ABSTRACT The present study intends to investigate the effect of lithium (Li) and celecoxib (Cel) coadministration on the behavioral status and oxidative stress parameters in a rat model of

mania induced by dextroamphetamine (d-AMPH). Male Wistar rats were treated with d-AMPH or saline (Sal) for 14 days; on the 8th day of treatment, rats received lithium (Li), celecoxib (Cel),

Li plus Cel, or water until day 14. Levels of oxidative stress parameters were evaluated in the serum, frontal cortex, and hippocampus. d-AMPH administration induced hyperlocomotion in rats,

which was significantly reversed by Li and Cel coadministration. In addition, d-AMPH administration induced damage to proteins and lipids in the frontal cortex and hippocampus of rats. All

combination thereof reversed this alteration in this structure. Overall, data indicate hyperlocomotion and alteration in oxidative stress biomarkers in the cerebral structures of rats

receiving d-AMPH. Li and Cel coadministration can mitigate these modifications, comprising a potential novel approach for BD therapy. SIMILAR CONTENT BEING VIEWED BY OTHERS ACAMPROSATE

REDUCES ETHANOL INTAKE IN THE RAT BY A COMBINED ACTION OF DIFFERENT DRUG COMPONENTS Article Open access 19 October 2023 ANTIDEPRESSANT-LIKE EFFECTS OF PSYCHEDELICS IN A CHRONIC DESPAIR MOUSE

MODEL: IS THE 5-HT2A RECEPTOR THE UNIQUE PLAYER? Article Open access 11 January 2024 RECEPTOR AND METABOLIC INSIGHTS ON THE ABILITY OF CAFFEINE TO PREVENT ALCOHOL-INDUCED STIMULATION OF

MESOLIMBIC DOPAMINE TRANSMISSION Article Open access 28 September 2024 INTRODUCTION Bipolar disorder (BD) is a prominent, impactful psychiatric disorder affecting moods, whose lifetime

prevalence is ~ 5%1,2. The precise pathophysiology of BD remains unclear3. However, oxidative stress is linked to this condition, as alterations in the activity of antioxidant enzymes and

other oxidative disturbances have been reported in BD patients4. The clinical hallmark of BD is the manic episodes, including euphoria, hyperactivity, insomnia, or hypersexuality, so that

animal models able to reproduce mania are one of the experimental resources most used in BD research5,6. In this scenario, hyperlocomotion, altered pattern of sleep, and risk behavior were

observed in the animal model of mania induced by amphetamine7,8,9. In addition, administration of mood stabilizer drugs, including valproate, can counteract the effect of amphetamine on the

locomotion of rats submitted to such dopaminergic model, which supports its validity for the study of the mood disorder7. The main limitations of the mania model induced by dextroamphetamine

(d-AMPH) in rodents, besides it be a chemically induced model, include mimicking drug abuse symptoms10,11 and psychosis-related behaviors (at higher doses)12,13,14. The BD standard therapy

comprises lithium (Li, as carbonate salt) and anticonvulsants, such as valproate15. Nevertheless, certain side effects, namely weight gain, polyuria, bradykinesia, sexual dysfunction, and

others render the patients affected by the disorder prone to noncompliance to therapy16,17. Thus, the design of new therapeutic strategies aiming to minimize or eliminate such undesirable

consequences of traditional BD therapy is probably a promising field of research at present. On the other hand, celecoxib (Cel) was the first anti-inflammatory drug inhibiting the

cyclooxygenase-2 enzyme (EC 1.14.99.1) with approval for use by the US Food and Drug Administration (FDA)18. Cel was also showed to be useful as adjunct therapy of manic or depressive

symptoms19,20, in part owing to the finding that a proinflammatory state could be associated with BD21. An immune or inflammatory imbalance in the pathophysiology of this mood disorder could

constitute a new platform for the development of novel therapeutic approaches22. Therefore, the present study aimed to investigate the effect of Li and Cel coadministration on the

behavioral status and oxidative stress parameters in rats submitted to the dopaminergic model of mania induced by d-AMPH. MATERIAL AND METHODS ANIMALS Adult male Wistar rats (_Rattus

norvegicus_; 250–350 g) obtained from the Central Animal House of University of Southern Santa Catarina (UNESC) were used. Rats were caged in groups of five animals and had ad libitum access

to water and standard chow. A light/dark cycle (12:12 h; lights on at 7:00 h) at constant temperature (22 ± 1 °C) was maintained in the colony room. All experiments followed The “Principles

of Laboratory Animal Care” (National Institutes of Health publication no. 80–23, revised in 1996) and the “EC Directive 86/609/EEC”. This study was only carried out with previous approval

by the Local Ethics Committee on Animal Use for Research (protocol # 056/2015–2). All efforts were made to reduce the number of animals and their suffering. Thus, the experiment was carried

out with _n_ = 12 animals per group. REAGENTS d-AMPH was purchased from Sigma-Aldrich (Saint Louis, Missouri, United States), whereas Li (carbonate salt) was obtained from Eurofarma (São

Paulo city, São Paulo, Brazil) and Cel from Getz Pharma (Karachi, Pakistan). d-AMPH was diluted in saline solution (Sal; NaCl 0.9%) to enable the intraperitoneal (i.p.) administration of the

drug. Li and Cel tablets were macerated, and the resulting powder was added to water until form a suspension orally administered to the rats. These suspensions were then kept on a magnetic

mixer in order to maintain constant concentrations of the drugs during the administrations. EXPERIMENTAL DESIGN Rats received d-AMPH (2 mg per kg body weight [mg/kg]) or Sal during 14 days.

Each drug was administered once a day, i.p. From the day 8–14, animals from d-AMPH and Sal groups orally received Li (24 mg/kg), Cel (20 mg/kg), a combination thereof or water. Li was

administered twice a day (12:12 h), whereas Cel was only administered once a day. At day 15, rats received an i.p. injection of d-AMPH or Sal and 2 h later were submitted to the behavioral

analysis. Thus, the experimental groups in the present study are as follows: (i) Sal + water; (ii) Sal + Li; (iii) Sal + Cel; (iv) Sal + Li + Cel; (v) d-AMPH + water; (vi) d-AMPH + Li; (vii)

d-AMPH + Cel; and (viii) d-AMPH + Li + Cel. Dosage of Cel and d-AMPH was following previous studies7,23, but the dose of Li was equal to the half of those administered in the study

performed by Frey and coworkers7. BEHAVIORAL ANALYSIS Behavioral status was assessed through the open-field test. In this procedure, hyperlocomotion or hyperactivity induced in the animal

model is a parameter associated to mania, which characterizes the BD9. Open-field test was carried out in a 40 × 60 cm box, whose 50 cm-height-walls are made of brown fiberboard, except the

frontal wall, which is made of glass. The floor of the box is divided into nine equal rectangles by black lines. To freely explore the area for at least 5 min, the animals are gently put on

the left posterior square. During the procedure, the number of crossings and rearings provides consistent information on the rat behavior and locomotion24. SAMPLE PREPARATION After

behavioral analysis, rats were killed by decapitation without anesthesia, the skull was opened, and the cerebral content was excised and rapidly dissected on a chilled dish Petri. The

frontal cortex and hippocampus were isolated and cleaned from the subcortical structures and white matter. Peripheral blood samples were immediately collected after decapitation and

submitted to centrifugation at 10,000 rpm during 15 min aiming to obtain the serum. Until the analyses were performed, all samples were kept frozen at −80 °C. PROTEIN CARBONYL CONTENT The

determination of the carbonyl content was performed in samples of the cerebral structures and serum previously homogenized in sodium phosphate buffer 20 mM and potassium chloride 140 mM (pH

7.4). In brief, the principle of the method is based on the binding of carbonyl groups present in the samples to the 2,4-dinitrophenylhydrazine reagent (Sigma-Aldrich) forming aliphatic

hydrazones, whose absorbance values were spectrophotometrically determined at 360 nm wavelength (_λ_), using blanks to each sample. Such information correlates to the carbonyl group content

in the samples. Data were expressed as nmol/mL25. LEVEL OF THIOBARBITURIC ACID-REACTIVE SPECIES The levels of the thiobarbituric acid-reactive species (TBARS), malondialdehyde (MDA), were

measured in samples of the cerebral structures and serum homogenized in chilled PBS buffer (pH 7.4). Homogenates were mixed with trichloroacetic acid (Sigma-Aldrich) 10% aiming to form a

precipitate, and sodium sulfate was added to supernatants at a 1:1 v/v ratio. After centrifugation, thiobarbituric acid (Sigma-Aldrich) 0.67% was added to supernatants, at this same v/v

ratio. The resulting mixture was submitted to heating for 2 h and then cooled with water at room temperature. Measuring of absorbance values was performed in a spectrophotometer at _λ_ = 532

 nm. Data were expressed as MDA equivalents nmol/mg protein26. CATALASE ENZYME ACTIVITY The catalase (CAT; EC 1.11.1.6) activity was evaluated in samples of the cerebral structures and serum

according to a standardized procedure27. First, Triton 0.1% was added to the sample homogenates, and the resulting mixture was incubated on ice for 15 min. Hydrogen peroxide 30% v/v was

then added to potassium phosphate buffer 10 mM, pH 7.0, and the resulting solution was put on a quartz cuvette. SpectraMax microplate spectrophotometer (Molecular Devices, Sunnyvale,

California, United States) was calibrated with a blank separately run from phosphate buffer. After sample addition, a decrease in hydrogen peroxide absorbance was measured using the

microplate photometer at _λ_ = 240 nm during 3 min, with 30 s as an interval between measurements. Data were expressed as U/mg protein. GLUTATHIONE PEROXIDASE ENZYME ACTIVITY Glutathione

peroxidase (GPx; EC 1.11.1.9) activity in samples of the cerebral structures and serum was measured by Wendel’s method28, with tert-butyl hydroperoxide used as substrate. Into each tube

containing sample was added potassium phosphate buffer 100 mM, pH 7.0, ethylenediaminetetraacetic acid 1 mM, sodium azide 40 mM, reduced glutathione 100 mM, glutathione reductase (EC

1.6.4.2) 10 U/mL and reduced nicotinamide adenine dinucleotide phosphate 10 mM. The resulting mixture was incubated for 1 min at 25 °C. Thereafter, enzyme reaction was started after the

addition of tert-butyl hydroperoxide 10 mM. Blanks were prepared using phosphate buffer instead of the sample. A decrease in absorbance at _λ_ = 340 nm was followed during 300 s in a

SpectraMax microplate photometer. Calculated GPx activity was expressed as nmol min−1 mL−1. STATISTICAL ANALYSIS The variables were analyzed according to their distribution through Shapiro

Wilk’s test for normality. The Levene test assessed the homogeneity of variances among groups. All data were expressed as the mean ± standard error of the mean and were analyzed by three-way

analysis of variance (ANOVA) followed by Tukey’s test when _F_ value was significant. Statistica 7 software (Dell Software, Round Rock, TX, USA) was used to perform all analyses. The

differences between groups were rated as statistically significant at _p_ < 0.05. The software used to generate the figure graphs was GraphPad Prism version 5.00 for Windows (GraphPad

Software, San Diego, CA, USA). RESULTS BEHAVIORAL ANALYSES It was performed the open-field test to evaluate rat locomotion, expressed as the number of crossings and rearings (Fig. 1). It was

observed that rats receiving d-AMPH presented a marked pattern of locomotion characterized by an increased number of crossings and rearings, as compared with the Sal + water group animals.

Coadministration of Li and Cel reversed the increase in crossings and rearings induced by d-AMPH. Data from three-way ANOVA revealed significant effects of d-AMPH administration [crossing:

_F_(1, 80) = 18.84, _p_ < 0.001; rearing: _F_(1, 80) = 14.38, _p_ < 0.001], treatment [crossing: _F_(1, 80) = 5.50, _p_ = 0.02; rearing: _F_(1, 80) = 0.08, _p_ = 0.77], d-AMPH

administration × treatment interaction [crossing: _F_(1, 80) = 2.44, _p_ = 0.12; rearing: _F_(1, 80) = 3.63, _p_ = 0.06] and d-AMPH administration × Cel plus Li interaction [crossing: _F_(1,

80) = 0.55, _p_ = 0.46; rearing: _F_(1, 80) = 0.02, _p_ = 0.88]. PROTEIN CARBONYL CONTENT Figure 2 depicts the findings on carbonyl content determination. In rat serum, no significant

differences between groups were detected. However, this parameter was significantly increased in the frontal cortex and hippocampus of animals receiving water plus d-AMPH, as compared with

Sal + water group. Treatment with Li or Li plus Cel reversed the increase in carbonyl content induced by d-AMPH. Also, significant decreases in the carbonyl content were detected in the

frontal cortex of rats submitted to the model of mania that received Cel (d-AMPH + Cel group); however, carbonyl levels in this group remained higher than those detected in the Sal + water

group animals. Administration Li plus Cel to the animals submitted to the model of mania (d-AMPH + Li + Cel group) also reversed the increase in the carbonyl content induced by d-AMPH in the

hippocampus. Interestingly, a significant decrease in this parameter was detected in the hippocampus of rats receiving d-AMPH plus Li, as compared with Sal + water and d-AMPH + water

groups. Data from three-way ANOVA revealed significant effects of d-AMPH administration [frontal cortex: _F_(1, 28) = 11.91, _p_ < 0.01; hippocampus: _F_(1, 30) = 0.57, _p_ = 0.45; serum:

_F_(1, 32) = 0.03, _p_ _=_ 0.86], treatment [frontal cortex: _F_(1, 28) = 20.01, _p_ < 0.001; hippocampus: _F_(1, 30) = 13.91, _p_ < 0.001; serum: _F_(1, 32) = 2.06, _p_ _=_ 0.16],

d-AMPH administration × treatment interaction [frontal cortex: _F_(1, 28) = 0.92, _p_ = 0.35; hippocampus: _F_(1, 30) = 1.49, _p_ = 0.23; serum: _F_(1, 32) = 0.20, _p_ = 0.66] and d-AMPH

administration × Cel plus Li interaction [frontal cortex: _F_(1, 28) = 0.57, _p_ = 0.45; hippocampus: _F_(1, 30) = 1.30, _p_ = 0.26; serum: _F_(1, 32) = 0.01, _p_ = 0.92]. TBARS LEVELS The

next step of the present study was to evaluate the content of TBARS in serum, frontal cortex, and hippocampus samples of rats (Fig. 3). A significant decrease in this parameter was detected

in animals submitted to the model of mania receiving Li or Cel, as compared with the Sal + water group. In contrast, a marked increase in this parameter was observed in the frontal cortex

and hippocampus of rats only receiving water plus d-AMPH, as compared with Sal + water group. Animals submitted to the experimental model receiving Li or Cel (d-AMPH + Li or d-AMPH + Cel

groups), but not Li plus Cel (d-AMPH + Li + Cel), presented a significant decrease in TBARS level detected in the frontal cortex, as compared with the rats only receiving water plus d-AMPH.

Also, a significant decrease in this parameter was observed in the hippocampus of animals submitted to the model receiving Li, Cel or Li plus Cel, in comparison to the rats in similar

conditions but only receiving water plus d-AMPH. Data from three-way ANOVA revealed significant effects of d-AMPH administration [frontal cortex: _F_(1, 36) = 0.26, _p_ = 0.61; hippocampus:

_F_(1, 38) = 7.26, _p_ = 0.01; serum: _F_(1, 36) = 1.20, _p_ _=_ 0.66], treatment [frontal cortex: _F_(1, 36) = 1.11, _p_ = 0.30; hippocampus: _F_(1, 38) = 11.92, _p_ < 0.01; serum:

_F_(1, 36) = 0.01, _p_ _=_ 0.91], d-AMPH administration × treatment interaction [frontal cortex: _F_(1, 36) = 4.86, _p_ = 0.034; hippocampus: _F_(1, 38) = 13.05, _p_ < 0.001; serum:

_F_(1, 36) = 4.67, _p_ = 0.03] and d-AMPH administration × Cel plus Li interaction [frontal cortex: _F_(1, 36) = 11.70, _p_ < 0.01; hippocampus: _F_(1, 38) = 11.82, _p_ < 0.01; serum:

_F_(1, 36) = 0.33, _p_ = 0.56]. CAT ENZYME ACTIVITY Another important marker of oxidative stress evaluated in the present study was the activity of the CAT enzyme (Fig. 4). In rat serum, it

was detected no significant differences in this parameter between groups. Nevertheless, a significant decrease in CAT activity was observed in the frontal cortex and hippocampus of animals

submitted to the d-AMPH administration and receiving water, Li or Cel, as compared with the Sal + water group. A significant recovery of the enzyme activity in these cerebral structures was

only detected when the rats submitted to the experimental model received Li plus Cel, in comparison with the animals receiving water plus d-AMPH. Data from three-way ANOVA revealed

significant effects of d-AMPH administration [frontal cortex: _F_(1, 31) = 10.86, _p_ < 0.01; hippocampus: _F_(1, 27) = 4.92, _p_ = 0.03; serum: _F_(1, 32) = 2.86, _p_ _=_ 0.10],

treatment [frontal cortex: _F_(1, 31) = 2.03, _p_ = 0.16; hippocampus: _F_(1, 27) = 1.26, _p_ = 0.27; serum: _F_(1, 32) = 3.16, _p_ _=_ 0.085], d-AMPH administration × treatment interaction

[frontal cortex: _F_(1, 31) = 6.72, _p_ = 0.014; hippocampus: _F_(1, 27) = 1.54, _p_ = 0.22; serum: _F_(1, 32) = 0.96, _p_ _=_ 0.33] and d-AMPH administration × Cel plus Li interaction

[frontal cortex: _F_(1, 31) = 7.08, _p_ = 0.012; hippocampus: _F_(1, 27) = 2.96, _p_ = 0.097; serum: _F_(1, 32) = 0.73, _p_ _=_ 0.40]. GPX ENZYME ACTIVITY The last parameter investigated in

the present work was the activity of GPx enzyme (Fig. 5). In rat serum, a significant decrease in this parameter was detected in animals receiving d-AMPH plus Cel, as compared with Sal + 

water group. In contrast, a marked increase in the GPx activity was observed in the frontal cortex of rats only receiving water plus d-AMPH and in the hippocampus of animals submitted to the

d-AMPH administration and treated with Li plus Cel. In the frontal cortex, a significant decrease of this enzyme activity was detected in rats submitted to the d-AMPH administration and

treated with Li, Cel or Li plus Cel, in comparison with animals only receiving water plus d-AMPH. Data from three-way ANOVA revealed significant effects of d-AMPH administration [frontal

cortex: _F_(1, 32) = 22.15, _p_ < 0.001; hippocampus: _F_(1, 30) = 0.39, _p_ = 0.53; serum: _F_(1, 36) = 0.22, _p_ = 0.64], treatment [frontal cortex: _F_(1, 32) = 15.94, _p_ < 0.001;

hippocampus: _F_(1, 30) = 0.16, _p_ = 0.69; serum: _F_(1, 36) = 1.23, _p_ = 0.27], d-AMPH administration × treatment interaction [frontal cortex: _F_(1, 32) = 8.96, _p_ < 0.01;

hippocampus: _F_(1, 30) = 2.38, _p_ = 0.13; serum: _F_(1, 36) = 11.13, _p_ _<_ 0.01] and d-AMPH administration × Cel plus Li interaction [frontal cortex: _F_(1, 32) = 7.05, _p_ = 0.012;

hippocampus: _F_(1, 30) = 0.11, _p_ = 0.74; serum: _F_(1, 36) = 3.52, _p_ = 0.07]. DISCUSSION In the present study, d-AMPH administration elicited hyperlocomotion in rats, which correlates

with manic behavior or hyperactivity in BD patients9. Following the data provided by behavioral analysis, previous evidence showed that the administration of d-AMPH induces hyperactivity in

rats29,30. Furthermore, studies have suggested 47.5 mg/kg body weight as the therapeutic dose of Li7,30. It was observed here that the administration of such drug at a lower dose (24 mg/kg)

did not mitigate the hyperlocomotion induced by d-AMPH in the animals. However, this dose was used to investigate the putative therapeutic potential of Li and Cel coadministration, owing to

the need for potential reduction of Li side effects (at 47.5 mg/kg). The administration of Cel elicited no significant effect on the hyperactivity induced by d-AMPH in rats, but the

administration of this cyclooxygenase inhibitor (20 mg/kg) plus Li (24 mg/kg) significantly abrogated the effect of d-AMPH. Recently, a study showed that coadministration of these drugs in

the same doses also was implicated in a decrease in the hyperlocomotion of rats induced by d-AMPH31. Interestingly, it was reported that the administration of Cel during two weeks was showed

to reverse the hyperactivity observed in bulbectomized animals32. In addition, the role of certain anti-inflammatory drugs as potential adjuvants for BD therapy has been investigated. A

placebo-controlled, randomized trial showed that patients affected by such disorder receiving Cel during 1 week presented a significant improvement in their depressive symptoms, as compared

with the placebo group19. Cyclooxygenase inhibitors were also implicated in the modulation of behaviors depending on dopaminergic neurotransmission, as described in the study headed by Ross

using indomethacin in order to regulate the hyperactivity induced by d-AMPH (1 mg/kg)33. Evidence regarding the pharmacological action of Cel on the dopaminergic neuronal pathway is scarce

yet. Nevertheless, inhibition of cyclooxygenase-2 by this drug was implicated in the regulation of dopamine levels, as described in a schizophrenia model induced by intracranial injection of

epidermal growth factor in rats34. Moreover, Cel was reported to mitigate the degeneration of dopaminergic neurons induced by intrastriatal injection of 6-hydroxydopamine—an effect partly

mediated by inhibition of microglia activity35. Cel administration (20 mg/kg) also alleviated the behavioral abnormalities, dopaminergic dysfunction, and produced a decrease in the levels of

activated microglia in the brain of young rats submitted to the model of neuroinflammation induced by lipopolysaccharide36. Thus, here was speculate that Cel could regulate the activity of

dopaminergic signaling underlying the hyperactivity observed in rats receiving d-AMPH, whereas the administration of Li could enhance this modulation. Whether this central pharmacological

action of Cel involves the abrogation of microglia activation potentially induced by d-AMPH is an issue that requires further investigation. Indeed, there is evidence indicating that the

decrease in dopamine synthesis and increase in intracellular levels of such neurotransmitter could counteract and induce the activation of microglia in the striatum of animals,

respectively36,37, which provides a potential link between the administration of d-AMPH and inflammatory response in the dopaminergic model of mania using this drug. Besides, aberrant levels

of proinflammatory mediators termed cytokines has been reported in the serum of bipolar patients38. As amphetamines elicit persistent damage to dopaminergic neurons, the subsequent

microglia activation could, in turn, collaborate to the release of certain cytokines39. Thus, it cannot be ruled out that Li and Cel mutually act to mitigate the proinflammatory state

reported in animal models of mania and bipolar patients, possibly through the inhibition of cyclooxygenase-2 enzyme and regulation of cytokine levels40,41. Oxidative stress is also proposed

as a crucial factor for the cytotoxicity elicited by amphetamines42. The increase in the level of reactive oxygen species induced by d-AMPH may lead to the release of cytochrome _c_ and

mitochondrial DNA into the cytosol, subsequently resulting in cellular damage and inflammatory response43,44. Indeed, it was observed that the administration of d-AMPH induced oxidative

damage to lipids (evaluated as TBARS levels) and proteins (as carbonyl content), whereas decreased the activity of CAT and GPx antioxidant enzymes in rat brain. It is worthy to note that

Frey et al.8 also detected an increased level of TBARS in the hippocampus and frontal cortex samples of rats submitted to the dopaminergic model of mania, which was consistent to oxidative

stress in the brain of these animals. As oxidative stress is an imbalance between the generation of reactive oxygen species and the biological antioxidant defenses45, the present study

suggests that lipid and protein oxidative damage elicited by d-AMPH could in part be a consequence of the CAT and GPx inhibition. Administration of Cel significantly reversed the increased

TBARS level induced by d-AMPH in the brain of rats, whereas partially reversed the increased carbonyl content in the frontal cortex. Such finding corroborates by a study showing that the

administration of Cel can mitigate oxidative lipid damage46. However, the present study was the first to indicate that the administration of Cel significantly prevents the protein

carbonylation induced by d-AMPH. Potential mechanisms involved in the antioxidant and anti-inflammatory activity of Cel include a decrease in the synthesis of cytokines and the release of

excitatory amino acids, modulation of the inducible nitric oxide synthase (EC 1.14.13.39) pathway and decrease in the generation of hydroxyl radical (•OH)47. On the other hand, the decreased

activity of CAT in rats receiving d-AMPH was not affected by the Cel administration. Accordingly, Venugopal and Prakash48 showed a dose-dependent effect of Cel on the CAT activity in an

experimental model of neuroinflammation: 10 mg/kg was not able to alter the activity of the enzyme, whereas a significantly increased CAT activity was detected in response to a higher dose

of the drug (50 mg/kg). In this scenario, the dose of Cel used in the present study (20 mg/kg) was unable to modify the activity of this enzyme. However, Cel (20 mg/kg) modulated the

activity of GPx in animals submitted to the model of mania, whereas it was reported that the coadministration of Cel and cisplatin or tumoral necrosis factor (TNF)-α decreased the levels of

GPx49. Overall, these studies and the findings of the present study indicate that Cel regulation of CAT and GPx activities are part of antioxidant action mechanism of the drug. Under

previous work, administration of Li reversed the oxidative lipid damage in the brain of rats submitted to the model of mania8. Such drug was also implicated in decreased carbonyl content in

these animals. This finding seems to agree with other preclinical work, which showed that the administration of Li (47.5 mg/kg) reversed the increase in the carbonyl content induced by

methamphetamine50. Furthermore, Li was showed to prevent the mitochondrial electron transport chain complexes from damage elicited by d-AMPH29. Taking into account that reactive oxygen

species are mainly generated in mitochondria51, it could be suggested that Li exerts the aforementioned antioxidant roles partly through the modulation of the mitochondrial respiratory chain

activity. Indeed, neuroprotective activity was also assigned to this mood stabilizer, collaborating to its therapeutic properties52. It was also observed that the administration of Li

abrogated the alteration in the activity of GPx, but not in CAT, in animals receiving d-AMPH. This finding partly agrees with the paper performed by Macêdo and colleagues53, which showed

that Li at the therapeutic dose (47.5 mg/kg) significantly regulated GPx activity in the presence of lisdexamphetamine. In contrast to the present work, Li at the therapeutic range

significantly reversed the modification in the activity of CAT elicited by d-AMPH8. Although the activity of these enzymes was not linear in most of the samples, there was a linear

association between CAT and GPx activities, which indicates that each cerebral structure could present a typical pattern of antioxidant enzyme activity in response to d-AMPH.

Coadministration of Li and Cel counteracted the increase in cerebral carbonyl content and TBARS level in hippocampus of animals receiving d-AMPH. In contrast to the single administration of

each drug, only the combined approach was able to mitigate the alterations in the antioxidant enzymes detected in the model of mania. According to the described elsewhere, both Li and Cel

present antioxidant properties54,55. Concerning the combined administration of these drugs, Phelan and coworkers56 reported that Li presents a possible pharmacokinetic interaction with Cel.

More specifically, these researchers showed that the plasma level of Li increased by 99% when this drug was administered with Cel56, which could be related to the ability of Cel to decrease

Li renal clearance57. Thus, Cel could increase the plasma levels of the mood stabilizer, although the levels of Li in rat serum were not measured in the present study. On the other hand, it

cannot be ruled out that both drugs could also act synergistically. Indeed, Cel and Li exhibit either anti-inflammatory and antioxidant activities58,59, which could be of interest for BD, as

increased levels of inflammation markers (e.g., interleukin (IL)-1β, IL-6, TNF-α, and soluble receptors for IL-2 and TNF) were detected in the serum of bipolar patients60. These findings

are consistent with the inflammatory hypothesis for BD manic symptoms61. It is worthy to note that proinflammatory cytokines were implicated in the depletion of 5-hydroxytryptamine in the

central nervous system58. In contrast, Cel per se was also associated with a moderate antidepressant activity19,62,63, which could be in part related to the ability of the drug to enhance

5-hydroxytryptamine release in the medial prefrontal cortex64. Therefore, regarding present findings and all the studies above, it is possible that Li and Cel act in order to stabilize the

moods and prevent the oxidative damage by one or more of the following mechanisms: (1) regulation of the dopamine levels through inhibition of cyclooxygenase-2 triggered by Cel; (2)

inhibition of microglia activity via a decrease in dopamine synthesis in the striatum; (3) the decrease in the synthesis of cytokines and the release of excitatory amino acids, as well as

modulation of the inducible nitric oxide synthase pathway (especially Cel); (4) modulation of the electron transport chain activity, preventing the mitochondrial complexes from the damage

elicited by d-AMPH (especially Li); (5) a possible pharmacokinetic interaction between Li and Cel, characterized by a decrease in the renal clearance of the mood stabilizer induced by the

anti-inflammatory drug; (6) since proinflammatory cytokines were implicated in decreased 5-hydroxytryptamine levels in the brain, Cel could counteract this depletion, in part enhancing the

release of the neurotransmitter in the medial prefrontal cortex. In summary, hyperlocomotion and significant alteration in oxidative stress biomarkers were detected in the cerebral

structures of rats submitted to a model of mania induced by d-AMPH, corroborating with previous observations that such chemical species are involved in the pathophysiology of BD.

Administration of Li plus Cel can mitigate these imbalances, rendering this combined approach a potential novel therapeutic option to the management of BD. Additional preclinical research is

also needed to explore the safety of this promising combined therapy in the context of BD. LIMITATIONS OF THE STUDY Measurements of Li serum levels were not performed. Besides, one of the

most critical advantages of preclinical research in Psychiatry reflects the possibility to establish an engagement of a specific neurotherapeutic target. However, current findings are still

correlational and do not provide this level of evidence, which highlights the importance of further research in the field. Despite these drawbacks, the principal aims of the present study

were to provide additional evidence to support further preclinical and clinical research on the Li and Cel coadministration, as well as provide a drug repositioning strategy based on the

anti-inflammatory drug. REFERENCES * Proudfoot, J. G. et al. What happens after diagnosis? Understanding the experiences of patients with newly-diagnosed bipolar disorder. _Health Expect._

12, 120–129 (2009). Article  PubMed  PubMed Central  Google Scholar  * Subramaniam, M. et al. Impact of psychiatric disorders and chronic physical conditions on health-related quality of

life: Singapore Mental Health Study. _J. Affect. Disord._ 147, 325–330 (2013). Article  PubMed  Google Scholar  * American Psychiatric Association. Bipolar Disorder and Relationship. In

American Psychiatric Association (ed). Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5). American Psychiatric Press: Washington, DC, 2013, pp 123–155. * Andreazza,

A. C. et al. 3-Nitrotyrosine and glutathione antioxidant system in patients in the early and late stages of bipolar disorder. _J. Psychiatry Neurosci._ 34, 263–271 (2009). PubMed  PubMed

Central  Google Scholar  * Belmaker, R. H. & Bersudsky, Y. Bipolar disorder: mania and depression. _Discov. Med_ 4, 239–245 (2004). CAS  PubMed  Google Scholar  * Valvassori, S. S.,

Budni, J., Varela, R. B. & Quevedo, J. Contributions of animal models to the study of mood disorders. _Rev. Bras. Psiquiatr._ 35, S121–S131 (2013). Article  PubMed  Google Scholar  *

Frey, B. N. et al. Effects of lithium and valproate on amphetamine-induced oxidative stress generation in an animal model of mania. _J. Psychiatry Neurosci._ 31, 326–332 (2006). PubMed 

PubMed Central  Google Scholar  * Frey, B. N. et al. Increased oxidative stress after repeated amphetamine exposure: possible relevance as a model of mania. _Bipolar Disord._ 8, 275–280

(2006). Article  CAS  PubMed  Google Scholar  * Nestler, E. J. & Hyman, S. E. Animal models of neuropsychiatric disorders. _Nat. Neurosci._ 13, 1161–1169 (2010). Article  CAS  PubMed 

PubMed Central  Google Scholar  * Choi, F. Y., Ahn, S., Wang, Y. T. & Phillips, A. G. Interference with AMPA receptor endocytosis: effects on behavioural and neurochemical correlates of

amphetamine sensitization in male rats. _J. Psychiatry Neurosci._ 39, 189–199 (2014). Article  PubMed  PubMed Central  Google Scholar  * Valvassori, S. S. et al. The role of neurotrophic

factors in manic-, anxious- and depressive-like behaviors induced by amphetamine sensitization: Implications to the animal model of bipolar disorder. _J. Affect. Disord._ 245, 1106–1113

(2019). Article  CAS  PubMed  Google Scholar  * Groos, D. et al. Chronic antipsychotic treatment targets GIRK current suppression, loss of long-term synaptic depression and behavioural

sensitization in a mouse model of amphetamine psychosis. _J. Psychopharmacol._ 33, 74–85 (2018). Article  CAS  Google Scholar  * Issy, A. C., Dos-Santos-Pereira, M., Pedrazzi, J. F. C.,

Kubrusly, R. C. C. & Del-Bel, E. The role of striatum and prefrontal cortex in the prevention of amphetamine-induced schizophrenia-like effects mediated by nitric oxide compounds. _Prog.

Neuropsychopharmacol. Biol. Psychiatry_ 86, 353–362 (2018). Article  CAS  PubMed  Google Scholar  * Mishra, A., Mishra, A. K. & Jha, S. Effect of traditional medicine brahmi vati and

bacoside A-rich fraction of Bacopa monnieri on acute pentylenetetrazole-induced seizures, amphetamine-induced model of schizophrenia, and scopolamine-induced memory loss in laboratory

animals. _Epilepsy Behav._ 80, 144–151 (2018). Article  PubMed  Google Scholar  * Baldessarini R. J. Drug therapy of depression and anxiety disorders. In Brunton L. L., Lazo J. S., Parker K.

L. (eds). Goodman and Gilman’s Pharmacological Basis of Therapeutics, 11th edition. McGraw-Hill: New York, NY, 2006, pp 429–459. * Cheniaux, E. The pharmacological treatment of bipolar

disorder: a systematic and critical review of the methodological aspects of modern clinical trials. _Rev. Bras. Psiquiatr._ 33, 72–80 (2011). Article  PubMed  Google Scholar  * Rosa, A. R.,

Kapczinski, F., Oliva, R., Stein, A. & Barros, H. M. T. Monitoring the compliance to lithium treatment. _Rev. Psiq. Clin._ 33, 249–261 (2006). Google Scholar  * Whelton, A. et al.

Cyclooxygenase-2-specific inhibitors and cardiorenal function: a randomized, controlled trial of celecoxib and rofecoxib in older hypertensive osteoarthritis patients. _Am. J. Ther._ 8,

85–95 (2001). Article  CAS  PubMed  Google Scholar  * Nery, F. G. et al. Celecoxib as an adjunct in the treatment of depressive or mixed episodes of bipolar disorder: a double-blind,

randomized, placebo-controlled study. _Hum. Psychopharmacol._ 23, 87–94 (2008). Article  CAS  PubMed  Google Scholar  * Arabzadeh, S. et al. Celecoxib adjunctive therapy for acute bipolar

mania: a randomized, double-blind, placebo-controlled trial. _Bipolar Disord._ 17, 606–614 (2015). Article  CAS  PubMed  Google Scholar  * Modabbernia, A., Taslimi, S., Brietzke, E. &

Ashrafi, M. Cytokine alterations in bipolar disorder: a meta-analysis of 30 studies. _Biol. Psychiatry_ 74, 15–25 (2013). Article  CAS  PubMed  Google Scholar  * Barbosa, I. G.,

Machado-Vieira, R., Soares, J. C. & Teixeira, A. L. The immunology of bipolar disorder. _Neuroimmunomodulation_ 21, 117–122 (2014). Article  CAS  PubMed  PubMed Central  Google Scholar 

* Kaizaki et al. Celecoxib reduces brain dopaminergic neuronal dysfunction and improves sensorimotor behavioral performance in neonatal rats exposed to systemic lipopolysaccharide. _J.

Neuroinflammation_ 10, 45 (2013). Article  CAS  PubMed  PubMed Central  Google Scholar  * Broadhurst P. L. Experiments in psychogenetics: Application of biometrical genetics to the

inheritance of behavior. In Eisenk H. J. (ed). Experiments in Personality: Psychogenetics and psychopharmacology. Routledge & Kegan Paul: London, 1960, pp 31–71. * Levine, R. L.,

Williams, J. A., Stadtman, E. R. & Shacter, E. Carbonyl assays for determination of oxidatively modified proteins. _Methods Enzymol._ 233, 346–357 (1994). Article  CAS  PubMed  Google

Scholar  * Esterbauer, H. & Cheeseman, K. H. Determination of aldehydic lipid peroxidation products: malonaldehyde and 4-hydroxynonenal. _Methods Enzymol._ 186, 407–421 (1990). Article 

CAS  PubMed  Google Scholar  * Aebi, H. Catalase in vitro. _Methods Enzymol._ 105, 121–126 (1984). Article  CAS  PubMed  Google Scholar  * Wendel, A. Glutathione peroxidase. _Methods

Enzymol._ 77, 325–333 (1981). Article  CAS  PubMed  Google Scholar  * Valvassori, S. S. et al. Effects of mood stabilizers on mitochondrial respiratory chain activity in brain of rats

treated with d-amphetamine. _J. Psychiatr. Res._ 44, 903–909 (2010). Article  PubMed  Google Scholar  * Valvassori, S. S. et al. Lithium modulates the production of peripheral and cerebral

cytokines in an animal model of mania induced by dextroamphetamine. _Bipolar Disord._ 17, 507–517 (2015). Article  CAS  PubMed  Google Scholar  * Valvassori S. S. et al. Coadministration of

lithium and celecoxib attenuates the behavioral alterations and inflammatory processes induced by amphetamine in an animal model of mania. _Pharmacol. Biochem. Behav._ 183, 56–63 (2019).

Article  CAS  Google Scholar  * Borre, Y. et al. Celecoxib delays cognitive decline in an animal model of neurodegeneration. _Behav. Brain Res._ 234, 285–291 (2012). Article  CAS  PubMed 

Google Scholar  * Ross, B. M. et al. Cyclooxygenase inhibitor modulation of dopamine-related behaviours. _Eur. J. Pharm._ 450, 141–151 (2002). Article  CAS  Google Scholar  * Mizuno, M. et

al. A cyclooxygenase-2 inhibitor ameliorates behavioral impairments induced by striatal administration of epidermal growth factor. _J. Neurosci._ 27, 10116–10127 (2007). Article  CAS  PubMed

  PubMed Central  Google Scholar  * Sánchez-Pernaute et al. Selective COX-2 inhibition prevents progressive dopamine neuron degeneration in a rat model of Parkinson’s disease. _J.

Neuroinflammation_ 1, 6 (2004). Article  PubMed  PubMed Central  Google Scholar  * LaVoie, M. J. & Hastings, T. G. Dopamine quinone formation and protein modification associated with the

striatal neurotoxicity of methamphetamine: Evidence against a role for extracellular dopamine. _J. Neurosci._ 19, 1484–1491 (1999). Article  CAS  PubMed  PubMed Central  Google Scholar  *

Thomas, D. M., Francescutti-Verbeem, D. M. & Kuhn, D. M. Methamphetamine-induced neurotoxicity and microglial activation are not mediated by fractalkine receptor signaling. _J.

Neurochem._ 106, 696–705 (2008). Article  CAS  PubMed  PubMed Central  Google Scholar  * Rapaport, M. H., Guylai, L. & Whybrow, P. Immune parameters in rapid cycling bipolar patients

before and after lithium treatment. _J. Psychiatr. Res._ 33, 335–340 (1999). Article  CAS  PubMed  Google Scholar  * Yamamoto, B. K., Moszczynska, A. & Gudelsky, G. A. Amphetamine

toxicities: classical and emerging mechanisms. _Ann. NY Acad. Sci._ 1187, 101–121 (2010). Article  CAS  PubMed  Google Scholar  * Wang, H. M. et al. Inhibition of glycogen synthase kinase-3β

by lithium chloride suppresses 6-hydroxydopamine-induced inflammatory response in primary cultured astrocytes. _Neurochem. Int._ 63, 345–353 (2013). Article  CAS  PubMed  Google Scholar  *

ELnahas, E. M., Zeid, M. S., Kawy, H. S., Hendawy, N. & Baher, W. Celecoxib attenuates depressive-like behavior associated with immunological liver injury in C57BL/6 mice through TNF-α

and NF-κb dependent mechanisms. _Life Sci._ 163, 23–37 (2016). Article  CAS  PubMed  Google Scholar  * Feier, G. et al. Lithium and valproate modulate energy metabolism in an animal model of

mania induced by methamphetamine. _Pharm. Biochem. Behav._ 103, 589–596 (2013). Article  CAS  Google Scholar  * Andreazza, A. C. et al. Effects of mood stabilizers on DNA damage in an

animal model of mania. _J. Psychiatry Neurosci._ 33, 516–524 (2008). PubMed  PubMed Central  Google Scholar  * Cechinel-Recco, K. et al. Lithium and tamoxifen modulate cellular plasticity

cascades in animal model of mania. _J. Psychopharmacol._ 26, 1594–1604 (2012). Article  PubMed  CAS  Google Scholar  * Betteridge, D. J. What is oxidative stress? _Metabolism_ 49(2 Suppl 1),

3–8 (2000). Article  CAS  PubMed  Google Scholar  * Osman, E. Y. Effects of celecoxib or omega-3 fatty acids alone and in combination with risperidone on the behavior and brain biochemistry

in amphetamine-induced model of schizophrenia. _Pharm. Bioprocess_ 4, 113–125 (2016). Google Scholar  * Kronfol, Z. & Remick, D. G. Cytokines and the brain: Implications for clinical

psychiatry. _Am. J. Psychiatry_ 157, 683–694 (2000). Article  CAS  PubMed  Google Scholar  * Venugopal, J. & Prakash, R. Protective effect of COX inhibitors on lipopolysaccharide-induced

sickness behaviour or neuroinflammation and oxidative stress on male Wistar rats. _Int J. Pharm. Pharm. Sci._ 7, 240–245 (2015). Google Scholar  * Kuhar, M., Imran, S. & Singh, N.

Celecoxib enhances the chemotherapeutic response of cisplatin and TNF-α in SiHa cells through reactive oxygen species-mediated mitochondrial pathway. _Int J. Biomed. Sci._ 3, 176–184 (2007).

CAS  PubMed  PubMed Central  Google Scholar  * da-Rosa, D. D. et al. Differences between dextroamphetamine and methamphetamine: behavioral changes and oxidative damage in brain of Wistar

rats. _J. Neural. Transm. (Vienna)_ 119, 31–38 (2012). Article  CAS  Google Scholar  * Callaly, E. et al. Mitochondrial dysfunction in the pathophysiology of bipolar disorder: effects of

pharmacotherapy. _Mini Rev. Med. Chem._ 15, 355–365 (2015). Article  CAS  PubMed  Google Scholar  * Dell’Osso, L., Del Grande, C., Gesi, C., Carmassi, C. & Musetti, L. A new look at an

old drug: neuroprotective effects and therapeutic potentials of lithium salts. _Neuropsychiatr. Dis. Treat._ 12, 1687–1703 (2016). Article  PubMed  PubMed Central  Google Scholar  * Macêdo,

D. S. et al. Effects of lithium on oxidative stress and behavioral alterations induced by lisdexamfetamine dimesylate: relevance as an animal model of mania. _Prog. Neuropsychopharmacol.

Biol. Psychiatry_ 43, 230–237 (2013). Article  PubMed  CAS  Google Scholar  * Andreazza, A. C. et al. Serum S100B and antioxidant enzymes in bipolar patients. _J. Psychiatr. Res._ 41,

523–529 (2007). Article  PubMed  Google Scholar  * Bastos-Pereira, A. L. et al. Celecoxib prevents tumor growth in an animal model by a COX-2 independent mechanism. _Cancer Chemother.

Pharm._ 65, 267–276 (2010). Article  CAS  Google Scholar  * Phelan, K. M., Mosholder, A. D. & Lu, S. Lithium interaction with the cyclooxygenase 2 inhibitors rofecoxib and celecoxib and

other nonsteroidal anti-inflammatory drugs. _J. Clin. Psychiatry_ 64, 1328–1334 (2003). Article  CAS  PubMed  Google Scholar  * Rätz Bravo, A. E., Egger, S. S., Crespo, S., Probst, W. L.

& Krähenbühl, S. Lithium intoxication as a result of an interaction with rofecoxib. _Ann. Pharmacother._ 38, 1189–1193 (2004). Article  PubMed  Google Scholar  * Rosenblat, J. D., Cha,

D. S., Mansur, R. B. & McIntyre, R. S. Inflamed moods: a review of the interactions between inflammation and mood disorders. _Prog. Neuropsychopharmacol. Biol. Psychiatry_ 53, 23–34

(2014). Article  CAS  PubMed  Google Scholar  * Data-Franco, J. et al. Beyond the therapeutic shackles of the monoamines: New mechanisms in bipolar disorder biology. _Prog.

Neuropsychopharmacol. Biol. Psychiatry_ 72, 73–86 (2017). Article  CAS  PubMed  Google Scholar  * Teixeira, A. L., Salem, H., Frey, B. N., Barbosa, I. G. & Machado-Vieira, R. Update on

bipolar disorder biomarker candidates. _Expert Rev. Mol. Diagn._ 16, 1209–1220 (2016). Article  CAS  PubMed  Google Scholar  * Mousavi, S. Y. et al. A randomized, double-blind

placebo-controlled trial on effectiveness and safety of celecoxib adjunctive therapy in adolescents with acute bipolar mania. _J. Child Adolesc. Psychopharmacol._ 27, 494–500 (2017). Article

  CAS  PubMed  Google Scholar  * Goldstein, B. I., Kemp, D. E., Soczynska, J. K. & McIntyre, R. S. Inflammation and the phenomenology, pathophysiology, comorbidity, and treatment of

bipolar disorder: a systematic review of the literature. _J. Clin. Psychiatry_ 70, 1078–1090 (2009). Article  PubMed  Google Scholar  * Ayorech, Z., Tracy, D. K., Baumeister, D. &

Giaroli, G. Taking the fuel out of the fire: evidence for the use of anti-inflammatory agents in the treatment of bipolar disorders. _J. Affect. Disord._ 174, 467–478 (2015). Article  CAS 

PubMed  Google Scholar  * Johansson, D., Falk, A., Marcus, M. M. & Svensson, T. H. Celecoxib enhances the effect of reboxetine and fluoxetine on cortical noradrenaline and serotonin

output in the rat. _Prog. Neuropsychopharmacol. Biol. Psychiatry_ 39, 143–148 (2012). Article  CAS  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS The Translational Psychiatry

Program (USA) is funded by the Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth). The Center of

Excellence on Mood Disorders (USA) is funded by the Pat Rutherford Jr. Chair in Psychiatry, John S. Dunn Foundation and Anne and Don Fizer Foundation Endowment for Depression Research.

Translational Psychiatry Laboratory (Brazil) is one of the centers of the National Institute for Molecular Medicine (INCT-MM) and one of the members of the Center of Excellence in Applied

Neurosciences of Santa Catarina (NENASC). Its research is supported by grants from CNPq, FAPESC, Instituto Cérebro e Mente and UNESC. JQ is a 1 A CNPq Research Fellow and SSV is a 1D CNPq

Research Fellow. RBV is a holder of a CAPES studentship. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Translational Psychiatry Laboratory, Graduate Program in Health Sciences, University of

Southern Santa Catarina (UNESC), Criciúma, Santa Catarina, Brazil Samira S. Valvassori, Paula T. Tonin, Gustavo C. Dal-Pont, Roger B. Varela, José Henrique Cararo, Abel Freitas Garcia, 

Fernanda F. Gava, Samira Menegas & João Quevedo * Center of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of

Texas Health Science Center at Houston (UTHealth), Houston, TX, USA Jair C. Soares & João Quevedo * Neuroscience Graduate Program, The University of Texas MD Anderson Cancer Center

UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA João Quevedo * Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School,

The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA João Quevedo Authors * Samira S. Valvassori View author publications You can also search for this author

inPubMed Google Scholar * Paula T. Tonin View author publications You can also search for this author inPubMed Google Scholar * Gustavo C. Dal-Pont View author publications You can also

search for this author inPubMed Google Scholar * Roger B. Varela View author publications You can also search for this author inPubMed Google Scholar * José Henrique Cararo View author

publications You can also search for this author inPubMed Google Scholar * Abel Freitas Garcia View author publications You can also search for this author inPubMed Google Scholar * Fernanda

F. Gava View author publications You can also search for this author inPubMed Google Scholar * Samira Menegas View author publications You can also search for this author inPubMed Google

Scholar * Jair C. Soares View author publications You can also search for this author inPubMed Google Scholar * João Quevedo View author publications You can also search for this author

inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Samira S. Valvassori. ETHICS DECLARATIONS CONFLICT OF INTEREST JQ has the following disclosures: I. Clinical Research Support:

Janssen Pharmaceutical (Clinical Trial), Allergan (Clinical Trial) II. Advisory Boards, Speaker Bureaus, Expert Witness, or Consultant Daiichi Sankyo (Speaker Bureau) III. Patent, Equity, or

Royalty Instituto de Neurociencias Dr. Joao Quevedo (Stockholder) IV. Other Artmed Editora (Copyright), Artmed Panamericana (Copyright). ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer

Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. RIGHTS AND PERMISSIONS OPEN ACCESS This article is licensed under a Creative

Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the

original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in

the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended

use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit

http://creativecommons.org/licenses/by/4.0/. Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Valvassori, S.S., Tonin, P.T., Dal-Pont, G.C. _et al._ Coadministration of lithium

and celecoxib reverses manic-like behavior and decreases oxidative stress in a dopaminergic model of mania induced in rats. _Transl Psychiatry_ 9, 297 (2019).

https://doi.org/10.1038/s41398-019-0637-9 Download citation * Received: 04 November 2018 * Revised: 10 June 2019 * Accepted: 20 June 2019 * Published: 13 November 2019 * DOI:

https://doi.org/10.1038/s41398-019-0637-9 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not

currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative