Anti-depressant-like effects of cannabidiol and cannabidiolic acid in genetic rat models of depression

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Physiology & Behavior
journal homepage: www.elsevier.com/locate/physbeh
Brief communication
Effects of cannabidiol in males and females in two different rat models of
depression
Liat Shbiro
a
, Danielle Hen-Shoval
b,a
, Noa Hazut
c,a
, Kayla Rapps
c,a
, Shira Dar
b,a
, Gil Zalsman
d,e,f,g
,
Raphael Mechoulam
h
, Aron Weller
b,a
, Gal Shoval
d,e,⁎
a
Gonda Brain Research Center, Bar-Ilan University, Ramat Gan, Israel
b
Psychology Department, Bar-Ilan University, Ramat Gan, Israel
c
Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel
d
Geha Mental Health Center, Petah Tiqva, Israel
e
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
f
Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
g
Division of Molecular Imaging and Neuropathology, Department of Psychiatry, Columbia University, New York, NY, USA
h
Institute for Drug Research, Medical Faculty, Hebrew University, Jerusalem 91120, Israel
ARTICLE INFO
Keywords:
Depression
Cannabidiol
Animal models of depression
Wistar- Kyoto rats
Flinders Sensitive Line
ABSTRACT
The current study explores the therapeutic potential of Cannabidiol (CBD), a compound in the Cannabis plant,
using both sexes of 2 “depressive-like”genetic models, Wistar Kyoto (WKY) and Flinders Sensitive Line (FSL)
rats. Rats ingested CBD (30 mg/kg) orally. In the saccharin preference test, following a previous report of a pro-
hedonic effect of CBD in male WKY, we now found similar results in female WKY. CBD also decreased immobility
in the forced swim test in males (both strains) and in female WKY. These findings suggest a role for CBD in
treating mental disorders with prominent symptoms of helplessness and anhedonia.
Major depressive disorder (MDD) is a significant cause of incapacity
in the Western world. Various anti-depressant drugs are used in at-
tempts to relieve the debilitating symptoms [26]. Although these drugs
ease symptoms in about 60–70% of cases, there are numerous patients
who do not find relief and the rate of remission is low [10,30]. Fur-
thermore, a large portion of those who are responsive suffer from ne-
gative side effects such as dry mouth, abdominal pain, sexual dys-
function, increased anxiety, expressions of violence and even suicide
[5]. The main target of drugs currently in use to treat MDD is mono-
amine neurotransmission. Over 40 years of research into the role of
serotonin, a monoamine, has not resulted in the development of a
universally effective treatment or a cure for the disorder. Consequently,
there is great need for new pharmacological approaches both for
treatment of the non-responders, and to alleviate the wide-range of
adverse effects of the existing therapeutics.
The endocannabinoid system (ECS) may be a target for new anti-
depressant drugs. The ECS is important for daily regulation of many
basic functions such as cognition, perception, sleep, pain, appetite, re-
ward, as well as endocrine, cardiovascular and immune responses
[6,7,31]. There is increasing evidence supporting the role of the ECS in
the neurobiology of depression [24,42,43]. Specifically, the ECS system
can regulate hypothalamic-pituitary-adrenal (HPA) axis activity and it
plays a role in both the pathophysiology and treatment of MDD
[11,14–16,44]. Considering the potential of the ECS as a pharmacolo-
gical target, the recent increased usage of medical marijuana, typically
produced from Cannabis flowers or Cannabis plant resin extract, is not
surprising [4].
Although there is therapeutic potential in cannabis, there are
drawbacks as well. There are several compounds with different activ-
ities in cannabis and its activity depends on the quantity and ratio of
these constituents. The psychoactive Δ9 - tetrahydrocannabinol (THC),
a major constituent, causes most of the marijuana effects (the ‘high’),
but is also associated with adverse side effects such as anxiety, choli-
nergic deficits and immunosuppression [37]. A recent publication has
shown that THC treatment of adolescent male mice leads to long-term
cognitive and behavioral dysfunction [25].
By contrast, cannabidiol (CBD), which is also an abundant con-
stituent, causes anti-anxiety, anti-schizophrenia and anti-inflammatory
effects [17]. It also appears to block the above-mentioned long-term
cognitive and behavioral dysfunctions [25]. Despite these positive ef-
fects, there is a serious lack of carefully controlled clinical research in
the field. In pre-clinical research, CBD has been found to have
https://doi.org/10.1016/j.physbeh.2018.12.019
Received 6 September 2018; Received in revised form 14 November 2018; Accepted 14 December 2018
⁎
Corresponding author at: Adolescent Day Unit, Geha Mental Health Center, 1 Helsinki St., P.O. Box 102, Petah Tiqva 49100, Israel.
E-mail address: shovgal@tau.ac.il (G. Shoval).
Physiology & Behavior 201 (2019) 59–63
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protective properties in several animal models of neurodegeneration as
well as therapeutic-like effects in models of psychiatric disorders
[19,29,35,46,47]. Clinical trials have indicated potential benefits in the
management of Alzheimer's disease, multiple sclerosis (MS), Parkin-
son's disease and amyotrophic lateral sclerosis [18]. In accordance,
recent evidence from our lab showed that CBD had pro-hedonic effects
in male Wistar Kyoto (WKY) rats, a genetic model of depression. This
effect was manifested in increased consumption of a sweet solution in
the Saccharin Preference Test (SPT) and increased exploration of a
novel object and locomotion in the Novel Object Exploration Test
(NOE) [41].
In line with the behavioral data demonstrating antidepressant-like
effects, one proposed mechanism of action of CBD is through 5-HT1A
receptors [2,12,34,38,45]. These receptors modulate responses to
stressful stimuli and are proposed to mediate the effects of anti-
depressant drugs [3,22]. However, CBD has a wide range of pharma-
cological actions with several suggested mechanisms, though the pre-
cise mechanisms which underlie its therapeutic effects are still unclear.
Taken together, CBD has a polypharmacological profile, resulting in
multiple mechanisms of action possibly responsible for its high ther-
apeutic potential. Some of these may be involved in alleviating psy-
chopathologies such as MDD.
The aim of the current study was to expand the translational evi-
dence we have collected thus far and further examine CBD as a po-
tential anti-depressant agent at a dosage of 30 mg/kg, consumed with
food [41]. In our previous report, we showed the compound's potential
to relieve anhedonia-like symptoms in a genetic rat model. An addi-
tional key symptom in depression is hopelessness/helplessness, often
modeled in rodents by examining passive coping strategies using the
forced swim test (FST). Examining CBD's ability to reduce helplessness-
like behavior in addition to anhedonia will expand our understanding
of its clinical potential. Recent studies have indeed shown that CBD
exerts antidepressant-like effects in the FST in male mice and rats, at
least partially through serotonergic pathways ([9,39,40]). Another way
to examine its potential therapeutic significance would be to examine
its effect on female as well as male rats, as MDD is more prevalent in
women than in men [26]. Importantly, for convergent validity, the
present study investigated the influence of CBD on an additional genetic
rat model of depression, the Flinders Sensitive line (FSL). Both WKY and
the FSL rat models present many behavioral and physiological en-
dophenotypes that are often present in MDD making them valuable
models for studying depression (for reviews see [23,27]). The present
study examined the effects of acute oral self-administration of 30 mg/kg
of CBD on males and females of two genetic rat models of depression,
using both the SPT to assess anhedonia-like behavior and the FST for
despair-like behavior. The oral route was chosen as it is the preferred
translational option for potential use in humans. The study included
Wistar, FSL and WKY adult male and female rats approximately 70-
days-old. The rats were provided by Bar-Ilan University's colony, FSL
progenitors were provided by Prof. Overstreet (FSL) and WKY pro-
genitors were purchased from Envigo. Rats were housed in poly-
carbonate cages (38 × 21 × 18 cm), 2 per cage, in a temperature con-
trolled facility (22 + 1 °C), under 12 h–12 h light:dark cycle (lights on
at 07:00). Food and water were available ad libitum and a plastic tube
was in the cage for enrichment. The study protocol adheres to the
National Institutes of Health guide for the care and use of Laboratory
animals (NIH Publications No. 8023, revised 1978) and the ARRIVE
guidelines and it was approved by the Institutional Animal Care and
Use Committee (protocol #46-05-2017).
The FST was as described by Porsolt et al. [32] with modifications.
A Plexiglas cylinder 45.5 cm tall, 20 cm diameter was filled to 30 cm
with 24 ± 0.5 °C water. The animals were immersed in the Plexiglas
cylinder for 5 min.
The following measurements were recorded: immobility and strug-
gling durations were measured online using a stop watch. The criterion
for immobility was making only the minimal movements necessary to
keep the head above water. The criterion for struggling was making
active forepaw movements in and out of the water including climbing.
Swimming was defined as activity that is not immobility or struggling
and was calculated by subtracting total immobility + total struggling
from the total test time. At completion of the test, animals were dried
offwith a towel. The cylinder was cleaned and water changed between
test animals.
The SPT procedure was similar to that described in Shoval et al.
[41] with modifications. Saccharin (2,3 dihydro-3-ox-
onenzisosulfonazole purchased from Sigma) dissolved with tap water
was used in a 2-bottle test (vs. water) to assess relative preference.
Two days prior to the test day, animals were habituated to the SPT
conditions by placing them individually in test cages overnight with
both saccharin and water bottles in the same configuration as they
would be on the test day. The habituation procedure provided baseline
measures and aimed to reduce general levels of anxiety and neophobia
to the saccharin solution. The animals were not deprived of water or
food at any point. On the test day, 2 h after ingesting the CBD or vehicle
and after exposure to the FST, each animal was presented with 2
identical bottles (200 ml), one with saccharin (0.025%) and one with
drinking water. The animals had the opportunity to drink as much as
they wanted during the ensuing 18 h. The bottles were weighed before
and after the experiment. Bottles and nipples were checked for leakage
prior to the test.
The total consumption of water and saccharin in grams was mea-
sured and was used to calculate the preference ratio as followed:
×
+
(100 saccharin consumption)/(saccharin consumption
water consumption)
In order to prevent neophobia, a high-fat diet pellet with a 70-μl
drop of ethanol was given 2 times during the week prior to the ex-
periment (individually in a holding cage). CBD and vehicle solutions
were prepared immediately before use. On the test day, each animal
was placed in its holding cage and given the pellet, between 0900 and
1100 h (The rats completed eating the pellet within 5 min.). Either
30 mg/kg of CBD dissolved in 70 μl ethanol or 70 μl of ethanol (vehicle)
was laced onto this pellet of high fat rodent diet (D12492 Research
Diets, Inc. Rodent diet with 60% Fat, NJ USA). The consistency of the
pellets differs from standard rodent chow, they are soft, allowing for the
entire amount to be absorbed fully into the pellet. The animals con-
sumed the pellet without any need of coercion. Behavioral testing
began between 11:00–13:00 h, in a dedicated experimental room, 2 h
after the pellet was consumed (the same time frame in which we found
anti-depressive-like effects of CBD and its variant CBDA-ME [13,41]).
Two researchers performed each of the experiments. One prepared
the drug solutions and was therefore not “blind”to the group assign-
ment of the rats. The other was totally “blind”. Both researchers ob-
served all rats together, counterbalancing the roles in scoring im-
mobility or struggling between animals.
Experiment 1: Twenty-five male Wistar (mean weight: 250-350 g)
and 30 male WKY (mean weight: 200-250 g) were pretreated with
either 30 mg/kg of CBD or vehicle. Two hours after consumption of
the pellet they were exposed to the FST.
Experiment 2: Twenty-one WKY female rats (mean weight: 190-
250 g) consumed a pellet laced with CBD or vehicle solution (as
described above) on the experiment day. Two hours later, an FST
was conducted, to examine helplessness-like behavior. The rats were
then placed in their individual test cages to examine anhedonia-like
behavior overnigsht in the SPT.
Experiment 3: The same procedure as in Experiment 2 was con-
ducted with 24 FSL female rats (mean weight: 200–250 g).
Experiment 4: The same procedure as in Experiment 2 was con-
ducted with 34 FSL male rats (mean weight: 300–400 g).
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Between-group comparisons were performed by Student's t-test (for
2 group comparisons), and two-way multivariate or univariate analysis
of variance (MANOVA) followed up by one-way ANOVAs with tests for
simple main effects with Bonferroni adjustment on each dependent
variable (where appropriate). On the FST, two measures were assessed
with MANOVA: Immobility and swimming. Struggling was not included
in these analyses to allow degrees of freedom.
Results of the SPT in WKY females showed, as expected, that
baseline saccharin preference between control and treatment groups
were not significantly different using an independent-samples t-test.
However, an independent-samples t-test between the two treatment
conditions on the test day revealed significantly higher saccharin pre-
ference for the group treated with CBD compared to vehicle treated
controls (t [15]= 2.58, p = 0.021). (Vehicle: M = 73.3, SD = 6.06,
N = 8; 30 mg/kg CBD: M = 82.3, SD = 8.09, N = 9) (Table 1).
For FSL females there was no significant baseline difference in
preference between control and treatment using an independent-sam-
ples t-test. An independent-samples t-test on the test day did not show
significant differences between the two treatment conditions. (Vehicle:
M = 82.07, SD = 19.9, N = 13; CBD: M = 90.68, SD = 2.8, N = 11)
(Table 1). Similarly to the male FSL, as expected, no significant dif-
ference was found in baseline preference between control and treat-
ment groups. An independent-samples t-test on the test day did not
show significant differences between the two treatment conditions.
(Vehicle: M = 87.8, SD = 5.7, N = 9; CBD: M = 89.6, SD = 4, N = 10)
(Table 1).
For the male WKY (vs. Wistar controls) in the FST, a two-way
MANOVA was performed on the variables: immobility and swimming.
The MANOVA performed on the variables: immobility and swimming.
The MANOVA performed on the variables: immobility and swimming.
The MANOVA revealed a significant main effect of strain (F
(2,50) = 11.772, p < 0.001) and an interaction of strain x drug (F
(2,50) = 8.75, p < 0.01).
Tests for simple main effects with Bonferroni adjustment showed
that WKY treated with vehicle were significantly more immobile
(p < 0.05) than Wistar rats treated with vehicle, as in previous studies
(e.g., [23]). In addition, WKY rats treated with 30 mg/kg CBD were
significantly less immobile (p < 0.001) and swam significantly more
(p < 0.001) than WKY rats treated with vehicle (Fig. 1a&1b).
For the analysis of the female WKY, one way MANOVAs performed
on the variables: immobility and swimming, revealed a significant ef-
fect of CBD (F(2, 18)=6.318, p < 0.01). Tests for simple main effects
with Bonferroni adjustment showed that CBD significantly reduced
immobility and increased swimming (Fig. 2).
For the female FSL, one-way MANOVAs performed on the variables:
immobility and swimming, revealed no significant effects of CBD
(Fig. 3a).
For the Male FSL, one way MANOVAs performed on the variables:
immobility and swimming, revealed a significant effect of CBD (F(2, 27)
=6.005, p < 0.01). Tests for simple main effects with Bonferroni ad-
justment showed that CBD significantly reduced immobility, but not
swimming (Fig. 3b).
The current experiments indicate that oral administration of 30 mg/
kg of CBD has the potential to reduce depressive-like behavior in two
different genetic models of depression –WKY and FSL rats.
Additionally, we extended recent findings on the pro-hedonic effects of
the same dose of CBD in male WKY rats to females, strengthening the
accumulating evidence for CBD as a pharmacotherapeutic agent for
MDD.
The addition of the FST to the current study expands our under-
standing of the scope of CBD's therapeutic potential. Results of the FST
demonstrated that WKY of both sexes and male FSL rats were less im-
mobile and swam more when treated with CBD. A reduction in floating
behavior suggests that depression-like symptoms such as helplessness
have been improved, extending the application of the drug to alleviate
these types of symptoms. Female FSL rats however did not display any
change in behavior as measured by the FST. There is little research on
female FSL as a model of depression and since we did not compare them
to a control strain in this study we cannot conclude whether their
floating levels were indicative of healthy control levels, or rather, if
they modeled pathological coping behavior. Therefore, it is difficult to
draw conclusions on the effects of CBD using this model. It is plausible
that the lack of effects are similar to those demonstrated with Wistar
controls who seem not to be significantly affected by 30 mg/kg of CBD.
However, a control strain (Wistar) was only employed in the male WKY
experiment, to follow the design of our previous study in male WKY rats
[41]. Interpretation of the results should consider that the FST is a
controversial test for females, and that males and females may be re-
sponsive to different doses of the same drug [20]. While this may hold
for the FSL strain, in our current study WKY females were responsive to
this dose of CBD in a similar manner as male WKY rats.
While several studies [9,36,39,40,45] have reported a similar effect
Table 1
Saccharin preference (mean ± SEM) of female Wistar Kyoto (WKY) and male
and female Flinders Sensitive Line (FSL) (n = 10–15 in each group).
Vehicle 30 mg/kg CBD
WKY Females 73.3 (2.3) 82.3 (2.3)
⁎⁎
FSL Males 87.8 (1.8) 89.6 (1.2)
FSL Females 82.7 (6.2) 89.6 (0.9)
⁎⁎
p < 0.05.
Fig. 1. A) Duration of immobility (mean +SEM) in the FST of male Wistar Kyoto (WKY) rats that received orally vehicle or 30 mg/kg cannabidiol (CBD) (N =12 and
13 rats, respectively) versus Wistar control male rats that received vehicle or cannabidiol (CBD) (N = 13 and 17 rats, respectively). ***p < .001. B) Duration of
swimming (mean +SEM) in the FST of male WKY rats that received orally vehicle or 30 mg/kg CBD (N = 12 and 13 rats, respectively) versus Wistar control male
rats that received vehicle or CBD (N = 13 and 17 rats, respectively). ***p < .001.
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for CBD in their studies, using males of wild-type strains of mice or rats,
the present study was the first to show this anti-depressant effect in
specific genetic models of depression. Both the WKY and the FSL are
considered valuable models for studying depression, presenting many
behavioral and physiological endophenotypes that are often present in
MDD, without the need to use stress protocols to render them “de-
pressed”[23,27].
Interestingly, although Réus et al.'s [36] study used intraperitoneal
injection (IP), and the present study used oral administration, it was the
same dose of 30 mg/kg, out of several doses, that had an observable
effect. This indicates that even though the CBD in our study had to be
absorbed via the gut before entering blood circulation, most of it re-
mained as effective as in an IP injection, yet avoiding the stress asso-
ciated with injection. Taken together, these technical aspects
strengthen the findings of our research, setting this dose of CBD, per os
(orally), as a potential therapeutic for MDD. In humans, the active dose
of CBD in some disease states is extremely high. In schizophrenia, for
example, Leweke et al. [21] found that the effective dose is about
800 mg/day. Therefore, the development of more potent CBD-type
compounds is desirable.
The current study explored another key symptom in MDD: the di-
minished interest or pleasure in activities (DSM-5, [1]). This phenom-
enon, known as anhedonia, is a symptom that often appears in several
different mental illnesses. A classic test for assessing this in rodents is
the Saccharin Preference Test (SPT). As found in our previous study
with male WKY rats [41], the current study replicated the pro-hedonic
effect of 30 mg/kg of CBD with WKY females, strengthening CBD's
potential use to treat disorders with anhedonic symptoms.
Although FSL rats are considered a genetic model of some aspects of
depression, in contrast to WKY, they do not consistently show anhe-
donia-like behavior [28]. While use of relatively extreme stressors, and
comparison to a relatively extreme control strain can produce anhe-
donia-like behavior in FSL rats, less extreme conditions and comparison
with a wild-type (Sprague-Dawley) strain do not [23,33]. Thus, under
the present testing conditions it was expected that the pro-hedonic ef-
fect that was found with the WKY model would not be present in the
FSL model. Future studies should attempt to replicate this effect using
different methods to attain convergent validity.
This study was limited to surveying the acute effects of a single CBD
administration; considering that MDD is a chronic condition, the results
should be interpreted carefully. Further translational experiments are
needed to explore the long-term effects of chronic CBD exposure. A
chronic study would reveal the potential changes in the brain that
mediate the behavioral effects. In addition, investigating CBD's me-
chanisms is necessary in order to understand its action and its safety
profile [8]. The research presented here is the first to use two different
genetic rat models of depression, the WKY and the FSL rat strains, using
two divergent behavioral tests both in males and females.
In conclusion, the current results provide additional support to
previous data indicating that CBD may be a promising novel drug for
treating depression, a prevalent condition for which new therapeutic
approaches are necessary. It is plausible that CBD may also be of clin-
ical value in other disorders with prominent symptoms of helplessness
and/or anhedonia. Hence, CBD should be considered a viable
Fig. 2. A) Duration of immobility (mean + SEM) in the FST of female WKY rats that received orally vehicle or 30 mg/kg CBD (N = 9 and 12 rats, respectively).
**p < .01. B) Duration of swimming (mean + SEM) in the FST of female WKY rats that received orally vehicle or 30 mg/kg CBD (N = 9 and 12 rats, respectively)).
**p < .01.
Fig. 3. A) Duration of immobility and swimming (mean + SEM) in the FST of female Flinders Sensitive Line (FSL) rats that received orally vehicle or 30 mg/kg
cannabidiol (CBD) (N = 12 and 13 rats, respectively). B) Duration of immobility and swimming (mean + SEM) in the FST of male FSL rats that received orally vehicle
or 30 mg/kg CBD (N = 12 and 13 rats, respectively). **p < .01.
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psychopharmacological agent with the potential to relieve two rela-
tively common symptoms of mental illness.
Acknowledgements
This study was supported, in part, by a grant to GS from the
National Institute for Psychobiology in Israel (NIPI) the Dylan Tauber
Track (Grant 159-14-15).
The CBD preparation in RM's laboratory was supported by a dona-
tion from the Kessler Foundation, Boston.
Both funding sources had no further role in study design; in the
collection, analysis and interpretation of data; in the writing of the
report; and in the decision to submit the paper for publication.
Research by RM, AW and GS is currently partially supported by
Europacific Medical. This support started recently, after completion of
the study reported here.
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