Sildenafil, a phosphodiesterase type 5 inhibitor, reduces antidepressant-like activity of paroxetine in the forced swim test in mice

Pharmacological Reports 2012, 64, 1259–1266 ISSN 1734-1140

Copyright © 2012 by Institute of Pharmacology Polish Academy of Sciences

Short communication

Sildenafil, a phosphodiesterase type 5 inhibitor, reduces antidepressant-like activity of paroxetine in the forced swim test in mice Katarzyna Soca³a1, Dorota Nieoczym1, El¿bieta Wyska2, Ewa Poleszak3, Piotr WlaŸ1 

Department of Animal Physiology, Faculty of Biology and Biotechnology, Maria Curie-Sk³odowska University, Akademicka 19, PL 20-033 Lublin, Poland Department of Pharmacokinetics and Physical Pharmacy, Collegium Medicum, Jagiellonian University, Medyczna 9, PL 30-688 Kraków, Poland

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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: Background: Sildenafil, a selective phosphodiesterase 5 (PDE5) inhibitor, has recently been reported to influence the antidepressant activity of some antidepressant drugs. The present study was undertaken to investigate the involvement of the nitric oxide/cyclic guanosine 3’,5’-monophosphate/PDE5 (NO/cGMP/PDE5) signaling pathway in the antidepressant activity of paroxetine and to assess the interaction between paroxetine and sildenafil, in the forced swim test in mice. Methods: Swim trials were conducted by placing mice in glass cylinders filled with water for 6 min. Total behavioral immobility was measured during the last 4 min of the test. Changes in locomotor activity were measured with photoresistor actimeters. Serum and brain paroxetine concentrations were assayed by the HPLC method. Results: Paroxetine at a dose of 1 mg/kg significantly decreased immobility time in the forced swim test, while sildenafil (5, 10 and 20 mg/kg) in a dose-dependent manner reduced the antidepressant activity of paroxetine. Pharmacokinetic studies did not show any significant changes in paroxetine concentration in serum and brain tissue as compared to paroxetine treatment alone. Conclusions: The results suggest that paroxetine may exert its antidepressant action by decreasing cGMP levels and sildenafil, as a drug which has the opposite effect on the processes mediated via the NO/cGMP/PDE5 signaling pathway, may decrease the efficacy of paroxetine. However, the co-administration of paroxetine with sildenafil resulted in a potent reduction (80%) of locomotor activity, which suggests that the reversal of antidepressant action of paroxetine may have been a result of locomotor deficits. Further studies are required to explain the mechanism underlying this phenomenon. Key words: phosphodiesterase 5, sildenafil, paroxetine, depression, erectile dysfunction, antidepressant, forced swim test, mice

Introduction Nitric oxide (NO), a multifunctional signaling molecule, is synthesized from L-arginine by nitric oxide synthase (NOS) as a response to Ca2+-influx follow-

ing activation of N-methyl-D-aspartate (NMDA) glutamate receptors. The physiological actions of NO are mainly mediated by its primary receptor – soluble guanylate cyclase (sGC) which converts guanosine 5’-triphosphate (GTP) into cyclic guanosine 3’,5’Pharmacological Reports, 2012, 64, 1259–1266

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monophosphate (cGMP). Cyclic GMP plays a pivotal role in signal transduction pathways [38, 54]. It acts with three main downstream effectors, i.e., cGMPdependent protein kinases, cGMP-regulated phosphodiesterases (PDEs) and cGMP-gated ion channels [22]. The intracellular level of cGMP is regulated by PDEs, such as PDE5, which degrades cGMP in corpus cavernosum. Targeting PDE5 with sildenafil (an active compound of Viagra®) elevates cGMP concentrations and promotes penile erection [40]. The diversity of targets allows the NO/cGMP pathway to exert multiple physiological effects in cardiovascular, gastrointestinal, immune and central nervous systems [4, 6, 7, 23]. Most importantly, NO has a modulatory effect on the extracellular level of neurotransmitters such as serotonin, dopamine, g-aminobutyric acid, histamine and glutamate [12, 20, 27, 37, 41, 46, 51]. When an excessive amount of NO is produced, this small gas molecule changes from a physiological messenger to a neurotoxic compound. Nitric oxide may be a key mediator of excitotoxic neuronal injury. Moreover, it has been implicated in the pathophysiology of depression, anxiety disorder, Alzheimer’s disease, Parkinson’s disease and epilepsy [10, 32, 33, 50, 54]. There is a growing body of evidence indicating the involvement of the NO/cGMP pathway in the neurobiology of depressive disorders [15, 17, 28, 53]. Numerous animal studies indicate that NOS inhibitors [16, 18] as well as sGC inhibitors [17] exert antidepressant effects and augment the efficacy of serotonergic antidepressants in the forced swim test in rodents. Joca and Guimaraes [19] showed that inhibition of neuronal NOS activity through intrahippocampal administration of 7-nitroindazole produces antidepressant-like behavior in rats. Chronic treatment with many effective antidepressant drugs leads to the down-regulation of b-adrenoreceptors [49]. A similar effect was noticed in mice chronically treated with NOS inhibitors [21]. Furthermore, nNOS–/– mice were reported to exhibit antidepressive behavior [55]. It was also shown that chronic mild stress exposure increased nNOS expression in the hippocampus, whereas nNOS inhibition prevented and reversed symptoms of depression in rats with chronic stress-induced depression [55]. In addition, elevated NO metabolite concentrations were reported in patients suffering from major depressive disorders and suicide attempters [25, 47]. Interestingly, it has been suggested that some antidepressant drugs, such as bupropion [9], venlafaxine 1260

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[8] or escitalopram [56], act via the NO/cGMP pathway and exert their anti-immobility action in the forced swim test in rodents by accumulation of cGMP. 7-Nitroindazole (an NOS inhibitor) as well as methylene blue (an inhibitor of both NOS and sGC) potentiated, while L-arginine (an NO donor) and sildenafil (a selective PDE5 inhibitor) reduced the antidepressant action of the above mentioned drugs in the forced swim test [8, 9, 56]. Paroxetine, a selective serotonin re-uptake inhibitor, was shown to inhibit NOS activity in both in vitro and in vivo studies. Since NO is a key mediator of penile smooth muscle relaxation, it is not surprising that paroxetine may cause erectile dysfunctions [1, 2]. Co-occurrence of depression and sexual dysfunctions results in a need for simultaneous treatment with antidepressants and drugs that improve erection such as sildenafil [35]. Since sildenafil may influence the antidepressant activity of paroxetine, the aim of the present study was to investigate the effect of sildenafil on the antiimmobility action of paroxetine in the forced swim test in mice – a validated and commonly used animal model for screening antidepressants. In order to evaluate the potential pharmacokinetic interactions between paroxetine and sildenafil, total brain and serum concentrations of paroxetine were determined.

Materials and Methods Animals

Naive male albino Swiss mice weighing 25–30 g were used in all experiments. The animals were purchased from a licensed breeder (Laboratory Animals Breeding, S³aboszów, Poland) and housed in groups of up to 10 mice in polycarbonate cages under standard laboratory conditions (temperature maintained at 23–25°C, humidity 50–60% and 12 h light/dark cycle, lights on at 6:00 a.m.). Tap water and food pellets (Murigran, Agropol S.J., Motycz, Poland) were continuously available. All experiments were performed between 8:00 and 16:00 h to minimize circadian influences, after at least 7 days of acclimatization. The experimental protocols were approved by the Ethical Committee of the Medical University in Lublin (license number 69/2009) and all procedures were in accordance with the European Communities Council Directive of 24 November 1986 (86/609/EEC).

Sildenafil and antidepressant-like activity of paroxetine Katarzyna Soca³a et al.

Drugs

Sildenafil citrate (kindly provided by Polpharma S.A., Starogard Gdañski, Poland) was dissolved in saline, while paroxetine (Arketis, Vipharm, Warsaw, Poland) was suspended in a 0.5% aqueous solution of methyl cellulose. All solutions and suspensions were prepared freshly and administered intraperitoneally (ip) in a volume of 0.1 ml per 10 g body weight, 30 min prior to the experiments. Control animals received an ip injection of a respective vehicle. The doses and pretreatment schedules were based on those reported in the literature and on previous experiments in our laboratory [13, 14, 24, 32, 33, 43]. Forced swim test

The test procedure was carried out according to the method described by Porsolt et al. [36]. Mice were individually forced to swim in glass cylinders (height 25 cm, diameter 10 cm) containing 10 cm of water maintained at 23–25°C. Animals were allowed to swim for 6 min. After the initial 2 min of vigorous activity, the total duration of immobility was recorded during the last 4 min of the test. The duration of immobility was defined as the time when the mouse remained floating passively, made no attempts to escape and showed only slow movements to keep its head above the water. Locomotor activity

Locomotor activity of mice was monitored by using actimeters (30 cm diameter, 12 cm high, MultiServ, Lublin, Poland) equipped with two perpendicular infrared light beams located 1.5 cm above the floor. Mice were placed individually in an actimeter, in which they were allowed to explore freely for 10 min. Locomotor activity was recorded as the number of interruptions of light beams over a 10 min period.

The brains were rapidly removed after decapitation, washed in saline and frozen on dry ice. The brains were then homogenized in 0.1 M phosphate buffered saline (pH 7.4). The amount of 200 μl of serum was mixed with 10 μl of imipramine solution in methanol as an internal standard. The samples were alkalized with 200 μl of 2 M sodium hydroxide and extracted with 3 ml of ethyl acetate : hexane (30:70, v/v). Similarly, 1 ml of brain homogenate was mixed with 20 μl of imipramine, alkalized with 500 μl of 2 M sodium hydroxide and extracted with 5 ml of dichloromethane : hexane : isoamyl alcohol (40:60:1, v/v/v). All samples were then shaken for 20 min (IKA VXR Vibrax, Germany). After centrifugation (1,500 × g for 15 min), the organic layer was transferred to a new tube, evaporated to dryness at 37°C under a stream of nitrogen and dissolved in 100 μl of methanol. Fifty microliters of this solution were injected into the HPLC system. The HPLC system (Thermo Separation Products, San Jose, CA, USA) consisted of a P100 isocratic pump, a Rheodyne 7125 injector (Rheodyne, Cotati, CA, USA) with a 50 μl sample loop, a UV100 Variable-wavelength UV/VIS detector, operating at 214 nm and an SP4400 (Thermo Separation Products, San Jose, CA, USA) integrator. All analyses were performed at ambient temperature (21°C) on a 250 × 4.6 mm LiChrospher®100 RP-18 column (Merck, Darmstadt, Germany) with 5 μm particles, protected with a guard-column (4 × 4 mm) with the same packing material. The mobile phase consisted of acetonitrile:50 mM potassium dihydrogen phosphate, pH 3.5 (40:60, v/v). The flow rate was set to 1 ml/min. The calibration curves were linear in the tested concentration ranges. The assay was reproducible with low intra- and inter-day variations (a coefficient of variation less than 10%). Serum and brain concentrations of paroxetine were expressed in ng/ml and ng/g of fresh tissue, respectively. Statistical analysis

Determination of serum and brain paroxetine concentrations

Serum and brain concentrations of paroxetine were determined by the high performance liquid chromatography (HPLC) method. After drug pretreatment, mice were killed by decapitation. The trunk blood was collected into polyethylene tubes. Serum was isolated 1 h after blood coagulation by centrifugation at 5,000 × g for 10 min at 4°C and frozen at –30°C.

All results are presented as the means ± standard error of the mean (SEM). Data obtained in behavioral tests were evaluated by using a one-way analysis of variance (ANOVA) followed by the Student-NewmanKeuls post-hoc test for multiple comparisons. Serum and brain concentrations of paroxetine were compared using the unpaired Student’s t-test. Statistical significance was noted when p values were equal to or less than 0.05. Pharmacological Reports, 2012, 64, 1259–1266

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Tab. 1. Effect of treatments on spontaneous locomotor activity in mice

Results

Treatment

Forced swim test

The effect of paroxetine alone and in combination with sildenafil on immobility time in the forced swim test in mice is shown in Figure 1 [ANOVA: F(4, 40) = 9.342, p < 0.001]. Paroxetine administered alone at a dose of 1 mg/kg significantly reduced the total immobility duration from 193 ± 6 s in the control group to 120 ± 11 s (p < 0.001). Co-administration of paroxetine with sildenafil at a dose of 5 mg/kg did not cause any additional effect on the immobility time as compared to the paroxetine-treated group (p > 0.05). However, sildenafil at a dose of 10 mg/kg significantly prolonged the total immobility to 161 ± 10 s in comparison with the paroxetine-treated group (p = 0.019) and abolished the anti-immobility action of paroxetine (p = 0.101 vs. control group). The highest dose of sildenafil (20 mg/kg) caused a further increase in immobility time, to 187 ± 13 s (p < 0.001 vs. the paroxetine treated group; p = 0.716 vs. the control group). Locomotor activity

The data obtained in the spontaneous locomotor activity test are presented in Table 1 [ANOVA: F(2, 26) = 10.154, p < 0.001]. Paroxetine administered alone did not affect locomotor activity in mice. The combined

Activity counts/ 10 min

0.5% methyl cellulose + saline

181.3 ± 18.6

Paroxetine (1 mg/kg) + saline

225.1 ± 22.9

Paroxetine (1 mg/kg) + sildenafil (20 mg/kg)

94.7 ± 19.7a,b

Paroxetine and sildenafil were administered ip 30 min before the experiment. Each experimental group consisted of 9–10 animals. Data are presented as the means ± SEM; = p < 0.01 vs. control group, > p < 0.001 vs. paroxetine treated group (one-way ANOVA followed by Student-Newman-Keuls post-hoc test)

administration of paroxetine with sildenafil at the highest dose of 20 mg/kg significantly reduced the activity counts (p < 0.001 vs. the paroxetine-treated group; p = 0.007 vs. the control group). Effect of sildenafil on serum and brain paroxetine concentrations

The effect of combined administration of paroxetine and sildenafil on serum and brain paroxetine concentrations in mice is shown in Table 2. Co-administration of sildenafil at a dose of 20 mg/kg with paroxetine at a dose of 1 mg/kg neither changed paroxetine concentrations in serum (p = 0.926) nor in brain tissue (p = 0.585).

Discussion

Fig. 1. Effect of paroxetine administered alone and in combination with sildenafil on immobility time in the forced swim test in mice. Both drugs were administered ip 30 min before the test. Control animals received 0.5% aqueous solution of methyl cellulose + saline. Each experimental group consisted of 9–12 animals. Data are presented as the means ± SEM. ** p < 0.01, *** p < 0.001 as compared to control group;  p < 0.05,  p < 0.001 as compared to paroxetinetreated group (one-way ANOVA followed by Student-Newman-Keuls post-hoc test)

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Numerous case reports, as well as clinical trials, mention sexual dysfunctions associated with antidepressant drug treatment, especially selective serotonin reuptake inhibitors [2, 31]. Drugs which affect serotonin reuptake may have a negative impact on all phases of the sexual cycle, including penile erection. The incidence of sexual dysfunctions caused by selective serotonin reuptake inhibitors is estimated at being between 30% and up to 70% [3, 35]. Distinct mechanisms underlying this phenomenon have been postulated, such as the effect on serotonin levels and nitric oxide inhibition [1, 3]. Amongst all selective serotonin reuptake inhibitors, paroxetine exerts particularly negative effects on sexual functions. The prevalence of sexual dysfunction associated with paroxetine treatment is estimated at 43–71% [2] and the

Sildenafil and antidepressant-like activity of paroxetine Katarzyna Soca³a et al.

Tab. 2. Effect of combined administration of paroxetine and sildenafil on serum and brain paroxetine concentrations in mice

Treatment

Paroxetine concentration Serum (ng/ml) Brain (ng/g)

Paroxetine (1 mg/kg) + saline

237.8 ± 39.0

91.0 ± 34.0

Paroxetine (1 mg/kg) + sildenafil (20 mg/kg)

232.2 ± 43.6

67.8 ± 22.1

Paroxetine and sildenafil were administered ip 30 min before decapitation. Each experimental group consisted of 9–10 animals. Data are presented as the means ± SEM

incidence of erectile dysfunction at 10–34% [39]. It is widely known that the NO/cGMP/PDE5 pathway is implicated in the mechanism of penile erection and paroxetine, as an NOS inhibitor [1, 11], affects erectile response. One of the most common management strategies for antidepressant-associated sexual dysfunction includes adding an antidote – sildenafil. It appears to be well tolerated and highly effective in men with concomitant depression and erectile dysfunction. Sildenafil inhibits cGMP degradation by inhibiting PDE5 and amplifies the effect of sexual stimulation [34, 42]. In our previous reports we showed that sildenafil affects animal behavior in the forced swim test in mice after central muscarinic receptor blockade with scopolamine. In the same study, sildenafil enhanced the antidepressant activity of the drug that exhibits cholinolytic properties – amitriptyline [45]. Moreover, sildenafil was reported to increase the antidepressant activity of mianserin and tianeptine in mice [44]. Another interesting observation was the reversal of the antiimmobility activity of magnesium, which was solely or partly due to hipermagnesemia caused by simultaneous treatment with magnesium and sildenafil [43]. Although paroxetine acts as an NOS inhibitor, any relationship between this effect and the clinical antidepressant efficacy of paroxetine remains elusive [30, 51]. The effect of sildenafil on the efficacy of paroxetine in depressed patients is also unknown. Here, we demonstrated that sildenafil reduced and, at higher doses, entirely eliminated the anti-immobility action of paroxetine in the forced swim test in mice. This indicates that paroxetine may exert its antidepressant effect in the above-mentioned animal model by inhibiting NO synthesis and thereby decreasing cGMP levels. Sildenafil, which has the opposite effect on the processes mediated via the NO/cGMP/PDE5 path-

way, may reverse the action of paroxetine. It is well documented that paroxetine suppresses NO formation by inhibiting neuronal NOS activity [1, 11, 52] but the influence of other antidepressant drugs on NOS expression is not clear. It was shown that inhibition of NO production enhanced the activity of selective serotonin reuptake inhibitors, such as fluoxetine, sertraline and citalopram in the forced swim test. In a similar fashion NOS inhibitors augmented the activity of a nonselective serotonin and noradrenaline reuptake inhibitor – imipramine. However, no interactions between NOS inhibitors and reboxetine, which is a selective noradrenaline reuptake inhibitor, were noticed. These findings suggest that inhibition of NOS activity may enhance the antidepressant efficacy of drugs that act via serotonergic mechanisms [15]. Furthermore, local administration of paroxetine, citalopram, imipramine and the atypical antidepressant drug, tianeptine decreased hippocampal NOS activity in rats [52]. In addition, reduction of brain NO levels was reported after fluoxetine treatment in rats [5]. Wegener et al. [52] postulated that, at therapeutic doses, antidepressant drugs which selectively inhibit reuptake of serotonin from the synaptic cleft do not directly inhibit NOS activity and NMDA receptors seem to be their primary target of action. Reduction of NMDA receptor activity in turn decreases NO/cGMP pathway activity. They concluded that inhibition of neuronal NOS activity is a secondary target for serotonergic antidepressants and these drugs inhibit NO production only under pathological conditions, i.e., disturbed glutamatergic transmission in depression [52]. It appears that the ability to suppress NOS activity cannot be limited only to selective serotonin inhibitors and other antidepressant drugs with serotonergic mechanism of action. Three antidepressant drugs from different classes (desipramine, fluoxetine and moclobemide) were shown to inhibit NOS activity in NMDA-treated PC12 cell line [26]. According to Li et al. [26] inhibition of the NMDA/Ca2+/NO signaling pathway may represent a common mechanism of action for all antidepressants. Nevertheless, it is still questionable whether the therapeutic potential of antidepressant agents is a result of their inhibitory effects on NMDA receptors and/or NOS activity or whether the NMDA/Ca2+/NO pathway represents a secondary target for antidepressant drugs [16, 26, 29, 52]. The main finding of the present study is that sildenafil reversed the anti-immobility action of paroxetine in the forced swim test in mice. Our results are partly Pharmacological Reports, 2012, 64, 1259–1266

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in line with Umathe and co-workers’ [48] studies where sildenafil was reported to eliminate the anticompulsive action of paroxetine in the marbleburying behavior test in mice. It is noteworthy that in the same study sildenafil increased brain nitrate levels [48]. This finding constitutes further support for the hypothesis that sildenafil may affect the clinical efficacy of paroxetine in depressed patients. The reversal of the anti-immobility effect of paroxetine caused by concomitant treatment with sildenafil may have either a pharmacodynamic or pharmacokinetic basis. In order to evaluate the potential pharmacokinetic interaction between these two agents, brain and serum paroxetine concentrations were analyzed. The results indicate that the effect observed in the forced swim test was related to pharmacodynamic rather than pharmacokinetic interactions because sildenafil did not alter paroxetine concentrations in either of the examined tissues. As with many behavioral tests, drugs that affect locomotor activity yield false positive or false negative results in the forced swim test. To avoid repetition, the effect of different doses of sildenafil on spontaneous locomotor activity in mice was not assessed in the present study. In our former study, we showed that sildenafil at doses ranging from 1.25 to 20 mg/kg caused no alteration in the activity counts [44]. In the present study, joint administration of paroxetine and sildenafil caused a significant decrease in motor activity in mice. Therefore, there is a possibility that the reversal of the anti-immobility action of paroxetine via sildenafil co-administration was solely or partially due to non-specific locomotor deficit and sedation. In conclusion, the results suggest that paroxetine may probably exert its antidepressant action by decreasing cGMP levels and reinforce the role of the NO/cGMP/PDE5 signaling pathway in the mechanism of action of paroxetine. However, changes in locomotor functions may have interfered with data obtained from the forced swim test. Thus, further studies are required to discover the complex interaction between paroxetine and sildenafil and to evaluate the risk/benefit ratio in patients simultaneously treated with these two compounds.

Acknowledgments: We gratefully acknowledge the technical assistance of Nina Kowalczyk. This study was supported by Funds for Statutory Activity of Maria Curie-Sk³odowska University, Lublin, Poland. The authors wish to thank Polpharma S.A. (Starogard Gdañski, Poland) for generous gift of sildenafil.

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Received: January 30, 2012; in the revised form: April 29, 2012; accepted: May 22, 2012.