ORIgINAl PAPERS - Advances in Clinical and Experimental Medicine

ORIgINAl PAPERS - Advances in Clinical and Experimental Medicine

OrIginal papers
Adv Clin Exp Med 2011, 20, 5, 559–565
ISSN 1230-025X
© Copyright by Wroclaw Medical University
Jalal Solati1, Abbas Ahmadi2, Ali-Akbar Salari3
The Effects of a New Derivative of Phencyclidine
on Anxiety- and Depression-Like Behaviors in Mice
Wpływ nowej pochodnej fencyklidyny na występowanie
objawów lęku i depresji u myszy
Department of Biology, Islamic Azad University, Karaj Branch, Karaj, Iran
Departments of Chemistry, Islamic Azad University, Karaj Branch, Karaj, Iran
3
Young Researchers Club, Islamic Azad University, Karaj Branch, Karaj, Iran
1
2
Abstract
Objectives. Phencyclidine and its derivatives display analgesic, stimulant, anticonvulsant effects in animals, due
to specific binding sites in the brain. The present study investigated the effects of phencyclidine (PCP) and a new
derivative of it (PND) on anxiety- and depression-like behaviors in animal models.
Material and Methods. Phencyclidine and it’s new derivative (PND) were synthesized and administered intraperitoneally to adult male NMRI mice in doses of 1, 5 and 10 mg/kg. The elevated plus maze (EPM) and forced
swimming test (FST), which are useful models for the selective identification of anxiolytic and antidepressant-like
effects of drugs, were used in the study.
Results. The results of the study demonstrated that intraperitoneal administration of PND (5 and 10 mg/kg) significantly increased the percentage of open-arm time (OAT %) and the percentage of open-arm entries (OAE %) in the
elevated plus maze in comparison with PCP-treated mice and the saline-treated control group; at those doses PND
also significantly decreased immobility times in the forced swimming test in comparison with the control group.
However, the PCP-treated group showed less immobility time in the FST in comparison with the PND group.
Conclusions. It seems that intraperitoneal injection of this new derivative of phencyclidine was more effective
than phencyclidine and than saline in modulating anxiety, but not in modulating depression-like behaviors in mice
(Adv Clin Exp Med 2011, 20, 5, 559–565).
Key words: phencyclidine, new derivative of phencyclidine, anxiety, depression, NMDA.
Streszczenie
Cel pracy. Fencyklidyna i jej pochodne wykazują działanie przeciwbólowe, pobudzające i przeciwdrgawkowe
u zwierząt, z uwagi na specyficzne miejsca wiązania w mózgu. W niniejszym opracowaniu badano wpływ fencyklidyny (PCP) i jej nowej pochodnej (PND) na zachowania lękowo-depresyjne na modelach zwierzęcych.
Materiał i metody. Fencyklidyna i jej nowa pochodna (PND) zostały zsyntetyzowane i podane dootrzewnowo dorosłym samcom myszy NMRI w dawkach 1, 5 i 10 mg/kg. W badaniu wykorzystano uniesiony labirynt
krzyżowy (EPM) i test wymuszonego pływania (FST), które są przydatnym modelami do selektywnej identyfikacji
przeciwlękowego i przeciwdepresyjnego działania leków.
Wyniki. Badanie wykazało, że dootrzewnowe podanie PND (5 i 10 mg/kg) znacznie zwiększyło czas przebywania
na otwartych ramionach krzyża (% OAT) oraz liczbę wejść na otwarte ramiona krzyża (% OAE) w teście uniesionego labiryntu krzyżowego w porównaniu z myszami, którym podawano PCP i sól fizjologiczną (grupa kontrolna);
w tych dawkach PND znacznie skróciła czas bezruchu w teście wymuszonego pływania w porównaniu z grupą
kontrolną. Jednak myszy, którym podawano PCP miały krótszy czas bezruchu w FST w porównaniu z myszami,
którym podawano PND.
Wnioski. Wydaje się, że dootrzewnowe podanie nowej pochodnej fencyklidyny było bardziej skuteczne niż podanie
fencyklidyny i soli w modulowaniu niepokoju, ale nie w modulowaniu zachowań depresyjnych u myszy (Adv Clin
Exp Med 2011, 20, 5, 559–565).
Słowa kluczowe: fencyklidyna, nowe pochodne fencyklidyny, niepokój, depresja, NMDA.
560
Glutamate is the major excitatory neurotransmitter in the central nervous system (CNS) of
mammals, and exerts its actions via two main
types of receptors: ionotropic receptors, which are
ligand-gated ion channel receptors that mediate
fast responses, and metabotropic receptors, which
are G protein-coupled and mediate slower modulatory responses [1, 2]. Three classes of ionotropic
glutamate receptors are distinguished: N-MethylD-aspartate (NMDA), α-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid (AMPA) and
Kainate [3]
Several studies have shown that as a result of
specific binding sites in the brain [4], phencyclidine
– 1-(1-phenylcyclohexyl)piperidine, CAS 956-901 (PCP, I ) – and its derivatives display anxiolytic
[5], analgesic [6], stimulant [7], anticonvulsant [8]
and behavioral effects [9], which are mediated by
various receptors. Several previous studies have
identified PCP as a non-competitive antagonist
of the NMDA receptor [10]. PCP and other PCP-like NMDA receptor antagonists have been shown
to produce anxiolytic effects [5, 11], and, studies
have been shown the antidepressant-like effects
of various NMDA receptors antagonists in animal models [3, 12, 13] There are at least three sites
where antagonists might block NMDA activation:
the NMDA site, the strychnine-insensitive glycine
site, and the PCP site [13, 14].
The aim of the present study was to examine
the anxiolytic and antidepressant effects of a new
derivative of phencyclidine derivative of phencyclidine – 1-(1-[2-ethylphenyl][cyclohexyl])-3-piperidinol (PND) on the elevated plus maze (EPM)
and forced swimming test (FST). The first experiment focussed on the effects of PND on the EPM
model of anxiety, and in the second experiment,
the effects of PND on the FST model of depression
were investigated. The results are compared to the
effects of PCP and to the control group.
Material and Methods
The Animals
Adult male NMRI mice from the Pasteur Institute of Iran (Tehran, Iran), weighing 30–40 g,
were housed in individual polycarbonate cages
with a controlled temperature of 24 ± 2°C and
a 12:12 h light/dark cycle (lights on at 7:30); they
had free access to food and water ad libitum, and
were allowed to adapt to the laboratory conditions
for at least one week before the tests. Seven animals
were used in each experiment. The experimental
procedures followed the National Institutes of
Health (NIH) Guide for the Care and Use of Labo-
J. Solati, A. Ahmadi, A.-A. Salari
ratory Animals and the guidelines of the Research
Council of the Department of Biology at the Karaj
branch of Islamic Azad University.
The Elevated Plus Maze (EPM)
The EPM is a plus-shaped wooden apparatus
that elevated to a height of 50 cm and consisted of
a central platform (5 cm × 5 cm); two open arms
(30 cm × 5 cm) and two enclosed arms (30 cm
× 5 cm × 15 cm) opposite to each other with an
open roof [15]. For doing anxiety test the EPM
was placed in the center of a quiet dimly-lit room
and behaviors of animals in the maze were recorded by a “blind” observer with a chronometer
who sat quietly one meter behind one of the closed
arms of the maze. Individual mice were placed in
the center of the plus maze, facing one of the open
arms, 30 minutes after their respective drug treatments. Following behaviors were measured for
each animal: (1) the amount of time spent in the
open arms, (2) the amount of time spent in the
closed arms, (3) the number of entries into the
open arms and (4) the number of entries into the
closed arms during the five-minute test period.
The maze was cleaned with distilled water after
each test and an entry was defined as entrance of
all four paws in the arm.
In order to calculate the OAT% and OAE%,
open-arm activity was quantified as the amount of
time that the animal spent in the open arms relative to the total amount of time spent in any arm
(open/total × 100), and the number of entries into
the open arms was quantified relative to the total
number of entries into any arm (open/total × 100)
[15–17]. Locomotor activity was considered as the
total number of closed-arm entries plus the total of
open-arm entries [18, 19].
The Forced Swimming
Test (FST)
The FST is among the most commonly used
tools for assessing antidepressants. The mice were
individually placed in transparent glass cylinders,
25 cm tall and 10 cm in diameter, filled with water
to a depth of 15 cm. The water was maintained at
a temperature of 25 ± 1°C and was replaced between individual tests. The total duration of immobility was recorded during the last four minutes of the six-minute test period. A mouse was
considered immobile when it stopped struggling
in the water and floated motionless except for the
movements necessary to keep its head above the
surface. Shorter periods of immobility are indicative of antidepressant-like effects [20].
561
Behavioral Effects of PCP and Its Derivative
Drug Synthesis
and Administration
Experiments 3 and 4
Preparations (Diagram 1)
1-(1-phenylcyclohexyl)piperidine (PCP, I)
This compound was prepared according to
Maddox et al. 1965 [21], from 1-piperidinocyclohexanecarbonitrile and phenyl magnesium bromide. The hydrochloride salt of I was prepared
using 2-propanol and HCl and was recrystallized
from 2-propanol [21].
1-[1-(2-methylphenyl)(cyclohexyl)]-3-piperidinol (PND, II)
This compound was prepared from nitrile
compound and 2-tolyl magnesium bromide (Grignard reagent) according to a published method.
The hydrochloride salt of it was prepared using
2-propanol and HCl and was recrystallized from
2-propanol in accordance with a method published
by Ahmadi et al [22].
The drugs were dissolved in sterile saline and
administered intraperitoneally (IP) 30 minutes before the test. All injections were performed with
a 1 ml insulin needle at a volume of 50 µl. The control animals received an IP injection of saline.
The Experimental Procedure
Experiment 1 – the Effect of PCP
on Anxiety-Like Behavior
Four groups of mice were used to evaluate the
effects of PCP on anxiety. The first group received
an IP injection of saline and the other three
groups received IP injections of PCP at doses of
1, 5 and 10 mg/kg. Each group then went through
the EPM as described above.
Experiment 2 – the Effect of PCP
on Depression-Like Behavior
In comparison with a saline control group,
three groups of mice received IP injections of PCP
(1, 5 and 10 mg/kg). Each group was then submitted to the FST as described above.
C H3
N
N
OH
P C P (I)
P D (II)
The structure of PCP (I) and PND (II)
Experiments 3 and 4 focussed on the effect of
PND on anxiety-like behavior and on depressionlike behavior by following the same procedures as
Experiments 1 and 2, but with PND at doses of 1,
5 and 10 mg/kg instead of PCP.
Statistical Analysis
Since data displayed normal distribution and homogeneity of variance, a one-way ANOVA was used
to compare the effects of different doses of drugs with
the saline control. In the case of significant differences, Tukey’s and Dunnett’s post hoc analyses were performed to assess specific group comparisons. Differences between experimental groups with p < 0.05 at
each point were considered statistically significant.
Results
The Effect of PCP
on Anxiety-Like Behavior
Figure 1 shows the effect of IP injections of
the different doses of PCP (1, 5 and 10 mg/kg) on
anxiety-like parameters in the EPM test. The one-way ANOVA showed an increase in OAT % [F (3,
24) = 5.267, p < 0.05] at the dose of 5 mg/kg and in
OAE % [F (3, 24) = 6.221, p < 0.05] at the doses of
1mg and 5mg, but no significant change was observed in locomotor activity [F (3, 24) = 1.121, p >
>0.05], indicating a low anxiolytic-like effect following IP administration of PCP to the mice.
The Effect of PCP on
Depression-Like Behavior
The effect of IP injections of PCP on the total
duration of immobility in the FST test is shown in
Fig. 2. The one-way ANOVA showed that at the
doses of 5 and 10 mg/kg, PCP induced a significant
reduction in the immobility time in comparison
with the control group [F (3, 24) = 9.132, p < 0.05];
but this was not observed at the 1 mg/kg dosage.
The Effect of PND
on Anxiety-Like Behavior
Figure 3 shows the effect of IP injections of
the different doses of PND (1, 5 and 10 mg/kg) on
anxiety-like parameters in the EPM test. Dosages of
5 and 10 mg/kg increased OAT % [F (3, 24) = 7.552, p
< 0.05] and OAE % [F (3, 24) = 6.633, p < 0.05], indicating an anxiolytic response to PND in comparison
with the control group. No significant changes were
observed in locomotor activity [F (3, 24) = 1.052, p >
562
J. Solati, A. Ahmadi, A.-A. Salari
Fig. 2. The effect of PCP (1, 5 and 10 mg/kg/50 µl,
IP) on depression-like behavior in the FST. Data are
expressed as means ± SEM (n = 7 mice per group).
Significant differences: ***p < 0.001 compared to the
saline-treated control group
Ryc. 2. Wpływ PCP (1, 5 i 10 mg/kg/50 uL, IP) na
zachowania depresyjne w FST. Dane wyrażono jako
średnie ± SEM (n = 7 myszy na grupę). Istotne różnice:
*** p < 0,001 w porównaniu z grupą kontrolną, której
podawano sól fizjologiczną
The Effect of PND on
Depression-Like Behavior
As shown in Figure 4, a significant decrease
in the immobility time in the FST was observed in
animals that received PND at dosages of 5 and 10
mg/kg when compared to the control group [F (3,
24) = 4.503, p < 0.05], showing antidepressant effects in mice
Fig. 1. The effect of different doses of PCP (1, 5 and
10 mg/kg/50 µl, IP) on anxiety-like behavior in the
EPM. The test was performed 30 min after injection.
Each bar represents means ± SEM (n = 7 mice per
group) of a) Open Arm Time %, b) Open Arm Entries
% and c) locomotor activity. Significant differences:
*p < 0.05 compared to the saline-treated control group
Ryc. 1. Wpływ różnych dawek PCP (1, 5 i 10 mg/
/kg/50 uL, IP) na zachowania lękowe w EPM. Test
przeprowadzono 30 min po wstrzyknięciu. Każdy słupek oznacza średnią ± SEM (n = 7 myszy w grupie)
z a) czas spędzony na ramionach otwartych krzyża,
b) wejścia na ramiona otwarte krzyża i c) aktywność
ruchowa. Istotne różnice: * p < 0,05 w porównaniu
z grupą kontrolną, której podawano sól fizjologiczną
0.05]. Moreover, the one-way ANOVA revealed that
at the doses of 5 and 10 mg/kg, PND significantly
decreased the levels of anxiety-related behaviors in
comparison with the PCP group: OAT % [F (3,
24) = 6.005, p < 0.05] and OAE % [F (3, 24) = 7.493,
p < 0.05], which means that the new derivative of
phencyclidine has more impact than phencyclidine
in reducing anxiety-like behavior.
Discussion
This study sought to determine whether PND
– a new derivative of PCP – is involved in reducing anxiety and/or depression-like behaviors. The
present findings indicate that both PCP and PND
are associated with reductions in anxiety and depression-like behaviors in animal models. The data
obtained indicate that IP administration of PCP
and PND increases OAT% and OAE%, but not locomotive activity, indicating that these chemicals
have an anxiolytic-like effect. Moreover, different
doses of PCP and PND significantly reduced the
immobility time in the FST, indicating antidepressant-like effects.
These findings indicate that PCP and its analog
induce their anxiolytic and antidepressant-like effects primarily by acting as NMDA receptor antagonists, blocking the activity of the NMDA receptor
[23, 24]. There is clinical evidence implicating the
NMDA receptor in various neurological disorders
[25]. The anxiolytic and antidepressant-like effects
of various antagonists of NMDA receptors have
been reported in numerous studies, and NMDA
Behavioral Effects of PCP and Its Derivative
563
Fig. 4. The effect of PND (1, 5 and 10 mg/kg/50 µl,
IP) on depression-like behavior in the FST. Data are
expressed as means ± SEM (n = 7 mice per group).
Significant differences: *p < 0.05 compared to the control group
Ryc. 4. Wpływ PND (1, 5 i 10 mg/kg/50 uL, IP) na
zachowania depresyjne w FST. Dane wyrażono jako
średnie ± SEM (n = 7 myszy na grupę). Istotne różnice:
* p < 0,05 w porównaniu z grupą kontrolną
Fig. 3. The effect of different doses of PND (1, 5 and 10
mg/kg/50 µl, IP) on anxiety-like behavior in the EPM.
The test was performed 30 min after injection. Each
bar represents means ± SEM (n = 7 mice per group) of
(a) Open Arm Time %, (b) Open Arm Entries % and
(c) locomotor activity. Significant differences: **p <
< 0.01 and ***p < 0.001 compared to the control group
Ryc. 3. Wpływ różnych dawek PND (1, 5 i 10 mg/
kg/50 uL, IP) na zachowania lękowe w EPM. Test
przeprowadzono 30 min po wstrzyknięciu. Każdy
słupek oznacza średnią ± SEM (n = 7 myszy w grupie)
z a) czas spędzony na ramionach otwartych krzyża,
b) wejścia na ramiona otwarte krzyża i c) aktywność
ruchowa. Istotne różnice: ** p < 0,01
i *** p < 0,001 w porównaniu z grupą kontrolną
receptor dysfunction appears to have a major role
in neurobiological disorders such as anxiety and
depression [3, 25–28]. Ketamine is an NMDA receptor antagonist and a derivative of PCP involved
in the modulation of emotional behaviors; its primary mechanism is blocking the NMDA receptor
at the PCP site within the ionotropic channel [29].
It has been shown that administering ketamine and
related NMDA antagonists has anxiolytic and anti-
depressant-like effects in animal models of anxiety
and depression, as well as in humans [29, 30].
PCP analogs have been shown to inhibit nicotinic acetylcholine receptor channels (nAChR) in
rats [31, 32]. Recent studies have also shown that
PCP has direct effects on serotonin (5-HT) receptors and that extracellular 5-HT levels in the brain
elevated by systemic administration of PCP [33,
34]. The serotonergic and nicotinic cholinergic
systems have been extensively implicated in an array of behavioral and physiological functions, including the control of anxiety and depression-like
behaviors [19, 35]. Therefore it seems that all of
the NMDA glutamatergic system, nicotinic acetylcholine receptors and serotonin (5-HT) receptors
could have a role in modulating the anxiolytic and
antidepressant effects of phencyclidine and its derivatives.
The results of the current study showed that
PND is more effective than PCP in the reduction
of anxiety-related behavior. The new PCP derivative administered in this study involved substitutions on the phenyl and piperidine rings that
increased its electron-donating and changed its
hydrophilic and polarity propertiesthat result in
enhanced pharmacological activity [22, 36, 37].
It seems that the strong electron-donating properties of the methyl group on the phenyl ring, as
well as the hydrophilic and polar properties of the
hydroxyl group on the piperidine ring of the PND
molecule, facilitate and alter interactions with
receptors. However, because of undesirable reactions with cationic intermediates, minor decreases
in receptor binding could be anticipated. On the
other hand, it is possible that structural changes in
564
J. Solati, A. Ahmadi, A.-A. Salari
PCP during the preparation of PND may affect the
interaction of the new derivative with the NMDA
receptor, or shift the affinity of the new derivative
to receptors like 5-HT or nAChR, whose role in
controlling anxiety and depression is well known.
The authors concluded that the results of the
present study indicate that IP injection of PND,
a new PCP derivative, produce a significant anxiolytic-like effect in comparison to PCP, while its effect on
depression-like behavior is less than that of PCP.
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Address for correspondence:
Jalal Solati
Department of Biology
Islamic Azad University, Karaj Branch
P.O. Box. 31485-313,
Iran, Karaj
Tel.: +98 261 443 6978
E-mail: [email protected]
Conflict of interest: None declared
Received: 6.01.2011
Revised: 23.02.2011
Accepted: 5.10.2011