European Journal of Pharmacology 638 (2010) 78–83

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European Journal of Pharmacology

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Behavioural Pharmacology

Involvement of dopamine receptors in the antidepressant-like effect of melatonin inthe tail suspension test

Ricardo W. Binfaré a, Michela Mantovani a, Josiane Budni a,Adair Roberto S. Santos b, Ana Lúcia S. Rodrigues a,⁎a Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazilb Departamento de Ciências Fisiológicas, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil

⁎ Corresponding author. Tel.: +55 48 37215043; fax:E-mail addresses: analucia@mbox1.ufsc.br, alsrodri@

0014-2999/$ – see front matter © 2010 Elsevier B.V. Adoi:10.1016/j.ejphar.2010.04.011

a b s t r a c t

a r t i c l e i n f o

Article history:Received 18 August 2009Received in revised form 18 March 2010Accepted 12 April 2010Available online 18 April 2010

Keywords:AntidepressantDepressionDopaminergic systemMelatoninTail suspension test

Melatonin was previously shown to produce an antidepressant-like effect in the tail suspension test. In thiswork the mechanisms underlying its antidepressant-like effect were further studied by investigating theinvolvement of the dopaminergic system in its antidepressant-like effect in the tail suspension test. Theeffect of melatonin (1 mg/kg, i.p.) was prevented by the pretreatment of mice with haloperidol (0.2 mg/kg, i.p., a nonselective dopaminergic receptor antagonist), SCH23390 (0.05 mg/kg, s.c., a selective dopamine D1receptor antagonist), and sulpiride (50 mg/kg, i.p., a selective dopamine D2 receptor antagonist). The i.p.administration of melatonin (0.01 mg/kg) or fluoxetine (1 mg/kg, a serotonin reuptake inhibitor) incombination with SFK38393 (0.1 mg/kg, s.c., a dopamine D1 receptor agonist) reduced the immobility timein the tail suspension test as compared with either drug alone. Moreover, the pretreatment with melatonin(0.01 mg/kg, i.p.) produced a synergistic effect with apomorphine (0.5 μg/kg, i.p., a dopamine D2 receptoragonist), but the pretreatment with fluoxetine (1 mg/kg, i.p.) was ineffective to potentiate the effect ofapomorphine. Dopamine receptor antagonists or agonists alone or in combination with melatonin did notaffect locomotor activity. These results indicate that the antidepressant-like effect of melatonin in the tailsuspension test is likely mediated by an interaction with the dopaminergic system, through an activation ofdopamine D1 and D2 receptors. Our data confirm the previous notion on the role exerted by melatonin indepression, suggesting that it might be further investigated as an alternative for the management ofdepression associated with anhedonia.

+55 48 37219672.gmail.com (A.L.S. Rodrigues).

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© 2010 Elsevier B.V. All rights reserved.

1. Introduction

Melatonin is secreted principally by the pineal gland at night inmost vertebrate species, including humans (Reiter and Korkmaz,2008). The rhythm of melatonin secretion may be impaired in variouspathological states and an alteration in its secretory pattern has beenfound in some psychiatric disorders, including depression (Maldo-nado et al., 2009; Reiter and Benitez-King, 2009; Srinivasan et al.,2006). This disease is also associated with desynchronization ofcircadian rhythms (Lader, 2007) and is postulated that exogenousmelatonin can act resynchronizing these rhythms and then improvingsuch depressive symptom (Pandi-Perumal et al., 2006). In addition,there are some reports which show that agomelatin, a melatonergicagonist and selective antagonist 5HT2C, is clinically effective inpatients with major depression (Loo et al., 2002; Pandi-Perumal et al.,2006) and appears to be more tolerable than other antidepressants(Montgomery, 2006; Zupancic and Guilleminault, 2006).

Melatonin was shown to produce an antidepressant-like effect inthe mouse tail suspension test (Mantovani et al., 2003; Prakhie andOxenkrug, 1998), and in the rat forced swimming test (Micale et al.,2006) two predictive models frequently used to evaluate the efficacyof drugs designed to treat depression (Cryan et al., 2005). Further-more, a recent study showed that melatonin administration pre-vented behavioral and physiological changes induced by the chronicmild stress model of depression in mice (Detanico et al., 2009), thusreinforcing the notion that this hormone possess antidepressantproperties and is effective in animal models of depression.

Several studies indicate that the dopaminergic system is implicat-ed in the pathophysiology of depression (Papakostas, 2006; Willneret al., 2005). Clinical data have shown that depression may be relatedto reduced dopamine levels and its metabolite homovanillic acid inthe brain in depressed and/or suicidal patients compared to normalindividuals (Engström et al., 1999; Hamner and Diamond, 1996;Mitani et al., 2006; Papakostas, 2006; Sher et al., 2006).

Preclinical studies reported that dopamine receptor agonistsenhance antidepressant effects of animals in the forced swimmingtest (Joca et al., 2000; Maj and Rogoz, 1999). Moreover, Yamada et al.(2004) showed that dopamine D1 and D2 receptors play a role in the

Fig. 1. Effect of pretreatment ofmicewith haloperidol (0.2 mg/kg, i.p., panel A;N=6–7),SCH23390 (0.05 mg/kg, s.c., panel B; N=6–7) or with sulpiride (50 mg/kg, i.p., panel C;N=8–10) on the melatonin-(1 mg/kg, i.p.) induced reduction in immobility time in thetail suspension test. Each column represents themean+S.E.M. **Pb0.01 comparedwiththe vehicle-treated control. #Pb0.01 as compared with melatonin group pretreatedwith vehicle.

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antidepressant-like effect of dopamine reuptake inhibitors in thismodel. In addition, Ossowska et al. (2002) showed that the increase inthe brain dopamine D1 receptors in the limbic system after chronicunpredictable stress model of depression is normalized by treatmentwith imipramine.

Some understanding of the role of melatonin in human physiologyand disease has emerged, but many functions and effects of melatoninare not still established (Claustrat et al., 2005), including the precisemechanisms underlying its antidepressant effects. Considering thatmelatonin produces antidepressant-like effect in preclinical studies(Detanico et al., 2009; Mantovani et al., 2003) and that dopaminemayplay an important role in depressive disorders, the present studysought to investigate the influence of dopaminergic system, partic-ularly dopamine D1 and D2 receptors subtypes, in the antidepressant-like effect of melatonin in the tail suspension test in mice.

2. Materials and methods

2.1. Animals

Male Swiss mice (30–40 g) were maintained at 21–24 °C with freeaccess to water and food, under a 12:12 h light:dark cycle (lights on at07:00 h). All manipulations were carried out between 11:00 and16:00 h, with each animal used only once. The experiments wereperformed after approval of the protocol by the institutional EthicsCommittee and all efforts were made to minimize animals sufferingand to reduce the number of animals used in the experiments.

2.2. Drugs and treatment

The following drugs were used: melatonin, haloperidol, R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-ben-zazepine hydrochloride (SCH23390), sulpiride, apomorphine, (±)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol hydrochloride(SKF38393) and fluoxetine (all from Sigma Chemical Company, St.Louis,MO, U.S.A.). All drugs were administered by intraperitoneal (i.p)route, except SCH23390 and SKF38393 that were administered bysubcutaneous (s.c.) route. All drugs were administered in a constantvolume of 10 ml/kg body weight. Drugs were dissolved in saline,except haloperidol that was diluted in saline with 5% ethanol,melatonin that was diluted in saline with 2% ethanol and sulpiridethat was diluted in saline with 5% DMSO. Control animals receivedappropriate vehicle.

In the experiments designed to verify the involvement of thedopaminergic system in the mechanisms underlying the antidepres-sant-like effect of melatonin in the tail suspension test, mice were pre-treated with vehicle (control group), haloperidol (0.2 mg/kg, i.p., anonselective dopaminergic receptor antagonist), SCH23390 (0.05 mg/kg, s.c., a selective dopamine D1 receptor antagonist) or sulpiride(50 mg/kg, i.p., a selective dopamine D2 receptor antagonist) (Binfaréet al., 2009; Machado et al., 2007) and 30 min later they receivedvehicle or a dose of melatonin (1 mg/kg, i.p.) that was previouslyshown by our group to be effective in the tail suspension test(Mantovani et al., 2003). After 30 min the tail suspension test wascarried out. In another set of experiments, the effect of the combinedadministration of melatonin (0.01 mg/kg, i.p.) with SKF38393(0.1 mg/kg, s.c., a dopamine D1 receptor agonist) or apomorphine(0.5 g/kg, i.p., a dopamine D2 receptor agonist) was investigated.Melatonin or vehicle was administered 20 min before these agonists.A further 30 minwas allowed to elapse before the animalswere testedin the tail suspension test. In order to investigate the combined effectof SKF38393 or apomorphine with the well know serotonin reuptakeinhibitor (SSRI) fluoxetine, mice were pretreated with vehicle or witha sub-effective dose of fluoxetine (1 mg/kg, i.p.) 20 min beforereceiving an injection of vehicle, SFK38393 (0.1 mg/kg, s.c.) or

apomorphine (0.5 g/kg, i.p). After 30 min the animals were tested inthe tail suspension test (Binfaré et al., 2009).

2.3. Tail suspension test

The total duration of immobility induced by tail suspension wasmeasured according to the method described by Steru et al. (1985).Mice both acoustically and visually isolated were suspended 50 cmabove the floor by adhesive tape placed approximately 1 cm from thetip of the tail. Immobility time was recorded during a 6-min period(Binfaré et al., 2009; Mantovani et al., 2003).

2.4. Statistical analysis

Comparisons between experimental and control groups wereperformed by ANOVA followed by Newman–Keuls test whenappropriate. A value of Pb0.05 was considered to be significant.

3. Results

The results depicted in Fig. 1 show the effect of dopaminergicantagonists in the antidepressant-like effect ofmelatonin (1 mg/kg, i.p.)in the tail suspension test. Fig. 1A shows that the pretreatment of micewith the non-selective dopamine receptor antagonist haloperidol(0.2 mg/kg, i.p.) significantly prevented the decrease in the immobilitytime elicited by the melatonin (1 mg/kg, i.p.). There was a significant

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effect of haloperidol pretreatment [F(1,22)=16.13,Pb0.01], melatonintreatment [F(1,22)=13.90, Pb0.01] and haloperidol pretreatment×melatonin treatment interaction [F(1,22)=22.76, Pb0.01]. Moreover,the pretreatment of mice with SCH23390 (0.05 mg/kg, s.c.) alsoprevented the antidepressant-like effect elicited by melatonin(Fig. 1B). A two-way ANOVA showed significant differences forSCH23390 pretreatment [F(1,21)=6.62, Pb0.05], melatonin treatment[F(1,21)=10.64, Pb0.01] and SCH23390 pretreatment ×melatonintreatment interaction [F(1,21)=7.64, Pb0.05]. In addition, the resultsdepicted in Fig. 1C show that the pretreatment of animalswith sulpiride(50 mg/kg, i.p.) prevented the effect of melatonin in the tail suspensiontest. A two-way ANOVA showed significant differences for sulpiridepretreatment [F(1,33)=6.00, Pb0.05], melatonin treatment [F(1,33)=13.88, Pb0.01] and sulpiride pretreatment×melatonin treatmentinteraction [F(1,33)=12.64, Pb0.01]. Fig. 2 shows that the administra-tion of haloperidol, SCH23390 and sulpiride alone or in combinationwith melatonin did not significantly affect the ambulation in the open-field test (PN0.05).

The results in Fig. 3 illustrate the effect of the dopamine D1receptor agonists in the action of a sub-effective dose of melatonin(0.01 mg/kg, i.p.) or fluoxetine (1 mg/kg, i.p.) in the tail suspensiontest and open-field test. As presented in Fig. 3A, the pretreatment ofmelatonin (0.01 mg/kg, i.p.) produced a synergistic antidepressant-like when mice were treated with SKF38393 (0.1 mg/kg, s.c.) in thetail suspension test. The two-way ANOVA revealed significantdifferences of SKF38393 treatment [F(1,23)=10.42, Pb0.01] andmelatonin pretreatment×SKF38393 treatment interaction [F(1,23)=6.56, Pb0.05], but not for melatonin pretreatment [F(1,23)=1.77,P=0.19]. In addition, the results depicted in Fig. 3B show a synergisticeffect of pretreatment with fluoxetine and treatment with SKF38393(0.1 mg/kg, s.c.). A two-way ANOVA showed significant differences offluoxetine [F(1,20)=10.43, Pb0.01], SKF38393 treatment [F(1,20)=

Fig. 2. Effect of pretreatment of mice with haloperidol (0.2 mg/kg, i.p., panel A),SCH23390 (0.05 mg/kg, s.c., panel B) or with sulpiride (50 mg/kg, i.p., panel C) andtreatment with melatonin-(1 mg/kg, i.p.) on the number of crossings in the open-fieldtest. Each column represents the mean+S.E.M. of 5 animals. No significant differenceswere observed.

7.79, Pb0.05] and fluoxetine pretreatment×SKF38393 treatmentinteraction [F(1,20)=10.43, Pb0.01]. The administration of SKF38393alone or in combination with melatonin or fluoxetine did notsignificantly affect the ambulation in the open-field test (Fig. 3Cand D, respectively; PN0.05).

The results presented in Fig. 4A show the effect of apomorphine(0.5 g/kg, i.p.) in potentiating the action of a sub-effective dose ofmelatonin (0.01 mg/kg, i.p.) in the tail suspension test. The two-wayANOVA revealed significant differences of melatonin pretreatment[F(1,27)=6.80, Pb0.05], apomorphine treatment [F(1,27)=11.34,Pb0.01] and melatonin pretreatment×apomorphine treatmentinteraction [F(1,27)=11.66, Pb0.01]. Moreover, Fig. 4B shows thatthe pretreatment of mice with a sub-effective dose of fluoxetine(1 mg/kg, i.p.) and treatment with apomorphine (0.5 μg/kg, i.p.) didnot produce a synergistic effect in the tail suspension test. A two-wayANOVA did not show significant differences of fluoxetine pretreat-ment [F(1,24)=3.96, P=0.05], apomorphine treatment [F(1,24)=0.49, P=0.48] and fluoxetine pretreatment×apomorphine treat-ment interaction [F(1,24)=1.72, P=0.20]. The administration ofapomorphine alone or in combination with melatonin or fluoxetinedid not significantly affect the ambulation in the open-field test(Fig. 4C and D, respectively; PN0.05).

4. Discussion

Conventional antidepressants remain inadequate for severalindividuals, might produce side effects, and a delay of several weeksto achieve its clinical efficacy and even inefficacy is observed in somecases. These drugs generally interfere with transporter-mediatedreuptake of serotonin, noradrenaline, or both (Nemeroff and Owens,2002). Notably, without directly affecting extracellular levels ofdopamine, sustained administration of antidepressants and electro-convulsive therapy (ECT) enhances transmission at dopaminergicreceptors in the nucleus accumbens (Nestler and Carlezon, 2006).Besides the widely use of serotonergic and/or noradrenergic agentsfor treating depression, a strengthening of dopaminergic transmissioncould otherwise be achieved by direct blockade of dopaminetransporters, such as the antidepressant bupropion (Dhillon et al.,2008).

Since dopamine is the main neurotransmitter involved in themesolimbic reward pathways, it has been proposed that an increase indopaminergic neurotransmission might counteract the anhedonia(D'Aquila et al., 2000) that is considered a core feature of majordepressive disorder (Gorwood, 2008). In addition, it should beconsidered that dopamine reuptake enhances sexual function, mayimprove cognitive performance (El-Ghundi et al., 2007; Hull et al.,2004; Milan, 2009) and also enhances the antidepressant actions ofSSRIs in rodents and in humans (Milan, 2009; Prica et al., 2008;Trivedi et al., 2006). For these reasons, the discovery of new drugs orinnovative compounds that could activate the dopaminergic systemmay be particularly interesting for the treatment of depression and forremission of specific symptoms of depression such as anhedonia.

It has been shown that melatonin exerts antidepressant action inthe rat forced swimming test, chronic forced swimming-inducedbehavioral despair, tail suspension test and chronicmild stress inmice(Detanico et al., 2009; Mantovani et al., 2003; Micale et al., 2006). Theresults presented herein extend these literature data and suggest thatthe effect of melatonin in the tail suspension test is dependent, at leastin part, on an interaction with the dopaminergic system throughdopamine D1 and D2 receptor activation. Considering that thedopaminergic system has been implicated in depression and thatcompounds that enhance dopaminergic neurotransmission are usedto treat depression (Ascher et al., 1995; Papakostas, 2006; Wilkes,2006), the results that indicate that melatonin exerts synergisticeffects with dopaminergic agonists corroborates with the notion thatthis neurohormone exerts antidepressant properties.

Fig. 3. Effect of a sub-effective doses of melatonin (0.01 mg/kg, i.p., panel A) or fluoxetine (1 mg/kg, i.p., SSRI, panel B) in combination with SKF38393 (0.1 mg/kg, s.c., dopamine D1

receptor agonist) in the tail suspension test and on the number of crossings in the open-field test (panels C and D). Each column represents the mean+S.E.M. of 6–7 animals.**Pb0.01 compared with the vehicle-treated control.

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The tail suspension test is commonly used to detect andcharacterize the efficacy of antidepressant drugs and is sensitive tothese drugs after acute administration (Cryan et al., 2005). In spite ofthe large use of this test to assess the antidepressant activity of newdrugs, it is also an important tool to study neurobiological mechan-isms involved in antidepressant responses (Bourin et al., 2005; Steruet al., 1985). However, it should be considered that drugs enhancingthe locomotor activity may give a false positive effect in the tailsuspension test. Thus, in order to rule out the possibility that thereduction in the immobility time elicited by a drug is due to anenhancement in the locomotor activity, tests that assess thelocomotor activity of mice, mainly the open-field test, are usuallyemployed. A previous study of our group demonstrated thatmelatonin does not exert psichostimulant effect in the open-fieldtest when administered at doses that cause antidepressant-like action(Mantovani et al., 2003), which is further showed in the presentstudy. Moreover, it should be also noted that the administration of

Fig. 4. Effect of a sub-effective doses of melatonin (0.01 mg/kg, i.p., panel A) or fluoxetine (1receptor agonist) in the tail suspension test and on the number of crossings in the open-fi**Pb0.01 compared with the vehicle-treated control.

antagonists and agonists of dopamine receptors alone or in combi-nation with melatonin or fluoxetine did not significantly alter theambulatory behavior of mice. Hence, we can rule out the possibilitythat the behavioral effects observed in our study are due to locomotoralterations.

Besides the pharmacological evidence regarding the efficacy ofantidepressants with dopaminergic effects in the treatment ofdepression (Papakostas, 2006) there is also preclinical data indicatingthat the dopaminergic system underlies antidepressant-likeresponses in animal models of depression. Antidepressants can actby an augmentation of the dopaminergic neurotransmission in thelimbic system in different animal models (D'Aquila et al., 2000).Furthermore, dopamine receptor agonists are proposed as noveltherapeutic targets for depression treatment, as well as melatoninreceptor agonists (Holtzheimer and Nemeroff, 2008).

Considering the implication of dopaminergic activation in antide-pressant responses, this study investigated the possible influence of

mg/kg, i.p., SSRI, panel B) in combination with apomorphine (0.5 g/kg, i.p., dopamine D2

eld test (panels C and D). Each column represents the mean+S.E.M. of 7–9 animals.

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the dopaminergic system in antidepressant-like effect of melatonin inthe tail suspension test. Our results showed that the dopaminergicsystem is clearly involved in the antidepressant-like action ofmelatonin, since the pretreatment of mice with haloperidol,SCH23390 or sulpiride prevented the antidepressant-like effectevoked by melatonin. This result is in line with the finding thatdopamine D1 and D2 receptors are implicated to the anti-immobilityaction of antidepressants in the mouse forced swimming test. Yamadaet al. (2004) showed that the dopamine D1 selective antagonistSCH23390 or the selective D2 antagonist sulpiride prevented theantidepressant-like effect of two dopamine reuptake inhibitors,bupropion and nomifensine in the forced swimming test. In addition,Renard et al. (2001) demonstrated that the dopamine D1 receptoragonist SKF38393 enhanced the anti-immobility effect of antidepres-sants (SSRIs) in the same model. Furthermore, ECT used to treatdepressive states which are resistant to the usual antidepressantdrugs, causes a reduction in the immobility time in the tail suspensiontest that was antagonized by sulpiride, implicating the dopamine D2receptor in the antidepressant action of ECT (Teste et al., 1990). Inaddition, taking into account that dopamine receptor agonists havebeen shown to augment antidepressant-like effects found in animalbehavioral despair models (Joca et al., 2000; Maj and Rogoz, 1999;Vaugeois et al., 1996), in the present study the effect of the combinedtreatment of melatonin and dopamine D1 and D2 receptor agonistsSKF38393 and apomorphine, respectively, was investigated. It wasshown that the administration of a sub-effective dose of melatoninwith SKF38393 or apomorphine produced a reduction in theimmobility time, as compared with the administration of eitherdrug alone, suggesting a synergistic effect of melatonin with theseagonists in the tail suspension test. These results indicate that anactivation of dopamine D1 and D2 receptors are likely implicated inthe antidepressant-like effect of melatonin in the tail suspension test.It is tempting to speculate that an activation of the dopaminergicsystem elicited by melatonin may be a mechanism underlying itsantidepressant-like effect that may be beneficial for the treatment ofdepression associated with anhedonia. This hypothesis deservesfuture studies to investigate the involvement of the dopaminergicsystem in the antidepressant-like effect of melatonin in animalmodels that resemble human depression, like chronic mild stress aswell as neurochemical studies. In addition, taking into account thatdopamine receptor agonists have been shown to augment antide-pressant-like effects found in animal behavioral despair models,(Borsini et al., 1988; Joca et al., 2000; Maj and Rogoz, 1999; Vaugeoiset al., 1996) we attempted to investigate the effect of both agonistsSKF38393 and apomorphine on the effect of the well known SSRIantidepressant fluoxetine in the tail suspension test for positivecontrol purpose. In this set of the experiments, the effect of a sub-effective dose of fluoxetine was potentiated by the administration ofSKF38393, but not by apomorphine. Our results are in line with astudy in which SKF38393 administration, but not bromocriptine, adopamine D2 receptor agonist, potentiated the effect of fluoxetine inthe forced swimming test (Renard et al., 2001). Therefore, our studyemploying the tail suspension test is in accordance with theexperiments in which the combined treatment of melatonin andSKF38393 elicited synergistic effect, corroborating the notion that theantidepressant-like effect of the acutely administered fluoxetine isdependent on activation of dopamine D1 receptors, but not ofdopamine D2 receptors. However, a possibility that cannot be ruledout is that a chronic treatment with fluoxetine sensitizes postsynapticdopamine D2 receptors in the mesolimbic system, as suggestedpreviously (Collu et al., 1997) and that adaptive change secondary tothe activation of dopamine D1 receptors may be involved in theantidepressant effect of fluoxetine.

It should be considered that despite literature data suggestsantidepressant action for melatonin, it has been used in psychiatrybecause of its hypnotic, resynchronizing and antioxidant actions

(Maldonado et al., 2009). The present study clearly reinforces thenotion that melatonin has antidepressant properties, indicating thatthe antidepressant-like action of melatonin seems to bemediated by astimulation of the dopamine D1 and D2 receptors. This is inagreement with previous clinical and pre-clinical data that showthat compounds affecting the dopaminergic transmission or dopa-mine receptors might produce antidepressant action (Ascher et al.,1995; Joca et al., 2000; Waehrens and Gerlach, 1981). The high safetyprofile ofmelatonin and its virtual lack of toxicitymake it of interest inthe treatment of depression (Reiter and Benitez-King, 2009; Reiterand Korkmaz, 2008).

However, the results obtained with the tail suspension test shouldbe considered with caution and further animal studies and alsobiochemical studies that could confirm the interaction of melatoninand the dopaminergic system are welcomed. Moreover, taken intoaccount the results presented herein, further studies are necessary toestablish the role of melatonin in the depression states associatedwith anhedonia.

Acknowledgements

This work was supported by grants from the Conselho Nacional deDesenvolvimento Científico e Tecnológico (CNPq), Coordenação deAperfeiçoamento de Pessoal de Ensino Superior (CAPES), Fundação deApoio a Pesquisa Científica e Tecnológica do Estado de Santa Catarina(FAPESC), and FINEP “Rede Instituto Brasileiro de Neurociência(IBNNet)”# 01.06.0842-00, Brazil. A.R.S.S. and A.L.S.R. are researchfellows of CNPq.

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