Received: July 15, 2014; Revised: September 05, 2014; Accepted: September 09, 2014

© The Author 2015. Published by Oxford University Press on behalf of CINP.

International Journal of Neuropsychopharmacology, 2015, 1–10

doi:10.1093/ijnp/pyu041
Research Article

1
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research article

Cannabidiol Attenuates Sensorimotor Gating 
Disruption and Molecular Changes Induced by 
Chronic Antagonism of NMDA receptors in Mice
Felipe V. Gomes, PhD; Ana Carolina Issy, PhD; Frederico R. Ferreira, PhD; 
Maria-Paz Viveros, PhD; Elaine A. Del Bel, PhD; Francisco S. Guimarães, PhD

Department of Pharmacology, Medical School of Ribeirão Preto, University of São Paulo, Brazil (Gomes and 
Guimarães); Department of Physiology, Faculty of Odontology of Ribeirão Preto, University of São Paulo, Brazil 
(Issy and Del Bel); Center for Interdisciplinary Research on Applied Neurosciences, University of São Paulo, 
Brazil (Gomes, Issy, Del Bel, and Guimarães); Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, 
Brazil (Ferreira); Department of Physiology (Animal Physiology II), Faculty of Biology, Complutense University 
of Madrid, Spain (Viveros).

Correspondence: Felipe V. Gomes, MD, Department of Pharmacology, Medical School of Ribeirão Preto, University of São Paulo, 3900 Bandeirantes Ave, 
Ribeirão Preto, SP, 14049–900, Brazil (gomesfv@usp.br).

Abstract

Background: Preclinical and clinical data suggest that cannabidiol (CBD), a major non-psychotomimetic compound from 
Cannabis sativa, induces antipsychotic-like effects. However, the antipsychotic properties of repeated CBD treatment have 
been poorly investigated. Behavioral changes induced by repeated treatment with glutamate N-methyl-D-aspartate receptor 
(NMDAR) antagonists have been proposed as an animal model of schizophrenia-like signs. In the present study, we evaluated if 
repeated treatment with CBD would attenuate the behavioral and molecular modifications induced by chronic administration 
of one of these antagonists, MK-801.
Methods: Male C57BL/6J mice received daily i.p. injections of MK-801 (0.1, 0.5, or 1 mg/kg) for 14, 21, or 28 days. Twenty-four 
hours after the last injection, animals were submitted to the prepulse inhibition (PPI) test. After that, we investigated if 
repeated treatment with CBD (15, 30, and 60 mg/kg) would attenuate the PPI impairment induced by chronic treatment with 
MK-801 (1 mg/kg; 28 days). CBD treatment began on the 6th day after the start of MK-801 administration and continued until 
the end of the treatment. Immediately after the PPI, the mice brains were removed and processed to evaluate the molecular 
changes. We measured changes in FosB/ΔFosB and parvalbumin (PV) expression, a marker of neuronal activity and a calcium-
binding protein expressed in a subclass of GABAergic interneurons, respectively. Changes in mRNA expression of the NMDAR 
GluN1 subunit gene (GRN1) were also evaluated. CBD effects were compared to those induced by the atypical antipsychotic 
clozapine.
Results: MK-801 administration at the dose of 1 mg/kg for 28 days impaired PPI responses. Chronic treatment with CBD (30 
and 60 mg/kg) attenuated PPI impairment. MK-801 treatment increased FosB/ΔFosB expression and decreased PV expression 
in the medial prefrontal cortex. A decreased mRNA level of GRN1 in the hippocampus was also observed. All the molecular 
changes were attenuated by CBD. CBD by itself did not induce any effect. Moreover, CBD effects were similar to those induced 
by repeated clozapine treatment.

 International Journal of Neuropsychopharmacology Advance Access published January 24, 2015

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2 | International Journal of Neuropsychopharmacology, 2015

Conclusions: These results indicate that repeated treatment with CBD, similar to clozapine, reverses the psychotomimetic-
like effects and attenuates molecular changes observed after chronic administration of an NMDAR antagonist. These data 
support the view that CBD may have antipsychotic properties.

Keywords: antipsychotic, cannabidiol, cannabinoid, clozapine, NMDA receptor hypofunction, schizophrenia

Introduction
Cannabidiol (CBD), a major compound from Cannabis sativa, is 
devoid of the typical psychoactive effects induced by Δ9-tetrahy-
drocannabinol (THC). In fact, CBD attenuates the psychotomimetic 
effects induced by high doses of THC in humans (Zuardi et al., 1982; 
Bhattacharyya et al., 2010). These findings led to the hypothesis that 
CBD could have antipsychotic properties. Accordingly, several pre-
clinical studies have indicated that CBD induces antipsychotic-like 
effects (for review see Campos et al., 2012). These effects have also 
been described in open-label clinical studies (Zuardi et al., 1995, 
2006) and recently confirmed in a controlled, randomized, double-
blind clinical trial (Leweke et al., 2012). Nevertheless, the mecha-
nism of action of CBD is poorly understood.

Animal models based on acute and chronic administration 
of N-methyl-D-aspartate-receptor (NMDAR) antagonists, such 
as phencyclidine (PCP), ketamine, and MK-801, are widely used 
to investigate the neurobiology of schizophrenia and the effects 
induced by compounds with antipsychotic properties (Javitt and 
Zukin, 1991; Rujescu et al., 2006; Bubenikova-Valesova et al., 2008). 
Although the pathophysiology of schizophrenia is quite complex, 
involving several neurotransmitters, evidence indicates the partici-
pation of the glutamatergic system. For example, administration of 
NMDAR antagonists in rodents and humans can evoke positive and 
negative symptoms, as well as cognitive deficits that resemble those 
seen in schizophrenia patients, supporting the proposal that this 
treatment could be a valid animal model of this disorder (Krystal 
et al., 1994, 2005; Lisman et al., 2008). Moreover, in laboratory ani-
mals, the effects induced by chronic administration of these antago-
nists, unlike those seen after acute injection, are proposed to more 
closely resemble the behavioral, neurochemical, and neuroanatomi-
cal changes observed in schizophrenia patients (Jentsch and Roth, 
1999). Among these changes, a decrease in parvalbumin (PV) expres-
sion, a calcium-binding protein expressed in a subclass of fast-
spiking GABAergic interneurons centrally involved in information 
processing in the brain, has been observed after chronic treatment 
with NMDAR antagonists in rodents (Abdul-Monim et al., 2007). This 
finding has been consistently observed in the post-mortem brains of 
schizophrenia patients (Lewis et al., 2005) and has been suggested to 
be a consequence of an NMDAR signaling hypofunction (Gonzalez-
Burgos and Lewis, 2012).

The prepulse inhibition (PPI) test is a behavioral paradigm 
used to assess sensorimotor gating mechanisms. In a PPI 
test, a weaker non-startling stimulus (prepulse) presented at 
a short interval before a startling acoustic stimulus (pulse) 
reduces the processing of, and attenuates the response to, the 
latter stimulus (Braff and Geyer, 1990; Geyer et  al., 2001). It 
was originally proposed by Graham (1975) that the prepulse 
triggers sensory-neuronal processing routines that need to 
be protected against disruption, leading to inhibition of the 
subsequent response to the startling stimulus. A disruption in 
this inhibitory processes is frequently observed in schizophre-
nia patients (Braff, Geyer, Light, et al., 2001), and in other psy-
chiatric disorders as well (Braff, Geyer, and Swerdlow, 2001). 
Thus, although PPI deficit, even if experimentally induced, 
does not constitute an animal model of schizophrenia per se, 

it is a valid model to investigate sensorimotor gating disrup-
tion similar to that seen in schizophrenia patients, with face, 
predictive, and construct validity (Swerdlow et al., 2000; Geyer 
et al., 2001).

Although there are acute studies indicating positive effects 
of CBD in NMDAR-based animal models of schizophrenia (Long 
et al., 2006; Gururajan et al., 2011, 2012), at the moment no study 
has investigated the effects of this drug in models based on 
repeated administration of NMDAR antagonists. Therefore, in the 
present study we investigated whether repeated treatment with 
CBD would attenuate behavioral changes in the PPI test induced 
by chronic administration of the NMDAR antagonist MK-801. 
We also measured changes in PV expression in brain struc-
tures related to the neurobiology of schizophrenia, such as the 
medial prefrontal cortex (mPFC), dorsal striatum (dSTR), nucleus 
accumbens (NAc) core and shell, and dorsal hippocampus (den-
tate gyrus; DG, CA1, and CA3). Since a decrease in PV expression 
has been related to hypofunction of NMDAR-mediated neuro-
transmission, we evaluated the mRNA expression of the NMDAR 
GluN1 subunit gene (GRN1). The GluN1 subunit is an obligatory 
subunit of NMDAR and, although changes in its expression have 
been associated with schizophrenia (Weickert et al., 2013), few 
studies have analyzed the effects of chronic blockade of these 
receptors on mRNA expression of this gene. Finally, as the brain 
sites of CBD antipsychotic-like effects are unknown, we decided 
to evaluate changes in FosB/ΔFosB protein expression, a marker 
of neuronal activity. FosB/ΔFosB accumulates and persists in a 
region-specific manner in the brain for relatively long periods 
due to its stability in response to different kinds of chronic stim-
uli, including repeated administration of antipsychotics (Atkins 
et al., 1999).

Material and Methods

Animals

The experiments were performed using male C57BL/6J mice that 
were 6 weeks of age at the beginning of the treatment. Animals 
were housed in groups of four per cage (41 x 33 x 17 cm) in a tem-
perature-controlled room (243 ± 1°C) under standard laboratory 
conditions with free access to food and water and a 12 h light/
dark cycle (lights on at 6:00 AM). Procedures were conducted 
in conformity with the Brazilian Society of Neuroscience and 
Behavior guidelines for the care and use of laboratory animals, 
which are in compliance with international laws and politics. 
The institution’s Animal Ethics Committee approved the hous-
ing conditions and experimental procedures (process number: 
165/2010).

Drugs

The following drugs were used: CBD (THC Pharm), clozap-
ine (Tocris), and MK-801 (Sigma-Aldrich). CBD was diluted in 
2% Tween 80 in saline, while clozapine was diluted in saline 

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Gomes et al. | 3

supplemented with 30 μl of 0.1 M hydrochloric acid; the pH was 
adjusted to a value close to neutrality when necessary. MK-801 
was diluted in saline. The drugs were injected intraperitoneally 
(i.p.) in a 10 mL/kg volume.

Experimental Design

Animals received daily i.p. injections of saline or MK-801 (0.1, 
0.5, or 1 mg/kg) for 14, 21, or 28 days (n = 6–8/group). Twenty-
four hours after the last injection, the animals were submit-
ted to the PPI test. Based on the results of this experiment, 
we investigated whether repeated treatment with CBD (15, 30, 
and 60 mg/kg) or clozapine (1 mg/kg) would attenuate the PPI 
impairment induced by chronic treatment with MK-801 (1 mg/
kg) for 28  days (Figure  1). CBD or clozapine treatment began 
on the 6th day after the start of MK-801 administration and 
continued until the end of the treatment (n = 14/group). One 
day later, animals were submitted to the PPI. CBD and clo-
zapine were administered 30 min before MK-801 or saline. 
Immediately after the PPI test, animals were euthanized and 
their brains processed to assess changes in FosB/ΔFosB and 
PV protein expression (n = 7/group) or NMDA-receptor GluN1 
subunit gene mRNA expression (n = 5–7/group). The doses and 
the experimental design were based on previous studies (Long 
et al., 2006; Vigano et al., 2009; Casarotto et al., 2010; Elhardt 
et al., 2010; Guidali et al., 2011). We also tested the effects of a 
single CBD or clozapine administration in the last (28th) day of 
treatment with MK-801 in the PPI to test whether repeated CBD 
or clozapine administration would be required for the observed 
drug effects (n = 7/group; Supplementary Figure 1).

Mice showed a normal increase in body weight (measured 
every day) that was independent of treatment (Supplementary 
Figure 2).

Procedure

Pre-pulse Inhibition Test
The PPI test was performed according to a protocol previously 
described by our group (Issy et  al., 2009). Briefly, it was con-
ducted simultaneously in two identical startle response sys-
tems (Med Associates). A continuous acoustic signal provided 
a background white noise level of 65 ± 1 dB. The pulse (pulse 
alone) was a burst of white noise of 105 dB with a rise/decay 
of 5 ms and duration of 20 ms, and the prepulse intensities 
were set to 80, 85, and 90 dB of pure tone, 7 KHz frequency, 
and duration of 10 ms. The cages were calibrated before each 
test to ensure equal sensitivity of both response platforms 

throughout the procedure. The platform calibration was done 
by adjusting the gain on the load cell amplifier to 150 arbitrary 
units at a standard weight appropriated for mice (40 g). The 
limits of the load cell were −2047 to +2047 arbitrary units. After 
a 5 min acclimatization period in which mice received no stim-
uli except the background noise, they were presented with a 
series of 10 stimuli (pulse alone). The first 10 pulse-alone trials 
allowed the within-session habituation to the startle stimulus 
and were not considered for statistical analysis of the per-
centage of PPI. The PPI test consisted of 64 trials pseudoran-
domly divided into eight different categories presented with 
an inter-stimulus interval of 30 s: pulse alone (105 dB); prepulse 
alone (80, 85, or 90 dB); prepulse + pulse with 100 ms interval 
between prepulse and pulse; and null, where no stimulus was 
presented. Prepulse stimulus did not elicit an acoustic startle 
response. Mean acoustic startle response to pulse-alone (P) tri-
als and each prepulse + pulse (PP + P) trial was calculated for 
each subject. These data were used in the statistical analysis to 
assess drug-induced changes in startle amplitude and in PPI. 
The level of PPI was determined by expressing the PP + P startle 
amplitude as a percentage decrease from P startle amplitude, 
according to the following formula: %PPI  =  100–[100  × (PP + 
P/P)]. This transformation reduces statistical variability attrib-
utable to differences between animals and is a direct measure 
of the PPI level.

Immunohistochemical Detection of FosB/ΔFosB and PV
Some animals, immediately after the exposure to the PPI, were 
deeply anesthetized with a lethal dose of urethane (25%, 5 mL/
kg; i.p.) and transcardially perfused with phosphate buffered 
saline (PBS) followed by 4% paraformaldehyde in 0.1 M phos-
phate buffer. Then, the brains were removed and post-fixed in 
4% paraformaldehyde for 2 h. After that they were immersed in 
30% sucrose in 0.1 M phosphate buffer for cryoprotection over 
48 h. The brains were frozen at −40ºC on dry ice and isopentane 
and 25 µm-thick serial coronal sections were obtained using a 
cryostat microtome at -20ºC (CM-1900, Leica). The free-floating 
sections were rinsed (3 times, 5 min each) in PBS 0.1 M + 0.15% 
Triton-X (pH 7.4; washing buffer) and then pre-incubated for 
30 min with 1% hydrogen peroxide in PBS to remove endogenous 
peroxidase activity. To avoid unspecific activity, free-floating sec-
tions were also incubated in a solution containing 5% bovine 
serum albumin, washing buffer, and 5% normal goat (FosB/ΔFosB) 
or horse (PV) serum for 1 h. Sections were incubated overnight at 
21ºC with polyclonal rabbit anti-FosB/ΔFosB antibodies (1:1000, 
H-75, sc-7203, Santa Cruz Biotechnology) or monoclonal mouse 
anti-PV antibodies (1:1000, P227, Sigma-RBI). Subsequent to the 

Figure 1. Experimental design. The animals received daily i.p. injections of saline (SAL) or MK-801 (1 mg/kg) for 28 days. CBD (15, 30, and 60 mg/kg) or vehicle (VEH) 

treatment began on the 6th day after the start of MK-801 administration and continued until the end of the treatment. One day later, animals were submitted to the 

prepulse inhibition (PPI) test. Immediately after the PPI, their brains were removed and processed to assess immunohistochemical changes in FosB/ΔFosB and parval-

bumin (PV) expression and changes in mRNA expression of the NMDAR GluN1 subunit gene by RT-PCR. CBD effects were compared to those induced by the atypical 

antipsychotic clozapine (CLZ; 1 mg/kg).

http://ijnp.oxfordjournals.org/lookup/suppl/doi:10.1093/ijnp/pyu041/-/DC1
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https://www.researchgate.net/publication/26727375_Nitric_oxide_modulation_of_methylphenidate-induced_disruption_of_prepulse_inhibition_in_Swiss_mice?el=1_x_8&enrichId=rgreq-8b8fc97fb388a901bd6189374bdfc7ed-XXX&enrichSource=Y292ZXJQYWdlOzI3MTM4NjIwMTtBUzoxOTA2NTY2NjYyMzQ4ODFAMTQyMjQ2NzQ5OTI2MA==
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4 | International Journal of Neuropsychopharmacology, 2015

primary antibody incubation, sections were successively washed 
(washing buffer) and incubated for 1 h in a secondary antibody 
solution (PBS) containing biotinylated goat anti-rabbit or horse 
anti-mouse antibodies (1:400; Vector Laboratories). The sections 
were then incubated with the avidin-biotin immunoperoxidase 
complex for 2 h (1:300, Vectastain ABC kit, Vector Lab). Afterwards, 
FosB/ΔFosB and PV-like immunoreactivity were revealed by the 
addition of chromogen diaminobenzidine (DAB; Sigma-Aldrich) 
into acetate buffer, H2O2 0.02%, and nickel ammonium sulfate 1% 
or DAB into Tris-buffered saline and H2O2 0.02%, respectively. All 
the reactions were performed at the temperature of 21ºC.

Slides immunostaining for PV or FosB/ΔFosB were observed 
under phase contrast microscopy (Olympus BX50, Olympus). The 
microscope has an attached camera (Olympus DP72, Olympus) 
that captured the images for analysis with the help of the Image 
Pro-Plus 6.0 software (Mediacybernetics). The follow brain struc-
tures were evaluated: mPFC, dSTR, NAc core, and shell and dor-
sal hippocampus (DG, CA1, and CA3).

Quantification of PV or FosB/ΔFosB-positive cells was made 
with the 10X or 20X objective, respectively. An observer blinded 
to group assignment performed the analysis. For each brain 
structure, 3–4 tissue sections from each animal were analyzed. 
All stained cells in the whole area of each brain region of inter-
est were recorded (FosB/ΔFosB-mPFC: approximately 0.068 mm2; 
dSTR and NAc core and shell: 0.076 mm2; DG: 0.062 mm2; CA1: 
0.020 mm2; CA3: 0.024 mm2; PV-mPFC: approximately 0.27 mm2; 
dSTR and NAc core and shell: 0.30 mm2; DG: 0.062 mm2; CA1: 
0.020 mm2; CA3: 0.024 mm2). Immunoreactive cells were counted 
using ImageJ software (Research Services Branch, National 
Institutes of Health). Those cells with purple or brown impregna-
tions with areas between 10 and 80 µm2 were considered FosB/
ΔFosB- and PV-positive cells, respectively. As the brain struc-
tures evaluated are bilateral; the mean value was calculated. The 
results were expressed as the number of positive cells/0.1 mm2. 
Neuroanatomical sites were identified with the help of the 
Franklin and Paxinos mouse brain atlas (Franklin and Paxinos, 
2008). The anterior–posterior localization from bregma of the ana-
lyzed regions was: mPFC, 1.98–1.70 mm; dSTR and NAc core and 
shell, 1.54–0.98 mm; and dorsal hippocampus, -1.82 to -2.30 mm.

Real-Time Quantitative Polymerase Chain Reaction (RT-PCR)
Animals were deeply anesthetized with a lethal dose of ure-
thane (25%, 5 mL/kg; i.p.) and decapitated immediately after 
the exposure to the PPI. After decapitation, the frontal cortex, 
striatum, and hippocampus were collected by microdissec-
tion in RNAse-free conditions and stored at -80ºC until RNA 
isolation. Total RNA was extracted using Trizol (Invitrogen), 
and cDNA reaction was performed using 1 µg of total RNA in 
a high-capacity cDNA kit (Applied Biosystem) according to the 

manufacturer’s instructions. The relative level of mRNA expres-
sion of the NMDAR GluN1 subunit gene (GRN1) was evaluated 
in the StepOne real-time PCR system, using Applied Biosystems 
real-time master mix with Taqman® gene expression probes 
(Assay ID Mm01212171_s1). Total RNA was normalized based 
on Ct values for the glyceraldehyde-3-phosphate dehydroge-
nase (GAPDH) housekeeping gene (Assay ID Mm99999915_g1). 
All reactions were duplicated, and fold change was calculated 
using the 2−ΔΔCt method. Data are shown as a relative percentage 
of mRNA expression to the control group.

Statistical Analysis

The PPI results were analyzed by mixed-design analysis of vari-
ance (ANOVA) with treatment as the main independent factor 
and prepulse intensity (80, 85, and 90 dB) as the repeated fac-
tor. The immunohistochemical data were analyzed by two-way 
ANOVA using the first (vehicle, CBD, or clozapine) and the sec-
ond (MK-801 or saline) treatment as main factors. In cases of sig-
nificant interactions between factors, specific one-way ANOVAs 
were performed. The Student-Newman-Keuls (S-K-N) test was 
used for post hoc analysis. mRNA expression results failed to 
reach homogeneity of variances and were analyzed by Kuskal-
Wallis followed by the Dunn test. All data are represented as the 
mean ± the standard error of mean (SEM). Results of statisti-
cal tests with p < 0.05 were considered significant. Since there 
was no difference in PPI and immunohistochemical results 
between animals that received Tween80 2% in saline (used to 
dissolve CBD) + saline or saline supplemented with 30 μl of 0.1 M 
hydrochloric acid (used to dissolve clozapine) + saline, they were 
joined together in a control group (vehicle + saline).

Results

Effects of NMDAR Antagonist MK-801 for 14, 21 or 28 
days on PPI

There was a significant treatment effect only after 28  days of 
repeated drug administration, where animals treated with 
MK-801 1mg/kg had a greater PPI impairment compared to all 
other groups (F3,25 = 5.36, p = 0.005; S-N-K., p < 0.05; Figure 2). There 
was also a significant effect of intensity at all measurements, 
with louder prepulse stimuli causing greater PPI (F2,50  =  40.39–
40.9, p  <  0.001; Figure  2), but there was no significant interac-
tion between treatment and prepulse intensity (F6,50 = 1.55, p > 
0.05). MK-801 treatment for 14, 21, or 28 days did not modify the 
acoustic startle response to the pulse-only trials, which would be 
indicative of a motor-impairing effect (Supplementary Table 1).

Figure 2. Mice received daily i.p. injections of saline or MK-801 (0.1, 0.5, or 1 mg/kg) for 14, 21, or 28 days. Twenty-four hours after the last injection, the animals were 

submitted to the PPI test. MK-801 (1 mg/kg) disrupted PPI only after 28 days of treatment (n = 6–8/group). The data are presented as the mean ± SEM. *A general treat-

ment effect: p < 0.05 vs. all other groups using a mixed-design ANOVA followed by S-N-K.

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Gomes et al. | 5

CBD and Clozapine Effects on PPI Impairment 
Induced by MK-801

Both CBD (30 and 60 mg/kg) and clozapine attenuated the PPI 
disruption induced by treatment with MK-801 for 28  days 
(Figure  3). Mixed-design ANOVA indicated significant effects 
of prepulse intensity (F2,208= 103.4, p  <  0.001) and treatment 
(F7,104 = 4.6, p < 0.001). There was also an interaction between pre-
pulse intensity and treatment (F14,208 = 2.35, p = 0.005). One-way 
ANOVA analyses conducted at each prepulse intensity showed 
significant effects at 85 dB (F7,104  =  5.75, p  <  0.001) and 80 dB 
(F7,104  =  4.09, p  =  0.001). At 85 dB animals treated with vehicle 
+ MK-801 showed a significant impairment of PPI compared to 
control (vehicle + saline), an effect not prevented by clozapine or 
CBD (S-N-K, p < 0.05). At 80 dB, however, PPI impairment induced 
by MK-801 was attenuated by clozapine and CBD (30 mg/kg). 
Moreover, animals treated with CBD (60 mg/kg) + MK-801 pre-
sented a significantly lower PPI impairment compared to those 
receiving vehicle + MK-801 (S-N-K, p < 0.05).

The treatments did not modify the acoustic startle response 
to the pulse-only trials (Supplementary Table 2).

We also observed that CBD or clozapine administration given 
once on the last day of MK-801 treatment did not attenuate 
the chronic MK-801-induced PPI impairment (Supplementary 
Figure  3), indicating that CBD and clozapine effects seem to 
depend on the repeated treatment and are not due to the last 
injection of these drugs.

Changes in FosB/ΔFosB Expression in Specific Brain 
Regions

Quantification of FosB/ΔFosB-positive cells in the mPFC revealed 
significant effects of the first (vehicle, clozapine, or CBD; 
F2,36 = 4.00, p = 0.02) and second treatments (saline or MK-801; 
F1,36 = 4.84, p = 0.034) and an interaction between them (F2,36 = 4.39, 
p = 0.02; Figure 4A and B). Post hoc analysis showed that animals 
treated with vehicle + MK-801 had a significantly higher number 
of FosB/ΔFosB-positive cells compared to all other groups (S-N-
K, p < 0.05). Neither CBD (60 mg/kg) nor clozapine affected FosB/
ΔFosB expression in the mPFC per se (p > 0.05).

In the NAc core, there were also significant effects of the 
first (vehicle, clozapine, or CBD; F2,36  =  5.11, p  =  0.01) and sec-
ond treatments (saline or MK-801; F1,36  =  14.23, p  =  0.001) and 
an interaction between them (F2,36 = 3.93, p = 0.03; Figure 4C and 
D). It was observed an increase in the number of FosB/ΔFosB-
positive cells in the NAc core of vehicle + MK-801–treated mice 
compared to control (vehicle + saline group, S-N-K, p  <  0.05). 
Different from the mPFC, clozapine and CBD were unable to 
attenuate the MK-801-induced changes in the NAc core (S-N-K, 

p < 0.05). Clozapine per se also induced an increase in the num-
ber of FosB/ΔFosB-positive cells (S-N-K, p < 0.05), but CBD did not 
induce any change by itself (S-N-K, p > 0.05).

No change in FosB/ΔFosB expression was observed in the 
dSTR, NAc shell, DG, CA1, or CA3 (Supplementary Figure 4).

Changes in PV Expression in Specific Brain Regions

MK-801 induced a decrease in PV expression in the mPFC. This 
change was attenuated by concomitant treatment with CBD or 
clozapine. There was a tendency for a significant effect of the 
first treatment (F2,36 = 3.06, p = 0.060), a significant effect of the 
second treatment (F1,36  =  10.41, p  =  0.003), and an interaction 
between the treatments (F2,36 = 4.76, p = 0.015; Figure 5). Animals 
treated with vehicle + MK-801 presented a decrease in the num-
ber of PV-positive cells compared to control (vehicle + saline; 
S-N-K, p  <  0.05), a change attenuated by CBD and clozapine. 
Neither CBD nor clozapine affected PV expression in the mPFC 
(S-N-K, p > 0.05).

No change in the PV expression was observed in the dSTR, 
DG, CA1, or CA3 (Supplementary Figure 5). Moreover, PV immu-
nostaining was poorly detected in the NAc, indicating that PV 
may be expressed at levels below the limit of detection within 
the NAc core and shell. Indeed, low levels of PV-positive cells in 
the NAc were observed by Todtenkopf et al. (2004) in rats.

Changes in mRNA Expression of GRN1 in Specific 
Brain Regions

Animals treated with vehicle + MK-801 presented a significantly 
lower mRNA expression in the hippocampus compared to con-
trols (vehicle + saline; χ2  =  16.4, d.f.  =  5, p  =  0.006; Dunn test, 
p < 0.05; Figure 6). These effects were attenuated by CBD and clo-
zapine. The treatments did not modify GluR1 mRNA expression 
in the frontal cortex and striatum (p > 0.05; Figure 6).

Discussion

Corroborating the proposal that repeated administration of 
NMDAR antagonists could be a useful animal model of schizo-
phrenia, the results of the present study show that repeated 
administration of the NMDAR antagonist MK-801 for 28 days 
impaired PPI performed 24 h after the end of the treatment. 
No effect was observed after 14 or 21  days of MK-801 treat-
ment. These results are consistent with those indicating a lack 
of PPI impairment after repeated treatment with the NMDAR 
antagonist PCP for 14  days (Martinez et  al., 1999) and those 
showing cognitive deficits after 28  days of chronic intermit-
tent PCP treatment (Vigano et  al., 2009; Guidali et  al., 2011). 
Besides the PPI disruption, chronic MK-801 treatment also 
decreased the number of PV-positive cells in the mPFC and 
the mRNA levels of the NMDAR GluN1 subunit gene (GRN1) in 
the hippocampus. These molecular changes are proposed to 
be similar to those observed in schizophrenia patients (Lewis 
et  al., 2005; Weickert et  al., 2013). In addition, MK-801 treat-
ment also increased the number of FosB/ΔFosB-positive cells 
in the mPFC and NAc core. Both the behavioral and molecu-
lar changes induced by MK-801 treatment were attenuated 
by repeated treatment with CBD or the atypical antipsychotic 
clozapine.

The effects of clozapine and CBD on improving the PPI defi-
cits were seen only at the 80 dB prepulse intensity. This is not an 
uncommon finding, since drug effects may vary across prepulse 
intensities in the PPI session. Significant effects of the prepulse 

Figure  3. CBD (30 and 60 mg/kg) attenuated the PPI impairment induced by 

repeated treatment with MK-801 (1 mg/kg) for 28 days. Similar to CBD, clozapine 

(CLZ; 1 mg/kg) attenuated the MK-801-induced PPI disruption (n = 14/group). The 

data are presented as the mean ± SEM. *p < 0.05 vs. VEH + SAL group, #p < 0.05 vs. 

VEH + MK-801 group; mixed-design ANOVA followed by S-N-K.

http://ijnp.oxfordjournals.org/lookup/suppl/doi:10.1093/ijnp/pyu041/-/DC1
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http://ijnp.oxfordjournals.org/lookup/suppl/doi:10.1093/ijnp/pyu041/-/DC1
https://www.researchgate.net/publication/41668744_Cannabinoid_CB1_receptor_antagonism_prevents_neurochemical_and_behavioural_deficits_induced_by_chronic_phencyclidine?el=1_x_8&enrichId=rgreq-8b8fc97fb388a901bd6189374bdfc7ed-XXX&enrichSource=Y292ZXJQYWdlOzI3MTM4NjIwMTtBUzoxOTA2NTY2NjYyMzQ4ODFAMTQyMjQ2NzQ5OTI2MA==
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6 | International Journal of Neuropsychopharmacology, 2015

Figure 5. Effects of chronic MK-801 (1 mg/kg), clozapine (CLZ; 1 mg/kg), and CBD (60 mg/kg) treatment on PV protein expression in mouse mPFCs (n = 7/group). (A) 

MK-801 induced a decrease in the number of PV-positive cells in the mPFC. CBD and clozapine attenuated PV decrease in the mPFC. The data are presented as the mean 

± SEM. *p < 0.05 vs. VEH + SAL group, #p < 0.05 vs. VEH + MK-801 group; two-way ANOVA followed by S-K-N test. (B) Photomicrographs of PV-like immunoreactivity in 

the mPFC (10X; Bar = 200 μm). CC: corpus callosum; mPFC: medial prefrontal cortex.

Figure 4. Effects of chronic MK-801 (1 mg/kg), clozapine (CLZ; 1 mg/kg), and CBD (60 mg/kg) treatment on FosB/ΔFosB protein expression in the mice mPFC (A and B) and 

NAc core (C and D). MK-801 induced a significant increase in the number of FosB/ΔFosB-positive cells in the mPFC (A) and NAc core (C). CBD and clozapine blocked FosB/

ΔFosB increase in the mPFC, but did not modify FosB/ΔFosB increase in the NAc core. Clozapine also induced an increase in the number of FosB/ΔFosB-positive cells in 

the NAc core (C). The data are presented as the mean ± SEM (n = 7/group). *p < 0.05 vs. VEH + SAL group; two-way ANOVA followed by S-K-N test. Photomicrographs of 

FosB/ΔFosB-like immunoreactivity (20X; Bar = 100 μm) in the mPFC (B) and NAc core (D).



Gomes et al. | 7

intensity are usually seen (Blumenthal, 1996; Swerdlow et al., 2003, 
2007; Yee et al., 2005; Larrauri and Schmajuk, 2006; Issy et al., 2009). 
The biological significance of this sound-parameter dependence is 
not completely understood, but the novelty or the context associ-
ated with the preceding signal (prepulse) appears to be a critical 
factor (Blumenthal and Levey, 1989; Lane et al., 1991).

The present results are consistent with previous studies show-
ing a beneficial effect of CBD on PPI deficits in schizophrenia-like 
models that employ acute drug administration (Long et al., 2006; 
Levin et al., 2014). They also indicate, however, that repeated treat-
ment with CBD is necessary to counteract the PPI deficit induced 
by chronic MK-801. Moreover, contrary to the study by Long et al. 
(2012) showing tolerance after chronic CBD treatment for the PPI 
deficits presented by transgenic mice (Nrg1 TM HET), our results 
suggest that CBD repeated treatment does not induce tolerance.

Typical antipsychotics, such as haloperidol, seem to be unable 
to reverse behavioral changes induced by NMDAR antagonists in 
rodents. Atypical antipsychotics such as clozapine, olanzapine, 
and quetiapine, on the other hand, are effective in attenuating 
those changes (Geyer et al., 2001). Accordingly, CBD attenuation 
of PPI impairment induced by repeated MK-801 administration 
was similar to that produced by clozapine. Indeed, previous stud-
ies from our group suggest that CBD exhibits a profile similar 
to atypical antipsychotic drugs. For example, it does not induce 
catalepsy (Zuardi et  al., 1991; Moreira and Guimaraes, 2005), a 
characteristic extrapyramidal motor effect induced by typi-
cal antipsychotics. Moreover, similar to clozapine, a single CBD 
administration in rats induced c-Fos protein expression, a marker 
of neuronal activation, in the NAc and mPFC, but not in the stri-
atum (Guimaraes et  al., 2004). Despite these results, no study 
had investigated the pattern of neuronal activation induced by 
repeated treatment with CBD. Moreover, even if NMDAR antago-
nists alter cell activity in several structures involved in the neuro-
biology of schizophrenia and modulation of sensorimotor gating, 
such as the PFC, hippocampus, and NAc (Duncan et al., 1998), the 
brain regions involved in the effects induced by repeated admin-
istration of these drugs are not completely known. Therefore, 
we decided to investigate FosB/ΔFosB protein expression in the 
aforementioned brain structures. Whereas c-Fos and most of the 
other Fos-related proteins are highly unstable and therefore rap-
idly disappear after the stimulus, FosB and its truncated splice 
variant ΔFosB accumulate in specific brain regions after repeated 
exposure to several stimuli (Nestler et al., 1999). Once induced, 
these proteins are stable and persist in the brain for weeks after 
the original stimulus (Nestler et al., 1999). Thus, levels of FosB/
ΔFosB may vary regionally (depending on neuronal activity in 

normal animals) and/or be markedly influenced by drug treat-
ment or neurological disorders.

We observed an increase in FosB/ΔFosB expression in the 
mPFC and NAc core of animals repeatedly treated with MK-801. 
Concomitant treatment with CBD or clozapine attenuated the 
changes induced by MK-801 in the mPFC, but not in the NAc 
core. However, even if CBD exhibits a pre-clinical and clinical 
profile similar to clozapine from a phenotypic point of view, 
the mechanisms involved could be rather distinct. This could 
help to explain some differences observed in our study. For 
example, while CBD did not change FosB/ΔFosB expression per 
se, clozapine increased this expression in the NAc core. This 
latter effect partially corroborated previous findings in the lit-
erature (Rodriguez et  al., 2001; Grande et  al., 2004). Contrary 
to other studies (Kontkanen et  al., 2002), however, clozapine 
failed to increase FosB/ΔFosB expression in the mPFC and NAc 
shell. The reasons for these differences are unknown but could 
depend on different species, treatment schedules, and doses.

The mechanisms involved in the increase of FosB/ΔFosB 
expression in the mPFC induced by MK-801 are not completely 
understood. However, increased glutamate levels after long-
term treatment with NMDAR antagonists have been described 
in this brain region (Moghaddam et al., 1997; Wang et al., 2000). 
It may depend on the blockade of a tonic inhibitory influence of 
GABAergic interneurons over excitatory projections to the mPFC 
(Moghaddam et  al., 1997; Krystal et  al., 2003; Jodo et  al., 2005), 
leading to a disinhibition of glutamate release from neurons tar-
geted by those interneurons (Olney and Farber, 1995; Adams and 
Moghaddam, 1998). NMDAR blockade, therefore, may cause overall 
cortical excitation by disinhibiting glutamatergic pyramidal neu-
rons. Indeed, neuroimaging data suggest that the schizophrenia-
like symptoms caused by NMDAR antagonists are associated with 
frontal cortical activation (Lahti et al., 1995; Breier et al., 1997).

Increased FosB/ΔFosB expression has also been associated 
with neuroplastic/adaptive changes induced by chronic stimuli 
that promote synaptic remodeling, including repeated administra-
tion of antipsychotics, stress stimuli, and reward stimuli (Atkins 
et al., 1999; Nestler et al., 1999; Lobo et al., 2013). Moreover, viral-
mediated overexpression of ΔFosB in mouse PFC induced cognitive 
deficits (Dietz et al., 2014). These results suggest that changes in 
FosB/ΔFosB expression, in addition to indicating cellular activation 
after repeated stimuli, could also have functional consequences. 
Additional studies are clearly needed to address this question.

Another potentially important finding of the present study 
was the significant reduction in PV immunoreactivity induced 
by repeated MK-801 treatment in the mPFC, an effect attenuated 

Figure 6. Effects of chronic MK-801 (1 mg/kg), clozapine (CLZ; 1 mg/kg), and CBD (60 mg/kg) treatment on mRNA expression of the NMDAR GluN1 subunit gene (GRN1) 

in the (A) frontal cortex, (B) striatum, and (C) hippocampus. The data are presented as the mean ± SEM (n = 5–7/group). *p < 0.05 vs. VEH + SAL group; Kuskal-Wallis 

followed by the Dunn test.

https://www.researchgate.net/publication/286089347_Region-specific_induction_of_DFosB_by_repeated_administration_of_typical_versus_atypical_antipsychotic_drugs?el=1_x_8&enrichId=rgreq-8b8fc97fb388a901bd6189374bdfc7ed-XXX&enrichSource=Y292ZXJQYWdlOzI3MTM4NjIwMTtBUzoxOTA2NTY2NjYyMzQ4ODFAMTQyMjQ2NzQ5OTI2MA==
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8 | International Journal of Neuropsychopharmacology, 2015

by CBD. A more robust attenuation was induced by clozapine. 
Decreased GABAergic signaling is among the most consistent 
postmortem pathological changes observed in schizophre-
nia (Reynolds et al., 2002; Lewis et al., 2005). These deficits are 
largely restricted to GABAergic PV-positive interneurons (Lewis 
et al., 2005). It has been suggested that the PV interneuron dys-
function in schizophrenia could result from a hypofunction of 
NMDAR-mediated signaling (Belforte et  al., 2010; Moreau and 
Kullmann, 2013). These neurons synapse on the cell body or 
the axon initial segment of glutamatergic neurons, where they 
regulate pyramidal cell output. Furthermore, it is likely that a 
reduction in PV interneuron functionality results not only in 
a decreased inhibitory control over pyramidal cell activity, but 
also a reduction in the coordinated activity of large brain net-
works leading, for example, to a loss of the dopaminergic neu-
rotransmission regulation (Schwartz et  al., 2012). Changes in 
PV expression in the mPFC induced by MK-801, therefore, could 
contribute to increased neuronal activity in the mPFC and NAc 
core, reflected by the increase in the number of FosB/ΔFosB-
positive cells. Importantly, a decrease in PV immunoreactivity 
appears to be associated with reduced expression of PV protein, 
but not with a reduced number of PV interneurons (Hashimoto 
et al., 2003).

A decrease in the number of PV-positive cells is also con-
sistently observed in a diverse variety of animal models of 
schizophrenia (Penschuck et  al., 2006; Harte et  al., 2007), 
including repeated treatment with other NMDAR antagonists 
(Abdul-Monim et al., 2007; Amitai et al., 2012). Repeated keta-
mine treatment decreases PV levels in GABAergic interneurons 
in vitro and in the mouse PFC (Behrens et al., 2007). mRNA lev-
els of PV gene were also reduced in the PFCs of mice (Cochran 
et al., 2003) and monkeys (Morrow et al., 2007) after repeated 
PCP administration. Similar to our findings, Amitai et al. (2012) 
observed that repeated treatment with clozapine prevented 
the cognitive deficits and reduced PV expression in the PFC 
following repeated PCP treatment. Based on these pieces of 
evidence, it is possible to speculate that the attenuation of PV 
changes and MK-801-induced PPI impairment by CBD and clo-
zapine could be related. Moreover, the decrease in PV-positive 
cells was restricted to the mPFC. Since this region is thought to 
modulate, rather than mediate, PPI (Swerdlow et al., 2001), this 
result suggests that CBD effects depend on changes in modula-
tory PPI processes.

Even if changes in mRNA expression are difficult to interpret 
in the absence of information on the levels of the correspond-
ing protein, our results suggest that chronic blockade of NMDAR 
decreases mRNA expression of the NMDAR obligatory GluN1 
subunit. Changes in mRNA expression of the GluN1 subunit 
gene have already been reported in the post mortem brains of 
schizophrenia patients (Gao et al., 2000; Law and Deakin, 2001; 
Weickert et al., 2013). Few studies, however, have investigated the 
effects of repeated treatment with NMDAR antagonists on these 
changes. In our study, repeated MK-801 treatment decreased 
GluN1 mRNA expression in the hippocampus, but not in the 
frontal cortex and striatum, an effect that was also attenuated 
by CBD and clozapine. Even if contradictory results exist in the 
literature (Rujescu et al., 2006), reduction in mRNA expression 
of this subunit in the hippocampus of schizophrenia patients 
has been reported (Gao et al., 2000; Law and Deakin, 2001). In 
addition, a study using a single photon emission tomography 
ligand for NMDAR revealed that medication-free schizophrenia 
patients had lower NMDAR binding in the left hippocampus, 
a change not observed in clozapine-treated patients (Pilowsky 
et al., 2006).

In conclusion, the present results indicate specific behavio-
ral and molecular changes induced by chronic administration 
of the NMDAR antagonist MK-801. Repeated CBD treatment, 
similar to the atypical antipsychotic clozapine, reversed or 
attenuated MK-801-induced behavioral psychotomimetic-like 
effects and the associated molecular changes. These results are 
consistent with the proposal that CBD may have antipsychotic 
properties.

Supplementary Material

For supplementary material accompanying this paper, visit 
http://www.ijnp.oxfordjournals.org/

Acknowledgments

The authors thank José Carlos de Aguiar and Celia A. da Silva for 
technical assistance. FVG has a FAPESP fellowship (2010/17343-0). 
Research was supported by grants from FAPESP and CNPq.

Statement of Interest

The authors declare no conflicts of interest.

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