state [13]. Furthermore, resilience to stress-related disease and dysfunction may depend on the satisfactory functioning of the endocannabinoid system [4,[30][31][32][33]. ...
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The stress response is a well-defined physiological function activated frequently by life events. However, sometimes the stress response can be inappropriate, excessive, or prolonged; in which case, it can hinder rather than help in coping with the stressor, impair normal functioning, and increase the risk of somatic and mental health disorders. There is a need for a more effective and safe pharmacological treatment that can dampen maladaptive stress responses. The endocannabinoid system is one of the main regulators of the stress response. A basal endocannabinoid tone inhibits the stress response, modulation of this tone permits/curtails an active stress response, and chronic deficiency in the endocannabinoid tone is associated with the pathological complications of chronic stress. Cannabidiol is a safe exogenous cannabinoid enhancer of the endocannabinoid system that could be a useful treatment for stress. There have been seven double-blind placebo controlled clinical trials of CBD for stress on a combined total of 232 participants and one partially controlled study on 120 participants. All showed that CBD was effective in significantly reducing the stress response and was non-inferior to pharmaceutical comparators, when included. The clinical trial results are supported by the established mechanisms of action of CBD (including increased N-arachidonylethanolamine levels) and extensive real-world and preclinical evidence of the effectiveness of CBD for treating stress.
Although the etiopathogenesis of mental disorders is not fully understood, accumulating evidence support that clinical symptomatology cannot be assigned to a single gene mutation, but it involves several genetic factors. More specifically, a tight association between genes and environmental risk factors, which could be mediated by epigenetic mechanisms, may play a role in the development of mental disorders. Several data suggest that epigenetic modifications such as DNA methylation, post-translational histone modification and interference of microRNA (miRNA) or long non-coding RNA (lncRNA) may modify the severity of the disease and the outcome of the therapy. Indeed, these changes may help to identify patients particularly vulnerable to mental disorders and may have potential utility as biomarkers to facilitate diagnosis and treatment of psychiatric disorders. This article summarizes the most relevant preclinical and human data showing how epigenetic modifications can be central to the therapeutic efficacy of antidepressant and/or antipsychotic agents, as possible predictor of drugs response.
Introduction: The antidepressant properties of ketamine have been extensively demonstrated in experimental and clinical settings. However, the psychotomimetic side effects still limit its wider use as an antidepressant. It was recently observed that endocannabinoids are inolved in ketamine induced reward properties. As an increase in endocannabinoid signaling induces antidepressant effects, this study aimed to investigate the involvement of cannabinoid type 1 receptors (CB1R) in the antidepressant and psychostimulant effects induced by ketamine. Methods: We tested the effects of genetic and pharmacological inhibition of CB1R in the hyperlocomotion and antidepressant-like properties of ketamine. The effects of ketamine (10-20 mg/kg) were assessed in the open-field and the forced swim tests (FSTs) in CB1R knockout (KO) and wild-type (WT) mice (male and female), and mice pre-treated with rimonabant (CB1R antagonist, 3-10 mg/kg). Results: We found that the motor hyperactivity elicited by ketamine was impaired in CB1R male and female KO mice. A similar effect was observed upon pharmacological blockade of CB1R in WT mice. However, genetic CB1R deletion did not modify the antidepressant effect of ketamine in male mice submitted to the FST. Surprisingly, pharmacological blockade of CB1R induced an antidepressant-like effect in both male and female mice, which was not further potentiated by ketamine. Conclusions: Our results support the hypothesis that CB1R mediate the psychostimulant side effects induced by ketamine, but not its antidepressant properties.
Despite attaining significant advances toward better management of depressive disorders, we are still facing several setbacks. Developing rapid-acting antidepressants with sustained effects is an aspiration that requires thinking anew to explore possible novel targets. Recently, the lateral habenula (LHb), the brain’s “anti-reward system”, has been shown to go awry in depression in terms of various molecular and electrophysiological signatures. Some of the presumed contributors to such observed aberrations are astrocytes. These star-shaped cells of the brain can alter the firing pattern of the LHb, which keeps the activity of the midbrain’s aminergic centers under tight control. Astrocytes are also integral parts of the tripartite synapses, and can therefore modulate synaptic plasticity and leave long-lasting changes in the brain. On the other hand, it was discovered that astrocytes express cannabinoid type 1 receptors (CB1R), which can also take part in long-term plasticity. Herein, we recount how the LHb of a depressed brain deviates from the “normal” one from a molecular perspective. We then try to touch upon the alterations of the endocannabinoid system in the LHb, and cast the idea that modulation of astroglial CB1R may help regulate habenular neuronal activity and synaptogenesis, thereby acting as a new pharmacological tool for regulation of mood and amelioration of depressive symptoms.
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In agreement with the neurodevelopmental hypothesis of schizophrenia, prenatal exposure of Sprague-Dawley rats to the antimitotic agent methylazoxymethanol acetate (MAM) at gestational day 17 produces long-lasting behavioral alterations such as social withdrawal and cognitive impairment in adulthood, mimicking a schizophrenia-like phenotype. These abnormalities were preceded at neonatal age both by the delayed appearance of neonatal reflexes, an index of impaired brain maturation, and by higher 2-arachidonoylglycerol (2-AG) brain levels. Schizophrenia-like deficits were reversed by early treatment [from postnatal day (PND) 2 to PND 8] with the CB1 antagonist/inverse agonist AM251 (0.5 mg/kg/day). By contrast, early CB1 blockade affected the behavioral performance of control rats which was paralleled by enhanced 2-AG content in the prefrontal cortex (PFC). These results suggest that prenatal MAM insult leads to premorbid anomalies at neonatal age via altered tone of the endocannabinoid system, which may be considered as an early marker preceding the development of schizophrenia-like alterations in adulthood.
Rosmarinic acid (RA), an ester of caffeic acid and 3, 4‐dihydroxyphenyllactic acid, has anti‐inflammatory and neuroprotective activities. Herein, this study investigated in silico the drug‐likeness and the potential molecular targets to RA. Moreover, it tested the antidepressant‐like potential of RA in the lipopolysaccharide (LPS)‐induced depression model. RA (MW = 360.31 g/mol) meets the criteria of both Lipinski's rule of five and the Ghose filter. It also attends to relevant pharmacokinetic parameters. Target prediction analysis identified RA's potential targets and biological activities, including the peroxisome proliferator‐activated receptor (PPAR) and the cannabinoid receptors CB1 and CB2. In vivo, RA's acute, repetitive, and therapeutic administration showed antidepressant‐like effect since it significantly reduced the immobility time in the tail suspension test and increased grooming time in the splash test. Further, the pretreatment with antagonists of CB1, CB2, and PPAR‐γ receptors significantly blocked the antidepressant‐like effect of RA. Altogether, our findings suggest that cannabinoid receptors/PPAR‐γ signaling pathways are involved with the antidepressant‐like effect of RA. Moreover, this molecule meets important physicochemical and pharmacokinetic parameters that favor its bioavailability. RA constitutes a promising, innovative, and safe molecule for the pharmacotherapy of major depressive disorder.
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A novel test procedure for antidepressants was designed in which a mouse is suspended by the tail from a lever, the movements of the animal being recorded. The total duration of the test (6 min) can be divided into periods of agitation and immobility. Several psychotropic drugs were studied: amphetamine, amitriptyline, atropine, desipramine, mianserin, nomifensine and viloxazine. Antidepressant drugs decrease the duration of immobility, as do psychostimulants and atropine. If coupled with measurement of locomotor activity in different conditions, the test can separate the locomotor stimulant doses from antidepressant doses. Diazepam increases the duration of immobility. The main advantages of this procedure are (1) the use of a simple, objective test situation, (2) the concordance of the results with the validated "behavioral despair" test from Porsolt and, (3) the sensitivity to a wide range of drug doses.
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Depression has been associated with drug consumption, including heavy or problematic cannabis use. According to an animal model of depression and substance use disorder comorbidity, we combined the olfactory bulbectomy (OBX) model of depression with intravenous drug self-administration procedure to verify whether depressive-like rats displayed altered voluntary intake of the CB1 receptor agonist WIN55,212-2 (WIN, 12.5 μg/kg/infusion). To this aim, olfactory-bulbectomized (OBX) and sham-operated (SHAM) Lister Hooded rats were allowed to self-administer WIN by lever-pressing under a continuous [fixed ratio 1 (FR-1)] schedule of reinforcement in 2 h daily sessions. Data showed that both OBX and SHAM rats developed stable WIN intake; yet, responses in OBX were constantly higher than in SHAM rats soon after the first week of training. In addition, OBX rats took significantly longer to extinguish the drug-seeking behavior after vehicle substitution. Acute pre-treatment with serotonin 5HT1B receptor agonist, CGS-12066B (2.5-10 mg/kg), did not significantly modify WIN intake in OBX and SHAM Lister Hooded rats. Furthermore, acute pre-treatment with CGS-12066B (10 and 15 mg/kg) did not alter responses in parallel groups of OBX and SHAM Sprague Dawley rats self-administering methamphetamine under higher (FR-2) reinforcement schedule with nose-poking as operandum. Finally, dopamine levels in the nucleus accumbens (NAc) of OBX rats did not increase in response to a WIN challenge, as in SHAM rats, indicating a dopaminergic dysfunction in bulbectomized rats. Altogether, our findings suggest that a depressive-like state may alter cannabinoid CB1 receptor agonist-induced brain reward function and that a dopaminergic rather than a 5-HT1B mechanism is likely to underlie enhanced WIN self-administration in OBX rats.
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Most psychiatric disorders are characterized by emotional memory or learning disturbances. Chronic mild stress (CMS) is a common animal model for stress-induced depression. Here we examined whether 3 days of treatment using the CB1/2 receptor agonist WIN55,212-2 could ameliorate the effects of CMS on emotional learning (ie, conditioned avoidance and extinction), long-term potentiation (LTP) in the hippocampal-accumbens pathway, and depression-like symptoms (ie, coping with stress behavior, anhedonia, and weight changes). We also examined whether the ameliorating effects of WIN55,212-2 on behavior and physiology after CMS are mediated by CB1 and glucocorticoid receptors (GRs). Rats were exposed to CMS or handled on days 1–21. The agonist WIN55,212-2 or vehicle were administered on days 19–21 (IP; 0.5 mg/kg) and behavioral and electrophysiological measures were taken on days 23 and 28. The CB1 receptor antagonist AM251 (IP; 0.3 mg/kg) or the GR antagonist RU-38486 (IP; 10 mg/kg) were co-administered with WIN55,212-2. Our results show that CMS significantly modified physiological and behavioral reactions, as observed by the impairment in avoidance extinction and LTP in the hippocampal-accumbens pathway, and the alterations in depression-like symptoms, such as coping with stress behavior, weight gain, and sucrose consumption. The most significant effect observed in this study was that 3 days of WIN55,212-2 administration prevented the CMS-induced alterations in emotional memory (ie, extinction) and plasticity. This effect was mediated by CB1 receptors as the CB1 receptor antagonist AM251 prevented the ameliorating effects of WIN55,212-2 on extinction and LTP. The GR antagonist RU-38486 also prevented the CMS-induced alterations in extinction and plasticity, and when co-administered with WIN55,212-2, the preventive effects after CMS were maintained. The findings suggest that enhancing cannabinoid signaling could represent a novel approach to the treatment of cognitive deficits that accompany stress-related depression. Neuropsychopharmacology advance online publication, 13 November 2013; doi:10.1038/npp.2013.292
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.
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.
THIS PAPER has three major purposes: (1) to present the need for an experimental animal model of "depression," ie, why the creation of such a model would be useful; (2) to review pertinent evidence from a variety of fields which points to the feasibility of such a model; and (3) to discuss possible research strategies which could be used to create an experimental animal model of depression. Depression in man is a poorly defined entity. As Lehmann1 points out, the term may refer to a symptom, a syndrome, or a nosological entity. We are interested in the depressive syndrome which is often defined as consisting of both primary and secondary symptoms. The primary symptoms in man consist of a despairing emotional state and the depressive mood. The secondary symptoms vary and are less regularly found. They may include such things as social withdrawal, psychomotor retardation, an
Abnormalities in social behavior are found in almost all psychiatric disorders, such as anxiety, depression, autism, and schizophrenia. Thus, comprehension of the neurobiological basis of social interaction is important for a better understanding of numerous pathologies and improved treatments. Several findings have suggested that an alteration of cannabinoid receptor type 1 (CB1) receptor function could be involved in the pathophysiology of such disorders. However, the role of CB1 receptors is still unclear, and their localisation on different neuronal subpopulations may produce distinct outcomes. To dissect the role of CB1 receptors in different neuronal populations, we used male knockout mice and their respective control littermates [total deletion (CB1−/−); specific deletion on cortical glutamatergic neurons (Glu-CB1−/−) or on GABAergic interneurons (GABA-CB1−/−), and wild-type (WT) mice treated with the CB1 antagonist/inverse agonist SR141716A (3 mg/kg). Mice were required to perform different social tasks – direct social interaction and social investigation. Direct interaction of two male mice was not modified in any group; however, when they were paired with females, Glu-CB1−/− mice showed reduced interaction. Also, exploration of the male stimulus subject in the three-chamber social investigation test was almost unaffected. The situation was completely different when a female was used as the stimulus subject. In this case, Glu-CB1−/− mice showed reduced interest in the social stimulus, mimicking the phenotype of CB1−/− or WT mice treated with SR141716A. GABA-CB1−/− mice showed the opposite phenotype, by spending more time investigating the social stimulus. In conclusion, we provide evidence that CB1 receptors specifically modulate the social investigation of female mice in a neuronal subtype-specific manner.