depression is a psychiatric disorder characterized by the presence of affective , psychomotor , cognitive and neurovegetative symptoms that pervade all aspects of life and affect individual 's family and personal relationships , employment and general health .
however , the monoamine hypothesis explains several behavioral and neurochemical aspects of the changes in serotonin ( 5-hydroxytryptamine [ 5-ht ] ) , dopamine and norepinephrine levels in the brains of depressed patients .
5-ht is known to be directly involved in the modulation of cognition , mood , anxiety , aggression , pain and neuroendocrine function , affecting neurogenesis , apoptosis , axon branching and neuronal cell survival .
5-ht synthesis in the brain is highly dependent on the bioavailability of tryptophan in plasma .
reduction in the availability of 5-ht in neurons triggers the induction of indoleamine 2,3-dioxygenase ( ido ) .
ido is an enzyme that degrades tryptophan in tryptophan catabolites and nicotinamide , reducing the bioavailability of tryptophan for 5-ht synthesis .
prostaglandin e2 ( pge2 ) can also induce ido , and , in turn , increase interleukin ( il)-6 production .
in addition , the inflammatory hypothesis has gained widespread attention , suggesting that inflammation mediated by immune cell activation is a key factor in depression .
this hypothesis is supported by the fact that patients with depression have elevated levels of proinflammatory cytokines in plasma and cerebrospinal fluid .
a recent meta - analysis showed that the levels of the cytokines tumor necrosis factor  ( tnf- ) and il-6 are increased in the serum of patients with depression .
thus , some authors have contended that depression is characterized by activation of the inflammatory response through the increased production of proinflammatory cytokines , such as il-1 , il-6 and tnf- , and pge2 .
it is known as a non - steroidal anti - inflammatory drug ( nsaid ) that has an analgesic effect .
the effectiveness of piroxicam as an anti - inflammatory agent is mainly attributable to the inhibition of pge synthesis .
demonstrated that acute treatment with piroxicam was able to exert antidepressant - like effect in the forced swim test ( fst ) and that prolonged treatment was able to reverse the anhedonic state of rats induced by chronic mild stress model .
therefore , the aim of the present study was to investigate the antidepressant - like effect of piroxicam , focusing on the serotonergic neurotransmission .
fifty - six male wistar rats from our breeding colony , 3 months of age and weighing 280320 g at the beginning of the experiments , were used .
the animals were randomly housed in groups of five in polypropylene cages with wood shavings as bedding and maintained in a temperature - controlled room ( 22  2c ) on a 12 h/12 h light / dark cycle ( lights on at 7:00 am ) .
the studies were performed in accordance with the guidelines of the committee on the care and use of laboratory animals , united states national institutes of health . the experimental protocol complied with the recommendations of the federal university of paran and was approved by the university ethics committee ( protocol no .
the rats were randomly distributed into seven groups ( n = eight per group ) : 0.9% saline control group ; 3 mg / kg pizotifen ( non - selective 5-ht receptor antagonist ; novartis , so paulo , brazil ) ; 10 mg / kg sertraline as the positive control group ( selective 5-ht reuptake inhibitor ; ems , so paulo , brazil ) ; 10 mg / kg piroxicam ( nsaid ; ems , brazil ) ; 10 mg / kg sertraline + 10 mg / kg piroxicam ( to evaluate whether the mechanism of action of piroxicam , regarding its antidepressant - like effect , would be the same as a selective 5-ht reuptake inhibitor ) ; 10 mg / kg sertraline + 3 mg / kg pizotifen ; and 10 mg / kg piroxicam + 3 mg / kg pizotifen ( to evaluate the involvement of the serotonergic system in the antidepressant - like effect of piroxicam as a non - selective 5-ht receptor antagonist ) .
three administrations of the drugs ( piroxicam and sertraline ) were performed 1 , 5 and 24 h before testing the animals in the open field , followed by the fst .
piroxicam and sertraline were administered orally by gavage and pizotifen was administered intraperitoneally 30 min before gavage .
all the drugs were administered in a constant volume of 1.0 ml / kg . immediately after the fst , the brain of animals was dissected for neurochemical analysis .
the apparatus consisted of a round arena ( 100 cm diameter , 45 cm height ) , with the floor divided into 19 units .
the animals were gently placed on the right side of the open field and allowed to freely explore the arena for 5 min .
two motor parameters were recorded : locomotion frequency ( i.e. the number of crossings from one unit to another ) and rearing frequency ( i.e. the number of times the animals stood on their hind legs ) .
the open field was washed with 5% ethanol solution before the behavioral test to eliminate possible bias caused by odors left by previous rats .
the rats were placed in a tank ( 25 cm diameter , 60 cm height ) that contained water at a temperature of 24  1c and depth of 25 cm for 15 min .
twenty - four hours after the training session , the rats were subjected to the fst for 5 min , which was videotaped for subsequent quantification of the following parameters : immobility ( i.e. the lack of motion of the whole body , consisting of only small movements necessary to keep the animal 's head above the water ) , climbing ( i.e. vigorous movements with the forepaws in and out of the water , usually directed against the wall of the tank ) and swimming ( i.e. large forepaw movements that displaced water to move the body around the cylinder , more than necessary to merely keep the head above the water ) .
the water was changed after each animal to avoid the influence of water temperature and substances left from the previous session .
hippocampi were rapidly dissected after the fst and stored at -80c until the neurochemical quantification .
the endogenous concentrations of 5-ht and 5-hydroxyindoleacetic acid ( 5-hiaa ) were assayed using reverse - phase high - performance liquid chromatography ( hplc ) with electrochemical detection . briefly ,
the system consisted of a synergi fusion - rp c-18 reverse - phase column ( 150  4.6 mm i.d .
, 4 m particle size ) fitted with a 4 mm  3.0 mm pre - column ( security guard cartridges fusion - rp ) , an electrochemical detector ( esa coulochem iii electrochemical detector ) equipped with a guard cell ( esa 5020 ) with the electrode set at 350 mv and a dual electrode analytical cell ( esa 5011a ) , a lc-20at pump ( shimadzu ) equipped with a manual rheodyne7725 injector with a 20 l loop
. the column was maintained inside a temperature - controlled oven ( 25c , shimadzu ) .
the cell contained two chambers in series : each chamber included a porous graphite coulometric electrode , a double counter electrode and a double reference electrode .
oxidizing potentials were set at 100 mv for the first electrode and at 450 mv for the second electrode .
the tissue samples were homogenized with an ultrasonic cell disrupter ( sonics ) in 0.1 m perchloric acid containing sodium metabisulfite 0.02% and internal standard .
after centrifugation at 10,000 g for 20 min at 4c , 20 l of the supernatant was injected into the chromatograph .
the mobile phase , used at a flow rate of 1 ml / min , had the following composition : 20 g citric acid monohydrated ( merck ) , 200 mg octane-1-sulfonic acid sodium salt ( merck ) , 40 mg ethylene diamine tetraacetic acid ( edta ) ( sigma ) and 900 ml hplc - grade water .
the ph of the buffer running solution was adjusted to 4.0 then filtered through a 0.45 m filter .
methanol ( merck ) was added to give a final composition of 10% methanol ( v / v ) .
the neurotransmitter and metabolite concentrations were calculated using standard curves that were generated by determining in triplicate the ratios between three different known amounts of the internal standard .
smirnov test was used to ensure that the data satisfied the criteria for performing analysis of variance ( anova ) .
fifty - six male wistar rats from our breeding colony , 3 months of age and weighing 280320 g at the beginning of the experiments , were used .
the animals were randomly housed in groups of five in polypropylene cages with wood shavings as bedding and maintained in a temperature - controlled room ( 22  2c ) on a 12 h/12 h light / dark cycle ( lights on at 7:00 am ) .
the studies were performed in accordance with the guidelines of the committee on the care and use of laboratory animals , united states national institutes of health . the experimental protocol complied with the recommendations of the federal university of paran and was approved by the university ethics committee ( protocol no .
the rats were randomly distributed into seven groups ( n = eight per group ) : 0.9% saline control group ; 3 mg / kg pizotifen ( non - selective 5-ht receptor antagonist ; novartis , so paulo , brazil ) ; 10 mg / kg sertraline as the positive control group ( selective 5-ht reuptake inhibitor ; ems , so paulo , brazil ) ; 10 mg / kg piroxicam ( nsaid ; ems , brazil ) ; 10 mg / kg sertraline + 10 mg / kg piroxicam ( to evaluate whether the mechanism of action of piroxicam , regarding its antidepressant - like effect , would be the same as a selective 5-ht reuptake inhibitor ) ; 10 mg / kg sertraline + 3 mg / kg pizotifen ; and 10 mg / kg piroxicam + 3 mg / kg pizotifen ( to evaluate the involvement of the serotonergic system in the antidepressant - like effect of piroxicam as a non - selective 5-ht receptor antagonist ) .
three administrations of the drugs ( piroxicam and sertraline ) were performed 1 , 5 and 24 h before testing the animals in the open field , followed by the fst .
piroxicam and sertraline were administered orally by gavage and pizotifen was administered intraperitoneally 30 min before gavage .
all the drugs were administered in a constant volume of 1.0 ml / kg . immediately after the fst , the brain of animals was dissected for neurochemical analysis .
the apparatus consisted of a round arena ( 100 cm diameter , 45 cm height ) , with the floor divided into 19 units .
the animals were gently placed on the right side of the open field and allowed to freely explore the arena for 5 min .
two motor parameters were recorded : locomotion frequency ( i.e. the number of crossings from one unit to another ) and rearing frequency ( i.e. the number of times the animals stood on their hind legs ) .
the open field was washed with 5% ethanol solution before the behavioral test to eliminate possible bias caused by odors left by previous rats .
the rats were placed in a tank ( 25 cm diameter , 60 cm height ) that contained water at a temperature of 24  1c and depth of 25 cm for 15 min .
twenty - four hours after the training session , the rats were subjected to the fst for 5 min , which was videotaped for subsequent quantification of the following parameters : immobility ( i.e. the lack of motion of the whole body , consisting of only small movements necessary to keep the animal 's head above the water ) , climbing ( i.e. vigorous movements with the forepaws in and out of the water , usually directed against the wall of the tank ) and swimming ( i.e. large forepaw movements that displaced water to move the body around the cylinder , more than necessary to merely keep the head above the water ) .
the water was changed after each animal to avoid the influence of water temperature and substances left from the previous session .
hippocampi were rapidly dissected after the fst and stored at -80c until the neurochemical quantification .
the endogenous concentrations of 5-ht and 5-hydroxyindoleacetic acid ( 5-hiaa ) were assayed using reverse - phase high - performance liquid chromatography ( hplc ) with electrochemical detection .
briefly , the system consisted of a synergi fusion - rp c-18 reverse - phase column ( 150  4.6 mm i.d . , 4 m particle size ) fitted with a 4 mm  3.0 mm pre - column ( security guard cartridges fusion - rp ) , an electrochemical detector ( esa coulochem iii electrochemical detector ) equipped with a guard cell ( esa 5020 ) with the electrode set at 350 mv and a dual electrode analytical cell ( esa 5011a ) , a lc-20at pump ( shimadzu ) equipped with a manual rheodyne7725 injector with a 20 l loop .
the column was maintained inside a temperature - controlled oven ( 25c , shimadzu ) .
the cell contained two chambers in series : each chamber included a porous graphite coulometric electrode , a double counter electrode and a double reference electrode .
oxidizing potentials were set at 100 mv for the first electrode and at 450 mv for the second electrode .
the tissue samples were homogenized with an ultrasonic cell disrupter ( sonics ) in 0.1 m perchloric acid containing sodium metabisulfite 0.02% and internal standard .
after centrifugation at 10,000 g for 20 min at 4c , 20 l of the supernatant was injected into the chromatograph .
the mobile phase , used at a flow rate of 1 ml / min , had the following composition : 20 g citric acid monohydrated ( merck ) , 200 mg octane-1-sulfonic acid sodium salt ( merck ) , 40 mg ethylene diamine tetraacetic acid ( edta ) ( sigma ) and 900 ml hplc - grade water .
the ph of the buffer running solution was adjusted to 4.0 then filtered through a 0.45 m filter .
methanol ( merck ) was added to give a final composition of 10% methanol ( v / v ) .
the neurotransmitter and metabolite concentrations were calculated using standard curves that were generated by determining in triplicate the ratios between three different known amounts of the internal standard .
the kolmogorov  smirnov test was used to ensure that the data satisfied the criteria for performing analysis of variance ( anova ) .
in the open field test [ figure 1a ] , the frequencies of locomotion ( f6,55 = 1.399 , p = 0.2339 ) and rearing ( f6,55 = 0.5825 , p = 0.7425 ; figure 1b ) 1 h after acute administration revealed that none of the treated rats exhibited differences in these parameters compared with the control group .
keuls post hoc test ; mean  sem ) in the fst , swimming time significantly increased after acute treatment with sertraline , piroxicam and sertraline + piroxicam compared with the control group ( p < 0.05 , p < 0.05 and p < 0.001 , respectively ) .
the sertraline + piroxicam group also exhibited a significant increase in swimming time compared with the sertraline and piroxicam groups ( both p < 0.05 ; f6,55 = 8.115 , p < 0.0001 ; figure 2a ) .
the sertraline , piroxicam and sertraline + piroxicam groups exhibited a significant decrease in immobility time compared with the control group after acute treatment ( all p < 0.05 ; f6,55 = 4.407 , p = 0.00121 ; figure 2b ) .
only the sertraline + piroxicam group exhibited a decrease in climbing compared with the control group ( p < 0.05 ; f6,55 = 3.189 , p = 0.0010 ; figure 2c ) .
forced swim test ( a ) swimming , ( b ) immobility and ( c ) climbing time .
* p < 0.05 and * * * p < 0.001 compared with the saline group ; p < 0.05 compared with the sertraline and piroxicam groups ( one - way analysis of variance followed by the newman  keuls post hoc test ; mean  sem ) the levels of 5-ht in the hippocampus significantly increased in the sertraline ( p < 0.05 ) , piroxicam ( p < 0.05 ) , piroxicam + sertraline ( p < 0.001 ) , pizotifen ( p < 0.05 ) , pizotifen + sertraline ( p < 0.05 ) and pizotifen + piroxicam ( p < 0.05 ) groups compared with the control group .
additionally , the sertraline + piroxicam group exhibited a significant increase in the 5-ht levels compared with the sertraline and piroxicam groups ( both p < 0.05 ; f6,55 = 8.104 , p < 0.0001 ; figure 3a ) .
the pizotifen and pizotifen + piroxicam groups exhibited significant increases in the metabolite 5-hiaa ( p < 0.01 and p < 0.001 , respectively ) compared with the control group .
the sertraline ( p < 0.01 ) and piroxicam + sertraline ( p < 0.05 ) were found to have decreased 5-ht levels compared with the control group ( f6,55 = 22.14 , p < 0.0001 ; figure 3b ) .
the turnover of 5-ht in the hippocampus significantly decreased in the sertraline ( p < 0.001 ) , piroxicam ( p < 0.05 ) , piroxicam + sertraline ( p < 0.001 ) and pizotifen + sertraline ( p < 0.01 ) groups compared with the control group .
additionally , the sertraline + piroxicam group exhibited a significant decrease in the turnover of 5-ht levels compared with the piroxicam groups ( p < 0.001 ; f6,55 = 22.67 , p < 0.0001 ; figure 3c ) .
5-hydroxytryptamine ( 5-ht ) and 5-hydroxyindoleacetic acid ( 5-hiaa ) hippocampal ( a ) 5-ht , ( b ) 5-hiaa and ( c ) turnover 5-ht .
* p < 0.05 , * * p < 0.01 and * * * p < 0.001 compared with the saline group ; p < 0.05 compared with the sertraline and piroxicam groups , p < 0.001 compared with the piroxicam group ( one - way analysis of variance followed by the newman 
in the open field test [ figure 1a ] , the frequencies of locomotion ( f6,55 = 1.399 , p = 0.2339 ) and rearing ( f6,55 = 0.5825 , p = 0.7425 ; figure 1b ) 1 h after acute administration revealed that none of the treated rats exhibited differences in these parameters compared with the control group .
keuls post hoc test ; mean  sem ) in the fst , swimming time significantly increased after acute treatment with sertraline , piroxicam and sertraline + piroxicam compared with the control group ( p < 0.05 , p < 0.05 and p < 0.001 , respectively ) .
the sertraline + piroxicam group also exhibited a significant increase in swimming time compared with the sertraline and piroxicam groups ( both p < 0.05 ; f6,55 = 8.115 , p < 0.0001 ; figure 2a ) .
the sertraline , piroxicam and sertraline + piroxicam groups exhibited a significant decrease in immobility time compared with the control group after acute treatment ( all p < 0.05 ; f6,55 = 4.407 , p = 0.00121 ; figure 2b ) .
only the sertraline + piroxicam group exhibited a decrease in climbing compared with the control group ( p < 0.05 ; f6,55 = 3.189 , p = 0.0010 ; figure 2c ) .
forced swim test ( a ) swimming , ( b ) immobility and ( c ) climbing time .
* p < 0.05 and * * * p < 0.001 compared with the saline group ; p < 0.05 compared with the sertraline and piroxicam groups ( one - way analysis of variance followed by the newman  keuls post hoc test ; mean  sem )
the levels of 5-ht in the hippocampus significantly increased in the sertraline ( p < 0.05 ) , piroxicam ( p < 0.05 ) , piroxicam + sertraline ( p < 0.001 ) , pizotifen ( p < 0.05 ) , pizotifen + sertraline ( p < 0.05 ) and pizotifen + piroxicam ( p < 0.05 ) groups compared with the control group .
additionally , the sertraline + piroxicam group exhibited a significant increase in the 5-ht levels compared with the sertraline and piroxicam groups ( both p < 0.05 ; f6,55 = 8.104 , p < 0.0001 ; figure 3a ) .
the pizotifen and pizotifen + piroxicam groups exhibited significant increases in the metabolite 5-hiaa ( p < 0.01 and p < 0.001 , respectively ) compared with the control group .
the sertraline ( p < 0.01 ) and piroxicam + sertraline ( p < 0.05 ) were found to have decreased 5-ht levels compared with the control group ( f6,55 = 22.14 , p < 0.0001 ; figure 3b ) .
the turnover of 5-ht in the hippocampus significantly decreased in the sertraline ( p < 0.001 ) , piroxicam ( p < 0.05 ) , piroxicam + sertraline ( p < 0.001 ) and pizotifen + sertraline ( p < 0.01 ) groups compared with the control group .
additionally , the sertraline + piroxicam group exhibited a significant decrease in the turnover of 5-ht levels compared with the piroxicam groups ( p < 0.001 ; f6,55 = 22.67 , p < 0.0001 ; figure 3c ) .
5-hydroxytryptamine ( 5-ht ) and 5-hydroxyindoleacetic acid ( 5-hiaa ) hippocampal ( a ) 5-ht , ( b ) 5-hiaa and ( c ) turnover 5-ht .
* p < 0.05 , * * p < 0.01 and * * * p < 0.001 compared with the saline group ; p < 0.05 compared with the sertraline and piroxicam groups , p < 0.001 compared with the piroxicam group ( one - way analysis of variance followed by the newman 
in the present study , we found that acute treatment with piroxicam promoted an antidepressant - like effect in the fst , which was strongly associated with an increase in the 5-ht levels in the hippocampus .
moreover , this effect was potentiated by piroxicam + sertraline , but counteracted by administration of the non - selective 5-ht receptor antagonist pizotifen .
the involvement of the 5-ht system in the antidepressant - like effect of piroxicam was studied using non - selective 5-ht antagonists to examine behavioral responses to piroxicam in the fst . in the present study
the main advantage of this model is that it allows correlations to be made between the analyzed behaviors and different neurotransmitter systems ( e.g. swimming and the serotonergic system , climbing ) , and serotonin reuptake blockers increase swimming time .
according to the present results , the animals treated with piroxicam or sertraline exhibited an increase in swimming time compared with animals treated with saline .
additionally , the combination of piroxicam and sertraline potentiated the swimming time increase compared with either treatment alone .
this suggests that the observed changes are related to the serotonergic , given that the swimming time of piroxicam + sertraline group was higher when compared with the sertraline groups or piroxicam alone .
in addition , the data that showed reversal of the antidepressant - like effect of piroxicam by pizotifen pre - treatment supports the hypothesis that the 5-ht system is directly involved in the antidepressant effect of piroxicam .
furthermore , the increased 5-ht levels , inflicted by the piroxicam + sertraline treatment , contrasted with the reduced metabolite levels , possibly indicating a synergistic antidepressant effect promoted by those drugs .
however , it appears that such outcome , most likely , is an acute effect , as the 5-ht turnover rates are decreased in that group .
hence , it is conceivably the occurrence of a strong involvement of the serotonergic neurotransmission in the antidepressant mechanism generated by piroxicam .
several mechanisms have been proposed to account for the depressogenic action of cytokines , including decrease in the availability of plasma tryptophan ( i.e. the precursor of 5-ht ) in the brain by activation of the tryptophan - degrading enzyme ido .
the role of inflammation in the pathophysiology of depression has become more recognized in the literature , being described as the inflammatory or cytokine hypothesis of depression .
evidence suggests that continuous activation of the immune and/or chronic inflammation system can be one of the pathological processes of depression .
in addition , the neuronal cox-2 expression is related to apoptosis and it is involved in the response to stress . according to maes et al . ,
dysfunction in the serotonergic system in depression is the result of cell - mediated immune activation .
an initial inflammatory response in innate immunity initiates the activation of a cascade that results in the activation and recruitment of cells responsible for adaptive immunity .
therefore , proinflammatory cytokines released during the innate and adaptive immune responses can lead to the development of central nervous system disorders .
studies have shown that stress conditions are associated with an increase in the hypothalamic  pituitary  adrenal ( hpa ) axis activity and elevated serum corticosterone .
support the idea that activation of the hpa axis in response to chronic stress induces changes in the hippocampal serotonergic system , predisposing the individual to the development of depression .
thus , animal and human studies indicate that cytokines , such as tnf- , il-1 , il-6 and interferon , interact with many pathophysiological domains that characterize depression , including neurotransmitter metabolism , neuroendocrine function , synaptic plasticity and behavior . according to maes et al . , proinflammatory cytokines are able to reduce the level of 5-ht through the activation of ido .
ido is an enzyme that degrades tryptophan to catabolites of tryptophan ( trycats ) and nicotinamide , reducing the bioavailability of tryptophan for the synthesis of 5-ht , still being able to reduce the availability of 5-ht through the activation of ido .
an interesting finding of the present study was the synergistic antidepressant effect of piroxicam and sertraline .
the effect of fst piroxicam in rats appears to be different from the effect of sertraline .
one hypothesis to explain the present results may be related to changes in the levels of cytokines and pge2 after piroxicam treatment .
anti - inflammatory drugs , such as piroxicam , exert their actions by inhibiting inflammation and , consequently , cytokine release , thereby avoiding the activation of ido and preventing reductions of 5-ht .
in conclusion , the antidepressant - like effect of piroxicam is mediated , at least in part , by alterations in 5-ht systems probably induced by the enzyme ido .
this conclusion is supported by the fact that the non - selective blocker of serotonin receptors was able to inhibit the antidepressant - like effect of piroxicam on fst , despite the increase in hippocampal serotonin observed in animals treated with the same .
furthermore , the combined use of piroxicam and sertraline demonstrated a synergistic effect , suggesting that the antidepressant - like effect of piroxicam is due to different mechanisms of selective serotonin reuptake inhibitor .
 objective : to investigate the antidepressant - like effect of piroxicam with a focus on serotonergic neurotransmission.materials and methods : rats were randomly distributed into the following groups : 0.9% saline control ; 3 mg / kg pizotifen ; 10 mg / kg sertraline ; 10 mg / kg piroxicam ; 10 mg / kg sertraline + 10 mg / kg piroxicam ; 10 mg / kg sertraline + 3 mg / kg pizotifen ; and 10 mg / kg piroxicam + 3 mg / kg pizotifen . 
 all the drugs were dissolved in 0.9% saline . 
 three administrations of the drugs ( piroxicam and sertraline ) were performed 1 , 5 and 24 h before testing the animals in the open field followed by the forced swim test ( fst ) . 
 piroxicam and sertraline were administered orally by gavage and pizotifen was administered intraperitoneally 30 min before gavage . immediately after the fst 
 , the hippocampi were rapidly dissected for neurochemical analysis in high - performance liquid chromatography.results:acute treatment with piroxicam promoted an antidepressant - like effect in the fst , which was associated with an increase in serotonin levels in the hippocampus . 
 this effect was potentiated in the piroxicam + sertraline group but counteracted by administration of the non - selective serotonin receptor antagonist pizotifen.conclusion:these results suggest that the antidepressant - like effect of piroxicam in the fst is mediated by the serotonin system ; however , by different mechanisms from those of sertraline . 
INTRODUCTION
MATERIALS AND METHODS
Animals
Experimental design
Open field test
Modified FST
Determination of hippocampal 5-HT and metabolite concentrations
Statistical analysis
RESULTS
Effects of acute treatment on behavior
Determination of 5-HT and metabolite levels after acute treatment
DISCUSSION
CONCLUSION