Short communication
Influence of the phosphodiesterase type 5inhibitor, sildenafil, on antidepressant-likeactivity of magnesium in the forced swim testin mice
Katarzyna Soca³a1, Dorota Nieoczym1, Ewa Poleszak2, Piotr WlaŸ1
Department of Animal Physiology, Institute of Biology and Biochemistry, Maria Curie-Sk³odowska University,Akademicka 19,PL 20-033 Lublin, Poland
Chair and Department of Applied Pharmacy, Medical University of Lublin, ChodŸki 1, PL 20-093 Lublin, Poland
Correspondence: Piotr WlaŸ, e-mail: [email protected] Abstract: Magnesium, which acts as an antagonist of N-methyl-D-aspartate (NMDA) subtype of glutamate receptors, exerts antidepressant- like activity in animal models of depression. The present study was undertaken to elucidate the influence of sildenafil, a phosphodi- esterase type 5 inhibitor, on the anti-immobility action of magnesium in the forced swim test in mice. Swim sessions were conducted by placing mice in glass cylinders filled with water for 6 min and the duration of the behavioral immobility during the last 4 min of the test was evaluated. Locomotor activity was measured with photoresistor actimeters. Serum and brain magnesium levels were as- sayed spectrophotometrically. Magnesium at a dose of 30 mg/kg, ip significantly decreased the immobility time while sildenafil (5, 10 and 20 mg/kg, ip) in a dose-dependent manner reduced the antidepressant-like activity of magnesium. The co-administration of magnesium with sildenafil at the highest dose entirely abolished the antidepressant-like effect of magnesium and caused a statisti- cally significant increase in immobility duration as compared to the control group. Combination of magnesium with sildenafil re- sulted in a potent reduction (80%) of locomotor activity and pharmacokinetic studies showed a significant increase of magnesium concentration in serum (as compared to magnesium treatment alone) without changes within brain tissue in mice treated with mag- nesium and sildenafil. When given alone, sildenafil caused a significant increase in magnesium levels in both serum and brain. Our results indicate that a simultaneous treatment with magnesium and sildenafil results in hypermagnesemia in laboratory animals. However, the mechanism underlying this effect remains elusive. Key words: phosphodiesterase 5, sildenafil, magnesium, depression, erectile dysfunction, antidepressant, forced swim test, mice Introduction
PDE5) cell signaling pathway [6]. During sexual
Sildenafil, an active compound of Viagra, is the first-
stimulation, corpus cavernosum nerves and endothe-
line oral treatment for erectile dysfunction of multiple
lial cells release NO, which via guanylate cyclase ac-
etiologies. The mechanism of action of sildenafil in-
tivation promotes cyclic guanosine 3´,5´-monopho-
volves the nitric oxide/cyclic guanosine 3´,5´-mono-
sphate (cGMP) production. Cyclic GMP, in turn, al-
Pharmacological Reports, 2012, 64, 205211
lows corporal smooth muscle cells relaxation and
zures [2, 14]. Magnesium deficiency is quite com-
leads to an erection. The intracellular level of cGMP
mon. In general population, hypomagnesemia is
is regulated by PDE5 – an enzyme which hydrolyzes
estimated at 6.9% but it varies greatly depending on
cyclic nucleotides. Sildenafil works as a selective in-
patients’ general condition [14]. Numerous magne-
hibitor of PDE5. By inhibiting cGMP degradation, it
sium dietary supplements are available on the market
improves the relaxation of smooth muscles in the cor-
and magnesium supplementation is an important issue
pus cavernosum and thus resulting in erection [16,
in contemporary medicine. Moreover, it is one of the
44]. Sildenafil exerts various effects on the central
new emerging approaches in the treatment of depres-
nervous system. The recent data show that it pos-
sesses neuroprotective properties, enhances neuro-
Since both magnesium and sildenafil may alter glu-
tamatergic neurotransmission and magnesium supple-
The NO/cGMP pathway has also been implicated
mentation is of high probability in men taking silde-
in the neurobiology of depression. A number of ex-
nafil, the aim of the present study was to investigate
periments indicate that inhibitors of this pathway ex-
the effect of sildenafil on the antidepressant-like ac-
hibit antidepressant effects and enhance the efficacy
tivity of magnesium in the forced swim test in mice.
of serotonin reuptake inhibitors [17, 18, 20]. Nitric
In order to evaluate the potential pharmacokinetic in-
oxide plays an extremely important role in the central
teractions between sildenafil and magnesium, total
nervous system where it acts as a neuronal messenger.
brain and serum concentrations of magnesium were
It is involved in neurotransmission, synaptic plastic-
ity, perception of pain and learning [12]. The NO/cGMP pathway affects i.a., excitatory neurotransmis-sion mediated through the N-methyl-D-aspartate(NMDA) subtype of glutamate receptors [42]. Inter-
Materials and Methods
actions between NO/cGMP pathway and glutamater-gic neurotransmission are bidirectional. On the onehand, stimulation of NMDA receptor results in Ca2+
influx which leads to NO synthase activation and NOproduction. On the other hand, NO and cGMP modu-
The experiments were carried out on male Albino
late NMDA receptor activity and may regulate release
Swiss mice weighing 25–30 g, purchased from a li-
of glutamate by negative feedback mechanisms [18,
29, 42]. There is an increasing evidence for the in-
S³aboszów, Poland). The animals were housed in
volvement of NMDA-mediated neurotransmission in
groups of up to 10 mice in polycarbonate cages under
pathophysiology of depression and antidepressant-
standard laboratory conditions (temperature main-
like activity of NMDA receptor antagonists in animal
tained at 23–25°C, humidity 50–60% and 12 h
studies [19, 32, 33, 45]. Magnesium, which blocks the
light/dark cycle, lights on at 06:00 h) with free access
NMDA receptor channel in a voltage-dependent fash-
to food pellets (Murigran, Agropol S.J., Motycz, Po-
ion, also exhibits antidepressant activity in animal
land) and tap water. All experiments were performed
studies and clinical trials [7, 38, 40]. It is also active
following at least 7 days of acclimatization. The ex-
in an animal model of mania [1]. This second most
perimental protocols were approved by the Ethical
abundant intracellular cation plays a fundamental role
Committee of the Medical University in Lublin
in innumerable regulatory processes. It participates in
(license number 69/2009) and all procedures were in
over 325 different enzymatic reactions such as hy-
accordance with the European Communities Council
drolysis of high-energy phosphate groups or nucleic
Directive of 24 November 1986 (86/609/EEC).
acid and protein synthesis. It regulates conductivity ofion channels and is involved in hormone receptor
binding, muscle contraction and neurotransmitters re-lease [11, 13]. Therefore, magnesium depletion brings
Magnesium hydroaspartate (Farmapol, Poznañ, Poland)
about dramatic clinical implications ranging from hy-
and sildenafil citrate (Polpharma, Starogard Gdañski,
pertension, arrhythmias and neuromuscular hyperex-
Poland) were dissolved in saline and administered
citability to acute myocardial infarction or even sei-
intraperitoneally (ip) at a volume of 10 ml/kg, 30 min
Pharmacological Reports, 2012, 64, 205211
Sildenafil and antidepressant-like activity of magnesium
before the respective test. The dosage of magnesium
able reagent (Liquick Cor-Mg, Cormay, Lublin, Po-
refers to pure magnesium ions. Control animals re-
land) and reaction mixture absorbance was measured
ceived an ip injection of saline. The doses and pre-
at 520 nm employing a spectrophotometer (Hitachi
treatment schedules were selected on the basis of
U-3010, Tokyo, Japan). The magnesium concentra-
those reported in the literature and previous experi-
tions were expressed in mg/100 ml for serum and µg/g
ments from our laboratory [29–31, 35–38]. Forced swim test Statistical analysis
The test was conducted according to the method de-
All results are presented as the means ± standard error
scribed by Porsolt et al. [41]. Mice were placed indi-
of the mean (SEM) and evaluated by using one-way
vidually in glass cylinders (height 25 cm, diameter
analysis of variance (ANOVA) followed by Student-
10 cm). The cylinders contained 10 cm of water main-
Newman-Keuls post-hoc test for multiple comparison
tained at 23–25°C. Animals were allowed to swim for
or by unpaired Student’s t-test, where appropriate. A p
6 min. Total duration of immobility was recorded dur-
value less than or equal to 0.05 was considered to be
ing the last 4 min of the test. The duration of immobil-
ity was defined as the time when the mouse remainedfloating passively, made no attempts to escape andshowed only slow movements to keep its head abovethe water. Locomotor activity Forced swim test
Locomotor activity of mice was determined by using
The effect of magnesium, alone and in combination
actimeters (30 cm diameter, 12 cm high, MultiServ,
with sildenafil, on immobility time in the forced swim
Lublin, Poland) equipped with two perpendicular in-
test in mice is shown in Figure 1 (one-way ANOVA:
frared light beams located 1.5 cm above the floor.
F (4, 51) = 35.080; p < 0.001). Magnesium at a dose
Mice were placed individually in an actimeter for
of 30 mg/kg significantly decreased immobility time
5 min. After acclimatization, locomotor activity was
from 193.80 ± 4.38 s in the control group to 132.00
recorded as the number of interruptions of light beams
± 5.69 s (p < 0.001). Sildenafil in a dose-dependent
Determination of serum and brain magnesium concentration
After drug pretreatment, mice were sacrificed by de-capitation and the trunk blood was collected in poly-ethylene tubes. Serum was isolated 1 h after blood co-agulation by centrifugation at 5,000 × g for 10 min at4°C and frozen at –30°C. The brains were rapidly re-moved after decapitation, washed in saline and ho-mogenized (PRP 200, PRO Scientific Inc., Connecti-cut, USA) in 0.1 M phosphate buffered saline (pH7.4) at 26,000 rpm for 3 min at 4°C. The homogenateswere centrifuged at 21,000 × g for 30 min at 4°C andthe supernatant was frozen at –30°C. Fig. 1. The effect of sildenafil on the antidepressant-like activity of
Total magnesium concentration in serum and brain
magnesium in the forced swim test in mice. Magnesium and sildenafilwere administered ip 30 min before the test. Each experimental
homogenates was determined by using xylidyl blue
group consisted of 10–12 animals. Data are presented as the means
method. Ten microliters of thawed serum or brain su-
± SEM. ** p < 0.01, *** p < 0.001 vs. saline-treated group; p < 0.05,
p < 0.001 vs. magnesium-treated group (one-way ANOVA with
pernatant was mixed with 1 ml of commercially avail-
Student-Newman-Keuls post-hoc test)
Pharmacological Reports, 2012, 64, 205211
manner reduced the antidepressant-like activity of
mice is shown in Table 1 (one-way ANOVA: F (5, 53)
magnesium. The combination of magnesium with
= 7.710; p < 0.001). Sildenafil, at any dose tested, as
sildenafil at the highest dose of 20 mg/kg entirely
well as magnesium administered alone did not affect
abolished the antidepressant-like effect of magnesium
locomotor activity in mice. The combined administra-
and caused a statistically significant increase in total
tion of magnesium with sildenafil at the highest dose
duration of immobility as compared to saline-treated
of 20 mg/kg significantly reduced the activity counts
(p < 0.001 vs. the control group and magnesium-treated group). Locomotor activity Effect of sildenafil on serum and brain
The effect of sildenafil and combined administration
magnesium concentration
of sildenafil and magnesium on locomotor activity in
The effects of combined administration of magnesiumand sildenafil on serum (one-way ANOVA: F (2, 30)
Tab. 1. Effect of sildenafil and magnesium administered separately
= 118.92; p < 0.001) and brain (one-way ANOVA:
or jointly on spontaneous locomotor activity in mice
F (2, 30) = 4.169; p = 0.025) magnesium concentra-tions in mice are shown in Table 2. The administration
of magnesium at a dose of 30 mg/kg significantly in-
creased the concentration of magnesium in serum
(p < 0.001) as well as in the brain (p < 0.05) as com-pared to saline-treated group. Co-administration of
magnesium with sildenafil (20 mg/kg) caused an
additional increase in serum magnesium levels with
no effect on magnesium concentration within the
Magnesium (30 mg/kg) + sildenafil (20 mg/kg)
brain (p < 0.001 and p > 0.05 as compared to magne-sium-treated group, respectively).
Magnesium and sildenafil were administered ip 30 min before thetest. Each experimental group consisted of 9–10 animals. Data are
The influence of sildenafil administered alone on
presented as the means ± SEM. = p < 0.001 vs. saline-treated group;
serum (t-test p < 0.001) and brain (t-test p < 0.001)
> p < 0.001 vs. magnesium-treated group (one-way ANOVA withStudent-Newman-Keuls post-hoc test)
magnesium level is shown in Table 2. Sildenafilcaused a statistically significant increase in magne-sium concentrations in both serum and brain. Tab. 2. Effect of magnesium and sildenafil administered separately or jointly on serum and brain magnesium concentrations in mice Discussion
In recent years, there has been an increased interest in
A. Saline + saline
the involvement of magnesium in the pathophysiology
and treatment of depression. Magnesium deficiency isbelieved to contribute to mood disorders in spite of the
fact that blood tests of depressed patients provide fre-quently contradictory results. Serum/plasma levels of
B. Saline
magnesium ions in depressives may be elevated, de-
creased or may remain unchanged [10, 11, 24]. Nu-merous studies indicate that magnesium possesses po-
Magnesium and sildenafil were administered ip 30 min before de-
tent antidepressant-like properties in the forced swim
capitation. Each experimental group consisted of 9–12 animals. Data are presented as the means ± SEM. A: = p < 0.05, > p < 0.001 vs.
test in rodents and anxiolytic-like activity in the ele-
saline-treated group; ? p < 0.001 vs. magnesium-treated group
vated plus maze test in mice. In addition, the anti-
(one-way ANOVA with Student-Newman-Keuls post-hoc test). B: = p < 0.01, > p < 0.001 vs. saline-treated group (Student’s t-test)
immobility action of imipramine, citalopram and tia-
Pharmacological Reports, 2012, 64, 205211
Sildenafil and antidepressant-like activity of magnesium
neptine as well as of NMDA receptor antagonists and
Magnesium also activates the activity of guanylate
glycine* receptor ligands is enhanced by joint admini-
cyclase which promotes cGMP formation [34]. Per-
stration of magnesium [7, 36, 37, 40]. Apart from data
haps the influence of sildenafil and magnesium, ad-
obtained in animal studies, magnesium supplementa-
ministered alone, on the GABAergic neurotransmis-
tion was reported to be effective in the treatment of
sion was too weak to impair locomotor activity in
major depressive disorder [10], rapid cycling bipolar
mice and only when administered jointly they cause
affective disorder [5] and mania [21]. The antidepres-
noticeable behavioral response. Data from pharma-
sant- and anxiolytic-like effects of magnesium are
cokinetic studies revealed, nevertheless, that a distinct
most likely related to its antagonist properties to the
mechanism could be responsible for the reduction of
spontaneous locomotor activity in mice after com-
The present study demonstrates that the anti-
bined treatment with sildenafil and magnesium. Co-
immobility action of magnesium in the forced swim
administration of these two substances resulted in
test in mice was reduced by sildenafil in a dose-
a significant increase in magnesium serum level (by
dependent manner. Interestingly, sildenafil, at the
78%), as compared with magnesium treatment alone,
highest dose used, not only entirely abolished the
without changes within brain tissue. Magnesium
magnesium-induced antidepressant effect but also
overload occurs rarely, mainly because of excessive
prolonged the duration of immobility as compared to
intake of magnesium or failure of its excretion. Hy-
the control group. These results could imply that com-
permagnesemia is manifested by hypotension, brady-
bined administration of magnesium and sildenafil
cardia, hyporeflexia, neuromuscular hypoexcitability
leads to depressogenic effects. As the combination of
and sedation [9, 46, 47]. Clinical symptoms of mag-
magnesium with sildenafil resulted in a potent reduc-
nesium overload may mimic central anesthetic effect.
tion (80%) of the locomotor activity, changes in the
But in fact, they are due to the peripheral action of
general motor function may have interfered with data
magnesium [9]. The brain magnesium concentration
is tightly regulated and the blood-brain barrier pro-
Locomotion and exploratory behavior are regulated
tects against acute changes in the magnesium concen-
and mediated by various types of neurotransmitter
tration. An acute increase in plasma magnesium con-
systems, in particular mesolimbic dopaminergic path-
centration is usually not associated with an increase in
ways [3, 8, 25, 27]. Sildenafil, which acts through the
brain intracellular magnesium concentration [11, 15,
NO/cGMP/PDE5 pathway, may affect both excitatory
40]. In most animals, serum magnesium level reaches
and inhibitory neurotransmission [42]. Likewise,
1.8–2.7 mg/100 ml and sedation becomes evident at
magnesium is involved in signal transmission within
serum magnesium level of 4–5 mg/100 ml [28]. It
the central nervous system. It acts as non-competitive
seems that sildenafil administered with magnesium
antagonist of NMDA receptors [39], modulates the
leads to hypermagnesemia, as in the present study
turnover of different neurotransmitters such as amino
sildenafil elevated serum magnesium levels up to
acids, neuropeptides, cytokines and nitric oxide [11]
6.5 mg/100 ml. Thus, sildenafil might have enhanced
and participates in binding of monoamines to their re-
magnesium absorption from the peritoneal cavity
ceptors [4]. A common site of action for sildenafil and
and/or it could have impaired magnesium renal excre-
magnesium may be the GABAA receptor. Increased
tion. To establish the mechanism accountable for this
GABAergic transmission causes sedation and may
effect, in a separate experiment we assayed serum and
lead to the reduction of locomotor activity [26].
brain magnesium levels after single administration of
Huang et al. [22] showed that increased cGMP con-
sildenafil without magnesium pre-treatment. The in-
centration evoked by sildenafil treatment enhances
creased serum magnesium concentration (by 13%)
the release of GABA, while Poleszak [35] suggests
after sildenafil treatment implies that hypermagne-
that anxiolytic-like effects of magnesium are related
semia, observed in former experiment, was rather due
to its ability to activate GABAA-gated chloride chan-
to the malfunctioning of magnesium transport in kid-
nels. In addition, synergistic interaction of magne-
neys than the excessive magnesium intake from the
sium with benzodiazepines (diazepam and chlordi-
azepoxide) in the elevated plus maze test in mice ar-
Mammalian magnesium transport across biological
gue for the involvement of benzodiazepine/GABAA
membranes is mediated by two main systems: Na+-
system in the anxiolytic activity of magnesium [35].
dependent and Na+-independent pathways. Although in-
Pharmacological Reports, 2012, 64, 205211
tracellular magnesium level is precisely regulated, the
References:
exact mechanism is not fully understood [43] and lit-tle is known about the involvement of the NO/cGMP
1. Barbosa FJ, Hesse B, de Almeida RB, Baretta IP,
pathway in magnesium transport pathways. It is also
Boerngen-Lacerda R, Andreatini R: Magnesium sulfate
claimed that the peripheral and central magnesium
and sodium valproate block methylphenidate-induced
level may be regulated by different mechanisms [4].
hyperlocomotion, an animal model of mania. Pharmacol
The reabsorption of magnesium predominantly occurs
2. Bastani B, Pandurangan G: Intraperitoneal route of mag-
in the loop of Henle and the distal tubule [2] and ele-
nesium sulphate supplementation in a patient with severe
ments of the NO/cGMP may regulate renal functions
renal magnesium wasting. Nephrol Dial Transplant,
because NO as well as cGMP modulate many plasma
membrane transporters [23]. Ikari and co-workers
3. Cazalets J: Development ot the neural correlates of loco-
[23] showed that NO and cGMP up-regulate the
motion in rats. In: Handbook of brain and behaviour in hu-man development. Eds. Kalverboer A, Gramsbergen A,
Na+-dependent magnesium transport in renal epithe-
Kluwer Academic Publishing, Dordrecht, 2001, 447–467.
lial cells and it was suggested that under pathological
4. Chollet D, Franken P, Raffin Y, Malafosse A, Widmer J,
conditions, the increase in magnesium gradient with
Tafti M: Blood and brain magnesium in inbred mice and
a concomitant increase in NO and cGMP levels acti-
their correlation with sleep quality. Am J Physiol Regul
vates magnesium transport system across the plasma
Integr Comp Physiol, 2000, 279, R2173–R2178.
5. Chouinard G, Beauclair L, Geiser R, Etienne P: A pilot
study of magnesium aspartate hydrochloride (Magnesio-
Unexpectedly, in our study, sildenafil, when ad-
card) as a mood stabilizer for rapid cycling bipolar affec-
ministered alone, caused a 20% increase in magne-
tive disorder patients. Prog Neuropsychopharmacol Biol
sium level within the brain, which points at a redistri-
bution of magnesium from blood to the brain and
6. Corbin JD, Francis SH: Cyclic GMP phosphodiesterase-5:
target of sildenafil. J Biol Chem, 1999, 274, 13729–13732.
a failure of homeostatic regulations of magnesium
7. Decollogne S, Tomas A, Lecerf C, Adamowicz E,
concentration within the brain tissue. Because no
Seman M: NMDA receptor complex blockade by oral
changes in brain magnesium levels after joint admini-
administration of magnesium: comparison with MK-801.
stration of magnesium and sildenafil were noticed, it
Pharmacol Biochem Behav, 1997, 58, 261–268.
may be speculated that distinct mechanisms may be
8. Del Arco A, Segovia G, Mora F: Blockade of NMDA re-
ceptors in the prefrontal cortex increases dopamine and
accountable for regulation of the brain magnesium
acetylcholine release in the nucleus accumbens and motor
concentration under physiological and abnormal con-
activity. Psychopharmacology (Berl), 2008, 201, 325–338.
ditions such as magnesium overload. However, the
9. Durlach J, Durlach V, Bac P, Bara M, Guiet-Bara A: Mag-
explanation is not highly convincing and the subject
nesium and therapeutics. Magnes Res, 1994, 7, 313–328.
matter deserves further investigations. It would be ad-
10. Eby GA, Eby KL: Rapid recovery from major depression
using magnesium treatment. Med Hypotheses, 2006, 67,
visable to determine changes in magnesium level in
urine and to check whether sildenafil is able to change
11. Eby GA, III, Eby KL: Magnesium for treatment-resistant
magnesium concentration in mice chronically treated
depression: a review and hypothesis. Med Hypotheses,
In conclusion, our results indicate for the first time
12. Esplugues JV: NO as a signalling molecule in the nerv-
ous system. Br J Pharmacol, 2002, 135, 1079–1095.
that sildenafil reverse the anti-immobility action of
13. Fawcett WJ, Haxby EJ, Male DA: Magnesium: physiol-
magnesium in the forced swim test in mice and that
ogy and pharmacology. Br J Anaesth, 1999, 83, 302–320.
simultaneous treatment with magnesium and silde-
14. Fox C, Ramsoomair D, Carter C: Magnesium: its proven
nafil results in hypermagnesemia in laboratory ani-
and potential clinical significance. South Med J, 2001,
mals. Further studies are required to investigate the
15. Gee JB, Corbett RJ, Perlman JM, Laptook AR: Hypermag-
mechanisms underlying the observed phenomena.
nesemia does not increase brain intracellular magnesium innewborn swine. Pediatr Neurol, 2001, 25, 304–308.
16. Ghofrani HA, Osterloh IH, Grimminger F: Sildenafil: from
angina to erectile dysfunction to pulmonary hypertension
Acknowledgments:
and beyond. Nat Rev Drug Discov, 2006, 5, 689–702.
We gratefully acknowledge the technical assistance of Nina
17. Harkin A, Connor TJ, Burns MP, Kelly JP: Nitric oxide
Kowalczyk. This study was supported by Funds for Statutory
synthase inhibitors augment the effects of serotonin re-
Activity of Maria Curie-Sk³odowska University, Lublin, Poland. The authors wish to thank Polpharma S.A. (Starogard Gdañski,
uptake inhibitors in the forced swimming test. Eur Neu-
Poland) for generous gift of sildenafil.
ropsychopharmacol, 2004, 14, 274–281.
Pharmacological Reports, 2012, 64, 205211
Sildenafil and antidepressant-like activity of magnesium
18. Harkin AJ, Bruce KH, Craft B, Paul IA: Nitric oxide
aminocyclopropanecarboxylic acid. J Pharmacol Exp
synthase inhibitors have antidepressant-like properties
in mice. 1. Acute treatments are active in the forced
34. Padayatti PS, Pattanaik P, Ma X, van den Akker F: Struc-
swim test. Eur J Pharmacol, 1999, 372, 207–213.
tural insights into the regulation and the activation
19. Hashimoto K: Emerging role of glutamate in the patho-
mechanism of mammalian guanylyl cyclases. Pharmacol
physiology of major depressive disorder. Brain Res Rev,
35. Poleszak E: Benzodiazepine/GABAA receptors are in-
20. Heiberg IL, Wegener G, Rosenberg R: Reduction of
volved in magnesium-induced anxiolytic-like behavior
cGMP and nitric oxide has antidepressant-like effects in
in mice. Pharmacol Rep, 2008, 60, 483–489.
the forced swimming test in rats. Behav Brain Res, 2002,
36. Poleszak E: Modulation of antidepressant-like activity
of magnesium by serotonergic system. J Neural Transm,
21. Heiden A, Frey R, Presslich O, Blasbichler T, Smetana
R, Kasper S: Treatment of severe mania with intravenous
37. Poleszak E, WlaŸ P, Kêdzierska E, Nieoczym D, Wróbel
magnesium sulphate as a supplementary therapy. Psy-
A, Fidecka S, Pilc A et al.: NMDA/glutamate mechanism
of antidepressant-like action of magnesium in forced
22. Huang LJ, Yoon MH, Choi JI, Kim WM, Lee HG,
swim test in mice. Pharmacol Biochem Behav, 2007, 88,
Kim YO: Effect of sildenafil on neuropathic pain and
hemodynamics in rats. Yonsei Med J, 2010, 51, 82–87.
38. Poleszak E, WlaŸ P, Kêdzierska E, Nieoczym D, Wyska
23. Ikari A, Nakajima K, Taki S, Suketa Y: Up-regulation of
E, Szymura-Oleksiak J, Fidecka S et al.: Immobility
Na+-dependent Mg2+ transport by nitric oxide and cyclic
stress induces depression-like behavior in the forced
GMP pathway in renal epithelial cells. Eur J Pharmacol,
swim test in mice: effect of magnesium and imipramine.
24. Imada Y, Yoshioka S, Ueda T, Katayama S, Kuno Y,
39. Poleszak E, WlaŸ P, Kêdzierska E, Radziwoñ-Zaleska M,
Kawahara R: Relationships between serum magnesium
Pilc A, Fidecka S, Nowak G: Effects of acute and
levels and clinical background factors in patients with
chronic treatment with magnesium in the forced swim
mood disorders. Psychiatry Clin Neurosci, 2002, 56,
test in rats. Pharmacol Rep, 2005, 57, 654–658.
40. Poleszak E, WlaŸ P, Szewczyk B, Kêdzierska E, Wyska
25. Kalivas PW, Duffy P, Eberhardt H: Modulation of A10
E, Librowski T, Szymura-Oleksiak J et al.: Enhancement
dopamine neurons by gamma-aminobutyric acid ago-
of antidepressant-like activity by joint administration of
nists. J Pharmacol Exp Ther, 1990, 253, 858–866.
imipramine and magnesium in the forced swim test: Be-
havioral and pharmacokinetic studies in mice. Pharmacol
disease: anxiety, epilepsy, and insomnia. J Recept Signal
Porsolt RD, Bertin A, Jalfre M: Behavioral despair inmice: a primary screening test for antidepressants. Arch
27. Mora F, Segovia G, Del Arco A: Glutamate-dopamine-
Int Pharmacodyn Ther, 1977, 229, 327–336.
GABA interactions in the aging basal ganglia. Brain Res
42. Prast H, Philippu A: Nitric oxide as modulator of neu-
ronal function. Prog Neurobiol, 2001, 64, 51–68.
28. Mordes JP, Wacker WE: Excess magnesium. Pharmacol
43. Romani A: Regulation of magnesium homeostasis and
transport in mammalian cells. Arch Biochem Biophys,
29. Nieoczym D, £uszczki JJ, Czuczwar SJ, WlaŸ P: Effect
of sildenafil on the anticonvulsant action of classical and
44. Rosen RC, McKenna KE: PDE-5 inhibition and sexual
second-generation antiepileptic drugs in maximal
response: pharmacological mechanisms and clinical out-
electroshock-induced seizures in mice. Epilepsia, 2010,
comes. Annu Rev Sex Res, 2002, 13, 36–88.
45. Skolnick P, Popik P, Trullas R: Glutamate-based antide-
30. Nieoczym D, Soca³a K, Rundfeldt C, WlaŸ P: Effects of
pressants: 20 years on. Trends Pharmacol Sci, 2009, 30,
sildenafil on pentylenetetrazol-induced convulsions in
mice and amygdala-kindled seizures in rats. Pharmacol
46. Swaminathan R: Magnesium metabolism and its disor-
ders. Clin Biochem Rev, 2003, 24, 47–66.
31. Nieoczym D, Soca³a K, WlaŸ P: Lack of effect of silde-
47. Topf JM, Murray PT: Hypomagnesemia and hypermag-
nafil on cocaine-induced convulsions in mice. Pharmacol
nesemia. Rev Endocr Metab Disord, 2003, 4, 195–206.
48. Uthayathas S, Karuppagounder SS, Thrash BM,
32. Nowak G, Legutko B, Skolnick P, Popik P: Adaptation
Parameshwaran K, Suppiramaniam V, Dhanasekaran M:
of cortical NMDA receptors by chronic treatment with
Versatile effects of sildenafil: recent pharmacological ap-
specific serotonin reuptake inhibitors. Eur J Pharmacol,
plications. Pharmacol Rep, 2007, 59, 150–163.
33. Nowak G, Trullas R, Layer RT, Skolnick P, Paul IA:
Adaptive changes in the N-methyl-D-aspartate receptorcomplex after chronic treatment with imipramine and 1-
Received: July 6, 2011; accepted: September 1, 2011.
Pharmacological Reports, 2012, 64, 205211
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