Mechanism of synergistic action following co-treatment with pramipexole and fluoxetine or sertraline in the forced swimming test in rats

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1 Pharmacological Reports 26, 58, 493 ISSN Copyright 26 by Institute of Pharmacology Polish Academy of Sciences Mechanism of synergistic action following co-treatment with pramipexole and fluoxetine or sertraline in the forced swimming test in rats Zofia Rogó, Gra yna Skuza Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smêtna 12, PL Kraków, Poland Correspondence: Zofia Rogó, Abstract: The aim of the present study was to examine the effect of combined treatment of male Wistar rats with pramipexole and fluoxetine or sertraline in the forced swimming test. The obtained results showed that co-treatment with pramipexole (.1 mg/kg) and fluoxetine (1 mg/kg) or sertraline (5 mg/kg) (in doses inactive per se) exhibited antidepressant-like activity in the forced swimming test. Sulpiride (a dopamine D 2/3 receptor antagonist) and WAY 635 (a 5-HT 1A receptor antagonist), either being ineffective in the forced swimming test, inhibited the antidepressant-like effect induced by co-administration of pramipexole and fluoxetine or sertraline. However, SCH 2339 (a dopamine D 1 receptor antagonist) did not alter the effect of pramipexole given jointly with antidepressant drugs; on the other hand, S 3384 (a dopamine D 3 receptor antagonist) only partly decreased (in a statistically insignificant manner) that effect. Moreover, progesterone and BD 147 (a receptor antagonist) counteracted the antidepressant-like effect induced by co-administration of pramipexole and sertraline (but not pramipexole and fluoxetine). In that test, active behavior did not reflect the increases in general activity, since combined administration of pramipexole and fluoxetine or sertraline failed to enhance the locomotor activity of rats. None of the tested drugs (SCH 2339, sulpiride, S 3384, WAY 635, BD 147 and progesterone) alone or in combination with pramipexole and fluoxetine or sertraline changed locomotor activity. The results described in the present paper indicate that co-administration of pramipexole and fluoxetine or sertraline may induce a more pronounced antidepressive activity than does treatment with pramipexole alone, and that in addition to other mechanisms, dopamine D 2/3 and 5-HT 1A receptors may contribute to the antidepressant-like activity of pramipexole and fluoxetine or sertraline in the forced swimming test in rats. Moreover, 1 receptors may constitute one of the possible mechanisms by which co-administration of pramipexole and sertraline induces antidepressant-like activity in that test. Key words: pramipexole, fluoxetine, sertraline, forced swimming test, rats Introduction Behavioral and biochemical data indicate involvement of a dopamine neurotransmitter system in the pathophysiology of depression, as well as in the mechanism of action of antidepressant drugs (ADs) [6, 1, 29, 57, 6]. It has been shown that mesolimbic dopamine pathways are important to goal-directed behaviors, and that the hypofunction of this system may mediate anhedonia and a motivational apathy [61], i.e. behaviors which are the key features of major depression. Recent studies have focused on the potential role of specific dopamine receptors, including the dopamine D 3 receptor, in depression. Unlike the D 2 receptor Pharmacological Reports, 26, 58,

2 which is widely distributed throughout the brain [16], the D 3 receptor shows a relatively restricted distribution and is highly expressed in limbic areas [28, 53], i.e. regions involved in reward, emotional and cognitive processes. Chronic treatment with ADs has been reported to enhance D 3 receptor binding in rats [3]. Furthermore, studies by Lammers et al. [22] revealed a selective increase in dopamine D 3 receptor gene expression in rats (versus D 1 and D 2 ) following chronic treatment with fluoxetine and tranylcypromine, as well as chronic ECS. The highly expressed dopamine D 3 receptor in limbic areas and the effect of ADs on the expression of these receptors, indicate involvement, not only D 2, but also D 3 receptors in the mechanism of action of ADs [1, 29, 3, 38, 57, 6]. Pramipexole is a potent agonist belonging to the D 2 subfamily of dopamine receptors [36, 37], which has currently been approved for use in Parkinson s disease [2, 15, 25, 47,, 58]. It has little activity towards other receptor families, and within the D 2 subfamily it binds with the highest affinity to D 3 receptors. Some earlier studies showed that pramipexole also revealed activity in animal models of depression, including the chronic mild stress model [62] and the forced swimming test in rats [32] or mice [51]. Our earlier studies also demonstrated that pramipexole increased the antidepressive effect of imipramine and amitriptyline in the forced swimming test [32]. Interestingly, the selective serotonin reuptake inhibitors (SSRI) citalopram, fluoxetine and sertraline which, when given alone, were inactive in the forced swimming test in rats, enhanced the positive effect of pramipexole (reduction of the immobility time) [31, 32]. Furthermore, clinical studies reported efficacy of pramipexole either alone or as an adjunct to the therapy with ADs in depressed patients [9, 11, 19, 2, 23, 43, 54, 63]. It is well established that all the currently used ADs show therapeutic efficacy in a maximum of 67% of depressive patients. The problem of ADresistant depression has been the subject of an extensive study, and alternative treatments have been proposed (e.g. co-administration of ADs and dopamine D 3 agonists). Since a combination of pramipexole, a dopamine D 3 receptor agonist, and ADs (including SSRI) may help reduce their doses and, in consequence, also their side-effects, the aim of the present study was to examine the effect of combined treatment with pramipexole and fluoxetine or sertraline (at an ineffective dose) in the forced swimming test in rats (an animal model of depression). Additionally, we used dopamine (D 1, D 2/3,D 3 ), 5-HT 1A and sigma 1 ( 1 ) receptor antagonists to determine the role of those receptors in the antidepressant-like effect induced by joint treatment with pramipexole and fluoxetine or sertraline in the forced swimming test. Materials and Methods Animals and drug treatment The experiments were carried out on male Wistar rats (227 g). The animals had free access to food and water and were kept at a constant room temperature (22 ± 1 o C) on a 12-h light/dark cycle (light on at 7. h). Pramipexole (sc), fluoxetine and sertraline (ip), SCH 2339, sulpiride, S 3384 and BD 147 (ip) and WAY 635 or progesterone (sc) were dissolved in saline. All the drugs were injected in a volume of 2 ml/kg. Each experimental group consisted of 8 naive animals/dose, and the animals were used only once in each test. The experiments were performed by an observer blind to the treatment. All the experimental procedures were approved by the Local Bioethics Commission at the Institute of Pharmacology, Polish Academy of Sciences in Kraków. Substances used BD 147 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl- 2-(dimethylamino) ethylamine dihydrobromide (BD 147, Tocris Bioscience, Ellisville, USA), fluoxetine hydrochloride (FLU, Farmacom, Kraków, Poland), pramipexole dihydrochloride (PRA, Boehringer- Ingelheim, Germany), R(+)-SCH 2339 hydrochloride (R(+)-7-chloro-8-hydroxy-3-methyl-l-phenyl-2,2,4,5- tetrahydro- 1H-3-benzazepine hydrochloride) and () sulpiride (Research Biochemicals Inc., Natick, USA), sertraline hydrochloride (SER, Pfizer GmbH, Karlsruhe, Germany), N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)-cyclohexane-carboxamide trihydrochloride (WAY 635; synthesized by Dr. J. Boksa, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland). 494 Pharmacological Reports, 26, 58, 493

3 Mechanism of synergistic action following co-treatment of pramipexole and fluoxetine or sertraline Zofia Rogó et al. Forced swimming (Porsolt s) test The animals were subjected to two trials during which they were forced to swim in a measuring flask (4 cm high, 18 cm in diameter) filled with water (2325 o C) up to a height of 15 cm. There was a 24-h interval between the first and second trials; the first trial lasted 15 min, the second 5 min. The total duration (s) of immobility was measured during the second trial [45]. Pramipexole (.1 mg/kg), fluoxetine (5 or 1 mg/kg) and sertraline (2.5 or 5 mg/kg) were given three times at 24, 5 and 1 h before the test. In separate groups, pramipexole (.1 mg/kg) was injected jointly with fluoxetine (5 and 1 mg/kg) or sertraline (2.5 and 5 mg/kg), either being given three times as described above. SCH 2339 (.5 mg/kg), sulpiride (1 mg/kg) and S 3384 (.2 mg/kg) were given (ip) at 3 min, and WAY 635 (.1 mg/kg), BD 147 (3 mg/kg ip) or progesterone (2 mg/kg) (sc) at 15 min before joint treatment with pramipexole and ADs. Each group consisted of 8 rats. Locomotor activity Pramipexole (.1 mg/kg), fluoxetine (5 or 1 mg/kg) and sertraline (2.5 or 5 mg/kg) were given three times at 24, 5 and 1 h before the test (like in the forced swimming test). Also pramipexole (.1 mg/kg) was given in combination with fluoxetine (5 and 1 mg/kg) or sertraline (2.5 and 5 mg/kg) at 24, 5 and 1 h before the test. Dopamine receptor antagonists (SCH 2339, sulpiride and S 3384) and a 5-HT 1A receptor antagonist (WAY 635) or sigma 1 ( 1) receptor antagonists were examined (like in the forced swimming test). Locomotor activity was measured in photoresistor actometers (two light beams, two photoresistors; L W H=4 4 25cm)[31], in which the animals were individually placed. Activity counts were recorded for 3 min. Each group consisted of 8 rats. Data analysis The data were evaluated by a one-way analysis of variance (ANOVA), followed, when appropriate, by individual comparisons with the control using Dunnett s test. Results Forced swimming (Porsolt s) test Pramipexole (.1 mg/kg) did not change the immobility time in the forced swimming test (Figs. 1, 2 and 3). Neither fluoxetine (5 and 1 mg/kg) nor sertraline (2.5 and 5 mg/kg) modified the immobility time in rats. Joint administration of pramipexole (.1 mg/kg) and fluoxetine (1 mg/kg), or pramipexole (.1 mg/kg) and sertraline (5 mg/kg) produced antidepressant-like activity in the forced swimming test, decreased the immobility time (Figs. 2 and 3). A lower dose of fluoxetine (5 mg/kg) or sertraline (2.5 mg/kg) did not enhance the effect of pramipexole (.1 mg/kg) in that test (Fig.1). Sulpiride (1 mg/kg) and WAY 635 (.1 mg/kg) were ineffective in the forced swimming test (data not shown), but they inhibited the antidepressant-like effect induced by co-administration of pramipexole and fluoxetine (1 mg/kg) (Fig. 2), or pramipexole and sertraline (5 mg/kg) (Fig. 3). On the other hand, neither SCH 2339 (.5 mg/kg) nor S 3384 (.2 mg/kg) changed the immobility time (data not shown) nor did SCH 2339 alter the effect of pramipexole when given jointly with ADs. S 3384 only partly decreased (in a statistically insignificant manner) the effect of pramipexole + fluoxetine, or pramipexole + sertraline (Figs. 2A and 3A). Moreo PRA FLU 5 5 SER [mg/kg] Fig. 1. The effect of pramipexole (PRA.1 mg/kg) given alone or in combination with fluoxetine (FLU 5 mg/kg) or sertraline (SER 2.5 mg/kg) on the immobility time in the forced swimming test in rats. PRA, FLU or SER were given three times: at 24, 5 and 1 h before the test. The animals were observed for 5 min. The results represent the mean ± SEM (s) from 8 rats. The data were statistically evaluated by ANOVA, followed by Dunnett s test Pharmacological Reports, 26, 58,

4 ver, progesterone (2 mg/kg) and BD 147 (3 mg/kg) did not modify immobility time (data not shown), but it inhibited the antidepressant-like effect induced by co-administration of pramipexole and sertraline (Fig. 3B), but not PRA and FLU (Fig. 2B). Locomotor activity None of the tested drugs: pramipexole (.1 mg/kg), fluoxetine (1 mg/kg), sertraline (5 mg/kg) alone or A * p <.1 vs. vehicle # p <.1 vs. PRA + SER A PRA FLU SCH 2339 S 3384 SUL 2 1 B * p <.1 vs. vehicle # p <.1 vs. PRA + FLU [mg/kg] * p <.1 vs. vehicle # p <.1 vs. PRA + FLU PRA FLU WAY [mg/kg] PROG 2 BD Fig. 2. The influence of SCH 2339 (.5 mg/kg), S 3384 (.2 mg/kg) and sulpiride (1 mg/kg) (A), or WAY 635 (.1 mg/kg), progesterone (2 mg/kg) and BD 147 (3 mg/kg) (B), on the antidepressantlike effect induced by co-treatment with pramipexole (PRA.1 mg/kg) and fluoxetine (FLU 1 mg/kg) in the forced swimming test in rats. PRA was given jointly with FLU three times: at 24, 5 and 1 h before the test. SCH 2339, sulpiride and S 3384 were given at 3 min, and WAY 635, progesterone or BD 147 at 15 min before each injection of PRA + FLU. The animals were observed for 5 min. The results represent the mean ± SEM (s) from 8 rats. The data were statistically evaluated by ANOVA, followed by Dunnett s test PRA SER SCH [mg/kg] S SUL 1 B 3 * p <.1 vs. vehicle # p <.1 vs. PRA + SER PRA SER WAY PROG 2 BD in combination with pramipexole (.1 mg/kg) and fluoxetine (1 mg/kg) or sertraline (5 mg/kg) changed the locomotor activity of rats (data not shown). The dopamine receptor antagonists SCH 2339 (.5 mg/kg), S 2339 (.2 mg/kg) and sulpiride (1 mg/kg), or the 5-HT 1A receptor antagonist WAY 635 (.1 mg/kg) and progesterone (2 mg/kg) or BD 147 (3 mg/kg) at the doses used in the forced * # # # [mg/kg] Fig. 3. The influence of SCH 2339 (.5 mg/kg), S 3384 (.2 mg/kg) and sulpiride (1 mg/kg) (A), or WAY 635 (.1 mg/kg), progesterone (2 mg/kg) and BD 147 (3 mg/kg) (B), on the antidepressantlike effect induced by co-treatment with pramipexole (PRA.1 mg/kg) and sertraline (SER 5 mg/kg) in the forced swimming test in rats. PRA was given jointly with SER three times: at 24, 5 and 1 h before the test. SCH 2339, sulpiride and S 3384 were given at 3 min, and WAY 635, progesterone or BD 147 at 15 min before each injection of PRA + SER. The animals were observed for 5 min. The results represent the mean ± SEM (s) from 8 rats. The data were statistically evaluated by ANOVA, followed by Dunnett s test 496 Pharmacological Reports, 26, 58, 493

5 Mechanism of synergistic action following co-treatment of pramipexole and fluoxetine or sertraline Zofia Rogó et al. swimming test neither changed the locomotor activity in a statistically significant manner, nor did they decrease the effects induced by joint administration of pramipexole and fluoxetine, or pramipexole and sertraline (data not shown). Discussion In the present study, we examined the effect of combined treatment with pramipexole (a dopamine D 3 receptor agonist) and SSRI (fluoxetine or sertraline) in the forced swimming test in rats. Our results showed that co-treatment of pramipexole and fluoxetine or sertraline at doses inactive per se produced antidepressant-like activity in the forced swimming test since they reduced the immobility time of rats. Our earlier studies revealed that pramipexole at a higher dose (.3 mg/kg) produced antidepressant-like activity in the forced swimming test in rats, and that joint treatment with pramipexole (.3 mg/kg) and imipramine or amitriptyline (at doses active per se) evoked a more potent antidepressant effect than did administration of either of those substances alone [32]. The interaction was particularly interesting in the case of SSRIs, since co-administration of pramipexole at an active dose (.3 mg/kg) and SSRIs (citalopram, fluoxetine and sertraline) at doses inactive per se enhanced the antidepressant effect of pramipexole in Porsolt s test in rats [31, 32]. It is noteworthy that SSRI do not show antidepressant-like activity in the forced swimming test in rats, carried out in accordance with the original method of Porsolt [24, 31, 45]. Some authors described positive effects when higher doses of SSRIs were used, or when the test was conducted on mice [33, 4]. Moreover, Detke and Lucki [13] and Detke at al. [14] reported positive effects of such SSRIs as fluoxetine or sertraline in rats, when a modified forced swimming procedure was employed, using the separate scoring of immobility, swimming, climbing and diving. It is generally accepted that in the forced swimming test false positive effects can be induced by various dopamine stimulants used at doses increasing locomotor activity. In our experiment, neither pramipexole, nor fluoxetine, nor sertraline per se enhanced locomotor activity, nor did co-administration of those compounds increase locomotor activity. It is, therefore, unlikely that the positive effect observed in the forced swimming test was a simple consequence of general behavioral stimulation. It also seems unlikely that pharmacokinetic interactions between pramipexole and SSRI can contribute to the evident action in the forced swimming test, since a combination of the examined agents failed to change behavioral activity in the locomotor activity test. Furthermore, our present study showed that sulpiride (a dopamine D 2/3 antagonist [27]) given in the dose ineffective in the forced swimming test inhibited the antidepressant-like effect induced by co-administration of pramipexole and fluoxetine, or pramipexole and sertraline. In contrast, SCH 2339 (a dopamine D 1 antagonist) did not change the antidepressant-like effect evoked by joint treatment with pramipexole and fluoxetine or sertraline, but S 3384 (a dopamine D 3 antagonist [39]) only partly decreased that effect of pramipexole given with SSRIs. Moreover, WAY 635 (a 5-HT 1A antagonist [17]) at the dose inactive in Porsolt s test, decreased the antidepressant-like effect of pramipexole given with fluoxetine or sertraline. The above results suggest that probably dopamine D 2/3 and 5-HT 1A (but not dopamine D 1 ) receptors may play a role in antidepressant-like effects of pramipexole and SSRIs (fluoxetine or sertraline) in the forced swimming test in rats. Siuciak and Fujiwara [51] also showed that pramipexole reduced immobility time in the forced swimming test in mice, and that LU-2164, a D 3 selective antagonist, failed to block the antidepressantlike effect of that drug. In contrast, the efficacy of pramipexole was completely blocked by the D 2 antagonist haloperidol in the forced swimming test. No baseline differences were observed between knockout (C57BL/6J and B6129SF2/J) and wide-type mice of either background strain in locomotor activity or performance in the forced swimming test. Furthermore, in both background strains, pramipexole showed a similar efficacy in both wide-type and knockout mice in the forced swimming test. The above results suggest that the D 2 receptor rather than the D 3 one is important to the antidepressant-like activity observed for pramipexole in the mouse forced swimming test. On the other hand, there have been significant and consistent findings that AD treatments affect neurotransmission at dopamine synapses, including the sensitization of D 2 and D 3 receptor-mediated responses in the mesolimbic system. The mechanism of these ef- Pharmacological Reports, 26, 58,

6 fects, which still remains unclear, may reflect changes occurring in non-dopamine systems that interact with the dopaminergic synapse in the frontal cortex [18]. It has been suggested that SSRIs acting on the serotonergic system may indirectly affect dopamine pathways and that this action may play a role in antidepressant-like effects [8, 18, 55]. Moreover, numerous studies have shown neuronal connections between the dopamine and serotonin brain systems. Connections between serotonergic axons and dopaminergic cells in the substantia nigra and a nigroraphe pathway exist, suggesting either an indirect or direct connection between the cell bodies of dopaminergic and serotonergic neurons [21, 24]. Also microdialysis studies have demonstrated interactions between the serotonergic system and dopaminergic activity. For example, serotonergic stimulation of the prefrontal cortex [7], the striatum [42, 59], the limbic forebrain [42] or the nucleus accumbens [5, 41] potently released dopamine. Recent studies indicate that binding sites abound in limbic brain regions such as, e.g., the hippocampus and amygdala are involved in the modulation of emotional response [12]. Moreover, some ADs, e.g. sertraline, fluvoxamine (but not fluoxetine) [48, 49] or opipramol [46], show high affinity for binding sites; furthermore, 1 receptors may play some role in the mechanism of antidepressant action [26, 48, 52]. Also a potent antidepressant activity of 1 agonists (igmesine and OPC 14523) has been demonstrated by preclinical studies [1, 56]. Our present study showed that progesterone, a 1 receptor antagonistic neurosteroid, or BD 147, a novel receptor antagonist with preferential affinity for 1 sites [34, 35], given in a dose inactive per se inhibited the antidepressant-like effect induced by co-administration of pramipexole and sertraline (but not pramipexole and fluoxetine). The lack of effect of 1 receptor antagonists on the shortening of the immobility time of rats after joint administration of pramipexole and fluoxetine seems to be connected with a considerably poorer fluoxetine affinity for 1 receptors than that shown by sertraline. In the case of fluoxetine, still another mechanism may be involved. Of the SSRIs tested, fluoxetine the most potently enhanced the synthesis of allopregnanolone which has no significant affinity for 1 receptors, but shows an antidepressant-like effect [44]. Since sertraline exhibits high affinity for 1 binding sites, the above results indicate that 1 receptors may constitute one of the possible mechanisms by which sertraline induces antidepressant-like activity in the forced swimming test [31], and that this effect may be enhanced by pramipexole (a dopamine D 3 receptor agonist). In conclusion, the results obtained in the present study indicate that pramipexole, a dopamine D 3 agonist, interacts with SSRI (fluoxetine or sertraline) in the forced swimming test in rats, and that in addition to other mechanisms, dopamine D 2/3 and 5-HT 1A receptors may play a role in the antidepressant-like effect of pramipexole and fluoxetine or sertralione in that test in rats. Moreover, the above-described results indicate that 1 receptors may be one of the possible mechanisms by which co-administration of pramipexole and sertraline induces antidepressant-like activity in the forced swimming test. Since a combination of pramipexole, a dopamine D 3 receptor agonist, and an antidepressant drug (including SSRI) may help reduce their doses and, in consequence, also their sideeffects, these findings may be of particular importance in the case of drug-resistant patients, and may suggest a method of obtaining significant antidepressant actions while limiting side-effects. Acknowledgments: The authors wish to thankboehringer-ingelheim for pramipexole and Farmacom (Kraków, Poland) for fluoxetine. We are also indebted to Ms. E. Smolak, M.A., for the linguistic supervision of our paper. References: 1. Akunne HC, Zoski KT, Whetzel SZ, Cordon JJ, Brandon RM, Roman F, Pugsley TA: Neuropharmacological profile of a selective sigma ligand, igmesine: a potential antidepressant. Neuropharmacology, 21, 41, Bennett JP Jr, Piercey MF: Pramipexole a new dopamine agonist for the treatment of Parkinson s disease. J Neural Sci, 1999, 163, Borsini F: Role of the serotonergic system in the forced swimming test. Neurosci Behav Rev, 1995, 19, Borsini F, Meli A: Is the forced swimming test a suitable model for revealing antidepressant activity? Psychopharmacology, 1988, 94, Boulenguez P, Rawlins JNP, Chauveau J, Joseph MH, Michell SN, Gray JA: Modulation of dopamine release in the nucleus accumbens by 5-HT 1B agonists: involvement of the hippocampo-accumbens pathways. Neuropharmacology, 1996, 35, Brown AS, Gershon S: Dopamine and depression. J Neural Transm, 1993, 91, Chen J, Paredes W, Van Praag HM, Lowinson JH, Gardner EL: Presynaptic dopamine release is enhanced by 498 Pharmacological Reports, 26, 58, 493

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