SYNERGISTIC EFFECT OF IMIPRAMINE AND AMANTADINE IN THE FORCED SWIMMING TEST IN RATS. BEHAVIORAL AND PHARMACOKINETIC STUDIES

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1 Copyright 2004 by Ititute of Pharmacology Polish Academy of Sciences Polish Journal of Pharmacology Pol. J. Pharmacol., 2004, 56, ISSN SYNERGISTIC EFFECT OF IMIPRAMINE AND AMANTADINE IN THE FORCED SWIMMING TEST IN RATS. BEHAVIORAL AND PHARMACOKINETIC STUDIES Zofia Rogó 1,#, Gra yna Skuza 1, Maciej Kuœmider 1, Jacek Wójcikowski 2, Marta Kot 2, W³adys³awa A. Daniel 2 Department of Pharmacology, Department of Pharmacokinetics and Drug Metabolism, Ititute of Pharmacology, Polish Academy of Sciences, Smêtna 12, PL Kraków, Poland Synergistic effect of imipramine and amantadine in the forced swimming test in rats. Behavioral and pharmacokinetic studies. Z. ROGÓ, G. SKUZA, M. KUŒMIDER, J. WÓJCIKOWSKI, M. KOT, W.A. DANIEL. Pol. J. Pharmacol., 2004, 56, Our previous studies demotrated that joint administration of a tricyclic antidepressant drug, imipramine (IMI) with the uncompetitive antagonist of NMDA receptor, amantadine (AMA), produced stronger antidepressant effect in the forced swimming test (Porsolt s test) than the treatment with either of drugs given alone. Since it has been suggested that, in addition to their other functio, dopamine and 1 receptors may play a role in behavioral respoe in the forced swimming test, in the present study we examined the effect of sulpiride (dopamine D 2/3 receptor antagonist) and prazosin ( 1 receptor antagonist) on the effect of AMA given alone or in combination with IMI in the forced swimming test in rats. We also measured the level of IMI and its metabolite, desipramine, in the rat plasma and brain, 1 h after the forced swimming test. Joint treatment with IMI (5 or 10 mg/kg) and AMA (20 mg/kg) produced stronger antidepressantlike effect than either of agents given alone. Sulpiride (10 mg/kg) or prazosin (1 mg/kg) (ineffective in the forced swimming test) inhibited an antidepressant-like effect induced by co-administration of IMI and AMA. The active behaviors in that test did not reflect an increase in general activity, since combined administration of IMI and AMA failed to enhance the locomotor activity of rats, measured in the open field test. Also sulpiride and prazosin did not decrease the exploratory activity induced by co-administration of IMI and AMA. The above result suggests that the dopamine D 2/3 and 1 receptors may contribute to the mechanism of synergistic action of IMI and AMA in the forced swimming test in rats. The pharmacokinetic interaction can be excluded, since AMA did not change significantly the antidepressant level in the rat plasma and brain, measured 1 h after exposure to the forced swimming test. Key words: imipramine, amantadine, behavioral and pharmacokinetic studies, rats # correspondence; rogoz@if-pan.krakow.pl

2 Z. Rogó, G. Skuza, M. Kuœmider, J. Wójcikowski, M. Kot, W.A. Daniel INTRODUCTION It is known that all of currently used antidepressant drugs (ADs) show therapeutic efficacy in a maximum of 60 70% of patients. The problem of therapy-resistant depressive patients has been studied for a long time, but with no significant success. Generally, drug-resistant depression was treated with the use of the combination of various ADs. Therefore, there is a strong need for alternative treatments. Recently, much attention has been devoted to the glutamatergic system and to NMDA receptor antagonists in particular. The antidepressive properties of these compounds have been suggested for over a decade [46] and antidepressive-like actio have subsequently been shown in animal models for competitive NMDA receptor antagonists, such as CGP or AP-7, and for uncompetitive antagonists such as amantadine (AMA) or memantine [24, 27, 30]. Our previous studies demotrated that joint administration of tricyclic AD, imipramine (IMI) and uncompetitive antagonist of NMDA receptors, AMA, produced stronger antidepressant effect in the forced swimming test (measured as the shortening of immobility time) than the treatment with either of these drugs given separately [23, 37]. Moreover, studies of other authors showed that NMDA receptor antagonists, including AMA, induced indirect activation of the dopaminergic system (via blockade of the glutamatergic input) in animals [7]. It is also well known that ADs administered repeatedly enhance the reactivity of the central dopamine D 2/3 and 1 receptors in rats and mice [9 11, 18 21, 34, 36]. In the light of these data, the aim of the present study was to examine the effect of IMI and AMA given alone or in combination of IMI with AMA in the forced swimming test in rats. We also measured pharmacokinetic parameters, i.e. the level of IMI and its metabolite, desipramine (DMI), in the rat plasma and brain, 1 h after the forced swimming test. Moreover, we examined the influence of sulpiride (SUL, dopamine D 2/3 receptor antagonist) and prazosin (PRA, 1 receptor antagonist) on the effect of AMA (20 mg/kg) given alone or in combination with IMI (5 or 10 mg/kg) in the forced swimming test in rats. MATERIALS and METHODS Animals and drug treatment Male Wistar rats ( g) were kept at a cotant room temperature (22 ± 1 C) and a 12 h light/dark cycle with free access to food and water prior to the experiments. All drugs were dissolved in distilled water and injected intraperitoneally (ip) in a volume of 2 ml/kg. The rats that received different drug treatments were tested in a random order and were used only once in the experiments. All tests were conduced by an observer unaware of the treatment. Experimental protocols were approved by the local Ethics Committee and complied with the guidelines of the respoible agency of the Ititute of Pharmacology. Drugs Amantadine hydrochloride (Sigma, St. Louis, USA, AMA), imipramine hydrochloride (Pliva, Poland, IMI), prazosin hydrochloride (Research Biochemicals Inc., USA, PRA), ( )sulpiride (Research Biochemicals Inc., USA, SUL). Forced swimming test in rats The total immobility time of rats was assessed during a 5 min observation period according to Porsolt et al. [31]. AMA (20 mg/kg) and IMI (5 or 10 mg/kg) were administered three times at 24, 5 and 1 h before the test. IMI was also co-injected with AMA at the doses and times stated above. SUL (10 mg/kg) or PRA (1 mg/kg) were given (ip)30min before IMI and AMA. Control rats were injected with vehicle. Each group coisted of 8 rats. Exploratory activity in the open field test in rats Exploratory activity was assessed in the elevated open field test. A black circular platform 1 m in diameter without walls was divided into six symmetrical sectors and elevated 50 cm above the floor. The laboratory room was dark and only the center of the open field was illuminated, with a 75 W bulb placed 75 cm above the platform. At the beginning of the test, animals were placed gently in the center of the platform and allowed to explore. Their exploratory activity in the open field, i.e. the time of walking, number of sector line crossings (ambulatio), episodes of peeping under the edge of the area and rearing were assessed for 5 min. IMI (5 and 10 mg/kg) and AMA (20 mg/kg) were given three 180 Pol. J. Pharmacol., 2004, 56,

3 SYNERGISTIC EFFECT OF IMIPRAMINE AND AMANTADINE times at 24, 5 and 1 h before the test (like in the forced swimming test). SUL (10 mg/kg) or PRA (1 mg/kg) were given (ip) 30 min before IMI and AMA. Control rats were injected with vehicle. There were 8 rats in each group. Drug assay in the rat plasma and brain Concentratio of IMI and its metabolite DMI were measured at 1 h after the forced swimming test. The concentratio of antidepressants were determined according to the method described by Sutfin and Jusko [43] and modified by Daniel and Wójcikowski [6]. To 1 ml of plasma containing IMI and DMI, 300 l of 25% ammonium hydroxide were added and the drugs were extracted with 2 ml of hexane containing 1.5% of isoamyl alcohol (v/v). The brai were homogenized in distilled water (1:3, w/v). The obtained homogenates were alkalized with natrium hydroxide (ph = 12) and extracted with 6 ml of hexane containing 1.5% of isoamyl alcohol. Extraction efficiency of the parent compound and its metabolite amounted to about 96%. The residue obtained after evaporation of the plasma and tissue extracts was dissolved in a mobile phase (described below) and injected into the LaChrom HPLC system (Merck-Hitachi), equipped with an L-7480 fluorescence detector. The Econosphere C18 analytical column (5 m, mm) was purchased from Alltech (Carnforth, England) and was maintained at an ambient temperature. The mobile phase coisted of methanol and acetonitrile (1:1, v/v) containing 1 ml/l of triethylamine. The flow rate was 1 ml/min. Fluorescence of the samples was measured at an excitation wavelength of 240 nm and 370 nm emission wavelength. Each group coisted of 6 8 rats. Data analysis The behavioral data were evaluated by a oneway analysis of variance (ANOVA), followed, when appropriate, by individual compariso with the control using Dunnett s test. The pharmacokinetic results were analyzed statistically using Student s t-test. RESULTS Forced swimming test in rats IMI at a dose of 10 mg/kg (but not 5 mg/kg) and AMA (20 mg/kg), given separately, exhibited an antidepressant-like activity in the forced swimming test, viz. they decreased the immobility time of rats. Combined treatment with AMA (20 mg/kg) and IMI (5 or 10 mg/kg) produced statistically significant and stronger inhibition of immobility than either of agents alone (Tab. 1, 2). SUL (10 mg/kg), given alone, was ineffective in the forced swimming test, but inhibited an antidepressant-like effect induced by AMA (20 mg/kg) or co-administration of AMA (20 mg/kg) with IMI (5 or 10 mg/kg) (Tab.1). However, PRA (1 mg/kg) did not change the immobility time in rats and did not alter the antidepressantlike effect of AMA (20 mg/kg) but only partly decreased the effect of AMA given jointly with IMI (5 or 10 mg/kg) (Tab. 2). Exploratory activity in the open field test in rats Neither IMI (5 or 10 mg/kg) nor AMA (20 mg/kg), given alone, changed exploratory activity (time of walking, ambulation, or peeping and rearing) in the open field test in rats. Co-administration of AMA and IMI (5 or 10 mg/kg) reduced that activity. SUL (10 mg/kg) or PRA (1 mg/kg), at doses used in the forced swimming test, neither changed exploratory behavior nor did it alter the effects induced by joint administration of AMA and IMI (5 or 10 mg/kg) (data not shown). Drug assay in the rat plasma and brain Both IMI and its metabolite DMI showed much higher concentratio in the brain than in the plasma. Thus, the total drug concentration in the brain (IMI + DMI) was 7 10 times higher than in the plasma. Moreover, the level of DMI in the plasma exceeded twice that of IMI, while in the brain the metabolite concentration was slightly lower compared to that of the parent compound. AMA did not significantly affect the plasma or brain concentratio of IMI and DMI, though a tendency to increase the brain level of both those compounds was visible at a lower dose of IMI (5 mg/kg) (Tab. 3). DISCUSSION In the present study, we examined the effect of SUL (dopamine D 2/3 receptor antagonist) and PRA ( 1 receptor antagonist) on the action of AMA given alone or in combination with IMI in the forced swimming test in rats. ISSN

4 Z. Rogó, G. Skuza, M. Kuœmider, J. Wójcikowski, M. Kot, W.A. Daniel Table 1. The influence of sulpiride (SUL) on the effect of combined treatment with imipramine (IMI) and amantadine (AMA) in the forced swimming test in rats Table 2. The influence of prazosin (PRA) on the effect of combined treatment with imipramine (IMI) and amantadine (AMA) in the forced swimming test in rats Drugs (mg/kg) Immobility time (s) (mean ± SEM) Drugs (mg/kg) Immobility time (s) (mean ± SEM) Vehicle IMI 5 AMA 20 IMI 5 + AMA 20 SUL 10 SUL 10 + AMA 20 SUL 10 + IMI 5 + AMA 20 IMI10 IMI 10 + AMA 20 SUL 10 + IMI 10 + AMA ± ± ± 7.1* 86.6 ± 8.8 # ± ± 9.7 # ± ± 10.9* 67.0 ± 9.3 ## ± IMI and AMA were given (ip) three times at 24, 5 and 1 h before the test. SUL was injected 30 min before IMI and AMA. The results represent mea ± SEM; n = 8.Thedata were statistically evaluated by ANOVA followed by individual compariso using Dunnett s test.*p<0.001 vs. vehicle-treated group, # p < vs. IMI 5 mg/kg- or AMA-treated group, ## p < vs. IMI 10 mg/kg- or AMA-treated group, + p < vs. IMI 5 mg/kg + AMA-treated group, ++ p < vs. IMI 10 mg/kg + AMAtreated group Our results indicated that the uncompetitive NMDA receptor antagonist AMA reduced the immobility time in the forced swimming test in rats, with efficacy comparable to that of tricyclic ADs. This is coistent with some earlier findings by Moryl et al. [27], who described a dose-dependent decrease in the immobility time following administration of AMA and memantine. Similar effects in the tests used for the screening of antidepressantlike activity have also been reported for other Vehicle IMI 5 AMA 20 IMI 5 + AMA 20 PRA 1 PRA 1 + AMA 20 PRA 1 + IMI 5 + AMA 20 IMI 10 IMI 10 + AMA 20 PRA 1 + IMI 10 + AMA ± ± ± 4.8* ± 5.5 # ± ± ± ± 5.1* 60.6 ± 7.2 ## ± IMI and AMA were given (ip) three times at 24, 5 and 1 h before the test. PRA was injected 30 min before IMI and AMA. The results represent mea ± SEM; n = 8.Thedata were statistically evaluated by ANOVA followed by individual compariso using Dunnett s test. * p < vs. vehicle-treated group, # p < vs. IMI 5 mg/kg- or AMA-treated group, ## p < vs. IMI 10 mg/kg- or AMA-treated group, + p < vs. IMI 5 mg/kg + AMA-treated group, ++ p < vs. IMI 10 mg/kg + AMA-treated group NMDA receptor antagonists [40, 46]. Moreover, our previous studies showed that AMA enhanced the antidepressant effect of IMI, in the forced swimming test [23, 37]. In the forced swimming test, false positive effects can be induced by various dopamine or noradrenaline stimulants used at doses increasing locomotor or exploratory activity [3]. In our experiment, neither AMA nor IMI given alone changed the exploratory activity (time of walking or ambulation) in the open field test in rats. Table 3. The concentratio of imipramine (IMI) and its metabolite desipramine (DMI) after administration of IMI alone or jointly with amantadine (AMA) at 1 h after the forced swimming test Drugs (mg/kg) Blood plasma (nmol/ml) Brain (nmol/g) IMI DMI IMI + DMI IMI DMI IMI + DMI IMI ± ± ± ± ± ± IMI 5 + AMA ± ± ± ± ± ± IMI ± ± ± ± ± ± IMI 10 +AMA ± ± ± ± ± ± IMI (ip) was administered alone or jointly with AMA (ip) at 24, 5 and 1 h before the test at doses stated above. The concentratio of IMI and DMI were measured at 1 h after the forced swimming test. All values represent mea ± SEM; n = 6 8. The data were statistically evaluated by Student s t-test; = not significant vs. IMI-treated group 182 Pol. J. Pharmacol., 2004, 56,

5 SYNERGISTIC EFFECT OF IMIPRAMINE AND AMANTADINE Also combined treatment with AMA and AD did not enhance, and even reduced, the exploratory activity, which suggested the lack of a pharmacokinetic interaction between AMA and IMI [23, 37]. First phase of IMI metabolism involves mainly its N-demethylation in a side chain and aromatic hydroxylation in position 2 [2, 8, 42]. The demethylation changes the pharmacological profile of the antidepressants, viz. IMI inhibits the neuronal uptake of both noradrenaline and serotonin while DMI is rather a selective inhibitor of noradrenaline uptake and displays weaker blocking effects on noradrenergic, cholinergic or histaminergic receptors [16, 32, 39]. Hydroxy-metabolites of IMI and DMI retain the pharmacological profile of their respective parent compounds, though their potency is somewhat lower. Studies carried out on rats showed that IMI and its metabolites reached coiderably higher concentratio in tissues than in plasma. Moreover, the DMI level exceeded that of IMI in plasma and in the brain after longer time intervals following IMI administration [5, 28]. In the plasma of patients, level of DMI, whose biological half-life is about twice as long as that of IMI (22.5 h vs. 12 h), usually surpasses times the plasma concentration of IMI [29] while the concentratio of hydroxy-metabolites are lower than their respective parent compounds [4, 33, 44]. Therefore, a sum of IMI and DMI concentratio represents the main active pool of the AD given in vivo. The present pharmacokinetic studies indicate that AMA does not significantly change the antidepressant (IMI and DMI) concentration in the brain during the experiment. Hence, any contribution of a pharmacokinetic interaction to the potentiation of IMI effect by AMA, observed in vivo in the forced swimming test, seems unlikely. On the other hand, a behavioral study showed that SUL (a dopamine D 2/3 antagonist [17] given alone was ineffective in the forced swimming test, but inhibited the antidepressant-like effect induced by co-administration of AMA and IMI. However, PRA (an 1 receptor antagonist) only partly decreased that effect of AMA given with IMI. SUL and PRA (at doses used in the forced swimming test) did not decrease the exploratory activity induced by co-administration of AMA and IMI. The above results suggest that the inhibition of the antidepressant-like effect by SUL or PRA cannot be attributed to a decrease in locomotor activity, and that dopamine D 2/3 and also 1 receptors may contribute to the mechanism of the synergistic action of AMA and IMI in the forced swimming test in rats. Long-term administration of AMA to mice was reported to increase the number of postsynaptic dopamine receptors in the striatum, which was shown with the use of [ 3 H]spiperidol [14]. Also after repeated administration of AMA or IMI alone, or a combination of IMI and AMA in rats, the binding of [ 3 H]quinpirole (a dopamine D 2/3 receptor agonist) was increased, and similar changes were observed in the level of mrna encoding dopamine D 2 receptors [35]. It should be mentioned here that AMA, an NMDA receptor antagonist, is not selective. For example, it has been shown that acute treatment with AMA is able to enhance the noradrenergic tramission [1, 25, 27, 45]. Our preliminary data indicated that AMA (10 mg/kg), given repeatedly, increased the clonidine-induced aggression in mice and enhanced the action of ADs, e.g. IMI. On the other hand, biochemical studies demotrated that the binding of [ 3 H]prazosin (B max or K D )to 1 receptors in rat cerebral cortex was not altered by repeated administration of IMI or AMA. However, the ability of the 1 receptor agonist, phenylephrine, to compete for those sites was significantly increased upon repeated administration of IMI jointly with AMA, which indicates the enhancement of their affinity for the agonist (our data in preparation). The above results suggest that AMA given repeatedly evokes hyperrespoiveness of 1 receptors. Such activity was observed earlier following repeated administration of ADs [19, 22, 36]. It should also be pointed out that AMA at therapeutic concentratio binds to the sigma 1 site [7]. Some findings indicate that the selective sigma 1 ligands, such as SA4503, are active in the forced swimming test and may thus be potential antidepressants [26, 41]. Therefore, the action of AMA at sites other than NMDA receptors may have contributed to its greater activity in the present study. It is noteworthy that AMA (used in Parkion s disease) does show some beneficial symptomatological effects in depressed patients [15, 47]. Additionally, preliminary studies indicated that joint administration of IMI ( mg/day) and AMA (150 mg/day) for six weeks resulted in clinical improvement, estimated with Hamilton s Depression Rating Scale in patients with ISSN

6 Z. Rogó, G. Skuza, M. Kuœmider, J. Wójcikowski, M. Kot, W.A. Daniel drug-resistant unipolar depression (a drop from 32.2 ± 1.2 to 12.2 ± 1.3 points) [13]. The plasma level of IMI in those patients was ng/ml, and it did not change during joint treatment with AMA, indicating the lack of pharmacokinetic interaction [12]. In conclusion, the results described in the present paper indicate that co-administration of IMI and AMA may induce a more pronounced antidepressive activity than treatment with IMI alone, and that in addition to other mechanisms, dopamine D 2/3 and 1 receptors may contribute to the synergistic action of IMI and AMA in the forced swimming test in rats. This finding may be of particular importance in the case of patients with drug-resistant depression, and may suggest a method of obtaining significant antidepressive effects while limiting side effects. Acknowledgment. The work was supported by grant No. 4 PO5B p02 from the State Committee for Scientific Research, Warszawa, Poland. REFERENCES 1. Allen RM: Role of amantadine in the management of neuroleptic induced extrapyramidal syndromes: overview and pharmacology. Clin Neuropharmacol, 1983, 6, Suppl 1, S64 S Bickel MH, Mindel R: Metabolism and biliary excretion of the lipophilic drug molecules, imipramine and desipramine in the rat. I. Experiments in vivo and with isolated perfused liver. Biochem Pharmacol, 1970, 15, Borsini F, Meli A: Is the forced swimming test a suitable model for revealing antidepressant activity? Psychopharmacology, 1988, 94, Br sen K, Gram LF, Klysner R, Bech P: Steady-state levels of imipramine and its metabolites: significance of dose-dependent kinetics. Eur J Clin Pharmacol, 1986, 30, Daniel W, Adamus A, Melzacka M, Szymura J, Vetulani J: Cerebral pharmacokinetics of imipramine after single and multiple dosages. Naunyn Schmiedebergs Arch Pharmacol, 1981, 317, Daniel WA, Wójcikowski J: The role of lysosomes in the cellular distribution of thioridazine and potential drug interactio. Toxicol Appl Pharmacol, 1999, 158, Danysz W, Parso CG, Kornhuber J, Schmidt WJ, Quack G: Aminoadamantanes as NMDA receptor antagonists and antiparkionian agents preclinical studies. Neurosci Biobehav Rev, 1997, 21, Dingel JV, Sulser F, Gillette JR: Species differences in the metabolism of imipramine and desipramine (DMI). J Pharmacol Exp Ther, 1964, 143, Dziedzicka-Wasylewska M, Kolasiewicz W, Rogó Z, Margas W, Maj J: The role of dopamine D 2 receptor in the behavioral effects of imipramine study with the use of antisee oligonucleotides. J Physiol Pharmacol, 2000, 51, Dziedzicka-Wasylewska M, Rogo R: The effect of prolonged treatment with imipramine on the biosynthesis and functional characteristics of D 2 dopamine receptors in the rat caudate putamen. Br J Pharmacol, 1998, 123, Dziedzicka-Wasylewska M, Rogo R, Klimek V, Maj J: Repeated administration of antidepressant drugs affects the level of mrna coding for D 1 and D 2 dopamine receptors in the rat brain. J Neural Tram, 1997, 104, Dziedzicka-Wasylewska M, Rogó Z, Solich J, Daniel W, Wójcikowski J, Dudek D, Wróbel A et al.: Clinical effect of joint administration of imipramine and amantadine in the patients with drug-resistant unipolar depression. Pol J Pharmacol, 2003, 55, Dziedzicka-Wasylewska M, Rogó Z, Solich J, Dudek D, Wróbel A, Ziêba A: Effect of joint administration of imipramine and amantadine on binding of [ 3 H]7-OH-DPAT to dopamine D 3 receptors in peripheral blood lymphocytes of the patients with drugresistant unipolar depression. Pol J Pharmacol, 2002, 54, Gianutsos G, Chute S, Dunn JP: Pharmacological changes in dopaminergic systems induced by longterm administration of amantadine. Eur J Pharmacol, 1985, 110, Huber TJ, Dietrich DE, Emrich HM: Possible use of amantadine in depression. Pharmacopsychiatry, 1999, 32, Javaid JI, Perel JM, Davis JM: Inhibition of biogenic amines uptake by imipramine, desipramine, 2-OHimipramine and 2-OH-desipramine in rat brain. Life Sci, 1979, 24, Levant B: The D 3 dopamine receptor: neurobiology and potential clinical relevance. Pharmacol Rev, 1997, 49, Maj J: Behavioural effects of antidepressant drugs given repeatedly on the dopaminergic system. In: Dopamine and Mental Depression. Ed. Gessa GL, Serra G, Oxford Press, 1990, Maj J: Antidepressants given repeatedly: pharmacological evaluation of their action. Pol J Pharmacol, 1991, 43, Maj J, Dziedzicka-Wasylewska M, Rogo R, Rogó Z: Effect of antidepressant drugs administered repeatedly on the dopamine D 3 receptors in the rat brain. Eur J Pharmacol, 1998, 351, Maj J, Dziedzicka-Wasylewska M, Rogó Z, Rogo R, Margas W: Effects of venlafaxine given repeatedly on 1, dopaminergic and serotonergic receptors in rat brain. Hum Psychopharmacol, 1999, 14, Maj J, Mogilnicka E, Klimek V, Kordecka-Magiera A: Chronic treatment with antidepressants: potentiation 184 Pol. J. Pharmacol., 2004, 56,

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