Lithium modulates energy metabolism in the frontal cortex of rats treated with ketamine

doi:10.21203/rs.3.rs-5236333/v1

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Lithium modulates energy metabolism in the frontal cortex of rats treated with ketamine

https://doi.org/10.21203/rs.3.rs-5236333/v1

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Bipolar Disorder (BD) is a chronic and highly debilitating psychiatric illness formerly called manic depression. Mood-stabilizing agents such as lithium (Li) are the primary drugs used to treat BD. Assessing the effect of these mood stabilizers is essential to develop a novel animal model of mania. Thus, the present work aimed to evaluate the ketamine (Ket) effect on tricarboxylic acid enzymes and mitochondrial respiratory chain complexes activity in the frontal cortex of rats for consolidation of an animal model of mania induced by Ket. Wistar rats received Ket (25 mg/kg) or saline for 14 days. Between days 8 and 14, the rats were treated with Li (47.5 mg/kg, twice daily) or saline for 14 days. On the 15th day, animals received a single injection of Ket or saline. After 30 minutes of the last injection, the locomotor activity was assessed, and tricarboxylic acid and mitochondrial respiratory chain complexes enzyme activities were measured in the frontal cortex. The administration of Ket for 14 days in rats induced hyperlocomotion in the open field test, and Li was able to reverse this effect. Moreover, animals treated with Ket increased the tricarboxylic acid cycle and mitochondrial respiratory chain complexes enzyme activities in the frontal cortex. Lit was able to reverse these effects, but could not reduce the mitochondrial respiratory chain complexes IV activity. These findings support the idea that the administration of Ket might be a promising pharmacological animal model of mania, but there is a limitation in construct validity for energy metabolism.

Bipolar Disorder

Ketamine

Lithium

Energy metabolism

Tricarboxylic acid cycle

Bipolar Disorder (BD) is a chronic psychiatric disorder characterized by the presence of one or more episodes of mania and frequent episodes of depression, in other words, BD exhibits two poles of bipolar mood or affective states that alternate between depression and its opposite, hypomania or mania (Andreazza et al., 2008). This disorder affects approximately 1% of individuals, is disabling, and is often life-threatening. Mania is characterized by racing thoughts, rapid speech, and increased energy and activity (Sato et al., 2002).

The symptoms associated with psychiatric disorders are complex. However some animal models can mimic the neurochemical and physiological characteristics of these conditions (Kato, 2007; Krystal et al., 2023). Animal models of mania are rare and generally based on the management of hyperlocomotion-inducing agents such as ketamine (Ket) (Frey et al., 2006; Ghedim et al., 2012; Krystal et al., 2023). Ket is a noncompetitive NMDA receptor antagonist, a glutamate ionotropic receptor (Moghaddam et al., 1997; Lamontagne et al., 2023). Studies suggest that the glutamatergic system is associated with the pathophysiology of mood disorders and may represent a new therapeutic target (Coyle and Duman, 2003; Maeng and Zarate, 2007). In addition, the increase in intracellular glutamate levels may induce neuronal hyperactivation, thus increasing energy demand (Dager et al., 2004)^, which may lead to dysfunction in energy metabolism.

Several studies suggest that the dysfunction of cellular energy metabolism, mainly in mitochondria, is associated with BD (Kato et al., 2001; Wang, 2007; Maurer et al., 2009; Anglin et al., 2012; Ghedim et al., 2012; Calarco et al., 2023; Menéndez-Valle et al., 2023). Energy, in the form of adenosine triphosphate (ATP), is obtained in the mitochondria through a sequence of reactions in which electrons liberated from reducing substrates, nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH), are transported to O2 through a chain of respiratory proton pumps (Brookes, 2004). An abnormal cellular energy state can alter neuronal function, plasticity, and brain circuits, and thereby to the cognitive and mood alteration characteristic of BD (Barrett et al., 2008; Quraishi et al., 2009; Calarco et al., 2023). However, few studies evaluate changes in the enzymes of the tricarboxylic acid (TCA) cycle in BD (Fonseca et al., 2005; Freitas et al., 2010; Menéndez-Valle et al., 2023).

In a previous study, lithium (Li) was able to reverse mitochondrial dysfunctions in an animal model of mania, suggesting that their action may be related not only to decreased dopamine but also to stabilize the function of mitochondria in BD (Valvassori et al., 2010; Spohr et al., 2022). Among the mood stabilizers, Li is the drug of choice in the treatment of acute manic episodes (Poolsup et al., 2000; Mitchell, 2013; Vieta and Valentí, 2013; Chen et al., 2014; Oruch et al., 2014; Lundberg et al., 2020) and preventing the relapses of manic attacks than hampering the depressive episodes (Geddes et al., 2004)

Therefore, the present study aimed to evaluate the activities of mitochondrial enzymes in the TCA cycle succinate dehydrogenase (SDH) and malate dehydrogenase (MDH), the respiratory chain complex (I, II, III, and IV) in the frontal cortex, and the locomotor activity of rats subjected to an animal model of mania induced by Ket and treated with Li.

This protocol was designed to mimic the prevention phase of mania treatment, as previously proposed (Frey et al., 2006a, b; Valvassori et al., 2010). 60 Wistar rats received either Sal or Li (Li, 47.5 mg/kg) i.p. twice a day for 14 days. From the 8th to the 14th day (treatment for 7 days), these animals also received Sal or Ket (25 mg/kg), i.p., once a day, totaling four experimental groups (n = 15 per group): Sal + Sal, Li + Sal, Sal + Ket, and Li + Ket. No behavioral assessment was performed between days 1 and 14. On the 15th day of treatment, the animals received a single injection of Ket or Sal, and locomotor activity was assessed using the open-field test 30 min after the injection. The rats were submitted to euthanasia by decapitation immediately after the open-field test, and frontal cortex was manually dissected on ice, rapidly frozen on dry ice, and stored at − 80°C to keep their integrity until assayed.

It is important to emphasize that animals treated with Li (47.5 mg/kg, i.p., twice a day for 7 or 14 days) had Li plasmatic levels between 0.6 and 1.2 mEq/L, as recommended in the treatment of BD patients (Frey et al., 2006a).

Behavioral assessment

Open field test

We used the open field test to assess locomotor activity (n = 15). The test was performed in a 40 x 60 cm open field surrounded by 50 cm-high walls made of brown plywood with a frontal glass wall. The floor of the open field was divided into 9 equal rectangles with black lines. The animals were gently placed on the left rear rectangle and were allowed to explore the arena. Crossings of the black lines were counted for 5 min. The locomotor activity was videotaped for 5 min, and later, the behavioral parameters manually counted. The rats were euthanized by decapitation right after the last open-field evaluation. The frontal cortex was dissected, rapidly frozen, and stored at -80°C to keep its integrity until assayed.

Biochemical analysis

Tissue and Homogenate Preparation

The frontal cortex was quickly isolated by hand dissection using a magnifying glass and a thin brush, and were was immediately dissected out and stored at -80 ºC to keep their integrity. The dissection was based on the histological distinctions described by Paxinos and Watson (1986). The frontal cortex was homogenized (1:10, w/v) in SETH buffer, pH 7.4 (250 mM sucrose, 2 mM EDTA, 10 mM Trizma base, and 50 IU/ml heparin). The homogenates were centrifuged at 8000g for 10 min at 4 ºC, and the supernatants were kept at -80 ºC to keep their integrity until being used for enzymes activity determination. The maximal period between homogenate preparation and enzyme analysis was always less than 5 days. Protein content was determined by the method described by Lowry et al. (1951) using bovine serum albumin as standard.

Malate Dehydrogenase Activity

MDH (n = 5–6) was measured as described by Kitto (1969). Aliquots were transferred into a medium containing 10 mM rotenone, 0.2% Triton X-100, 0.15 mM NADH, and 100 mM potassium phosphate buffer, pH 7.4, at 37º C. The reaction was started by the addition of 0.33 mM oxaloacetate. The absorbance was monitored as described above.

Succinate dehydrogenase activity

SDH activity (n = 5–6) was determined according to the method of Fischer et al. (1985) and measured by following the decrease in absorbance due to the reduction of 2,6-di-chloro-indophenol (2,6-DCIP) at 600 nm with 700 nm as a reference wavelength (ε = 19.1 mM − 1 cm − 1) in the presence of phenazine methosulfate (PMS). The reaction mixture consisting of 40 mM potassium phosphate, pH 7.4, 16 mM succinate, and 8 µM 2,6-DCIP was pre-incubated with 40–80 µg homogenate protein at 30°C for 20 min. Subsequently, 4 mM sodium azide, 7 µM rotenone, and 40 µM 2,6-DCIP were added, and the reaction was initiated by the addition of 1 mM PMS and was monitored for 5 min.

Activities of mitochondrial respiratory chain enzymes

Complex I activity (n = 5–6): NADH dehydrogenase (complex I) was evaluated according to Cassina and Radi (1996) by the determination of the rate of NADH dependent ferricyanide reduction at λ = 420 nm.

Complex II activity (n = 5–6): The activities of succinate-2,6-dichloroindophenol (DCIP)-oxidoreductase (complex II) were determined by the method described by Fischer et al. (1985). Complex II activity was measured by following the decrease in absorbance due to the reduction of 2,6-DCIP at λ = 600 nm.

Complex II–III activity (n = 5–6): The activity of succinate: cytochrome c oxidoreductase (complex III) was determined by the method described by Fischer et al. (1985). Complex II–III activity was measured by cytochrome c reduction using succinate as substrate at λ = 550 nm.

Complex IV activity (n = 5–6): The activity of cytochrome c oxidase (complex IV) was assayed according to the method described by Rustin et al. (1994), measured by following the decrease in absorbance due to the oxidation of previously reduced cytochrome c (prepared by reduction of cytochrome with NaBH4 and HCl) at λ = 550 nm with 580 nm as the reference wavelength (ɛ=19.1 mM − 1 cm − 1). The activities of the mitochondrial respiratory chain complexes were calculated as nmol•min − 1•mg. protein − 1.

Statistical analysis

Data were analyzed by Two-way analysis of variance (ANOVA) followed by Tukey post-hoc test when p values were significant (p < 0.05). All analysis were performed using the Statistical Package for the Social Science (SPSS) software.

Results for locomotor activity are shown in Table 1. The results indicated that Ket administered for 14 days induced hyperlocomotion in the open field test in rats. The Li treatment was able to reverse this effect by significantly reducing the number of Crossing and Rearing when compared to the Ket + Sal group. Two away ANOVA revealed significant differences for crossing [Ket induction: f (1.28): 71.01, p < 0.01; Li treatment: f (1.28): 40.31, p < 0.01 and interaction: f (1.28):36.87, p < 0.01] and rearing [Ket induction: f (1.28): 39.55, p < 0.01; Li treatment: f (1.28): 24.48, p < 0.01 and interaction: f (1.28):16.20, p < 0.01].

Figure 1 shows the TCA cycle by analyzing MDH (1A) and SDH (1B) in the frontal cortex. The group Ket + Sal showed a significant increase when compared to Sal + Sal group, also the group Ket + Li showed a significant decrease when compared to Ket + Sal group reverting the increase caused by Ket induction (1A, 1B). Two-way ANOVA showed significant difference for MDH [Ket induction: f (1,12): 194,58, p < 0.01; Li treatment: f (1,12): 209, 24, p < 0.01 and interaction: f (1,12): 181,48, p < 0,01] and SDH [Ket induction: f (1.12): 44.20, p < 0.01; Li treatment: f (1,12): 18,01, p < 0,01 and interaction: f (1,12): 27,67, p < 0,01].

As seen in Fig. 2, the mitochondrial respiratory chain complexes activity was evaluated in the frontal cortex. The group Ket + Sal showed a significant increase in all complexes (I, II, II-III, and IV) evaluated (2A, 2B, 2C, and 2D). However, the group with Li treatment (Ket + Li) reversed this increase when compared to Ket + sal group in complexes I, II, and II-III (2A, 2B, and 2C). Li treatment was not able to reverse the increase in activity of the IV (2D) complex. Two-way ANOVA showed significant difference for complex I [Ket induction: f (1,12): 15,51, p < 0,01; Li treatment: f (1.12): 10.56, p < 0.01 and interaction: f (1.12): 20.00, p < 0.01], complex II [Ket induction: (1.12): 34.08, p < 0.01; Li treatment: f (1,12): 17,13, p < 0,01 and interaction: f (1,12): 13,57, p < 0,01], complex II-III [Ket induction: f (1.12): 23.49, p < 0.01; Li treatment: f (1,12): 10,82, p < 0,01 and interaction: f (1,12): 20,27, p < 0,01], and IV complex [Ket induction: f (1.12): 674.19, p < 0.01; Li treatment: f (1.12): 1.15, p = 0.30 and interaction: f (1.12): 0.02, p = 0.88].

Ket is one of the anesthetic drugs that have different effects on mood and behavior in different doses. In low doses, it has antidepressant effects, and in higher doses, it causes excessive movement and behavior, such as becoming delirious. As seen in this study Ket administration in higher doses can be a promising animal model for mania. Ket induced hyperactivity in the open field test. Moreover, Ket administration increased the activities of the TCA cycle enzyme (MDH and SDH) and mitochondrial respiratory chain complex (I, II, III, and IV). Li was able to reverse almost totally these effects.

Ketamine, a dissociative anesthetic, in rodents induces psychotic behavior as hyperlocomotion (Canever et al., 2010; De Oliveira et al., 2011). Moreover, Ricker et al. (2011) showed that Ket therapy was able to induce prolonged mania associated with psychotic symptoms in a reflex sympathetic dystrophy patient. Therefore, our behavioral results corroborate with recent preclinical and clinical studies, indicating that Ket can induce an animal model of mania (Ghedim et al., 2012; Chaves et al., 2020). Ghedim et al. (2012) demonstrated that Li can reverse and prevent Ket-induced hyperlocomotion by causing changes in the membrane's excitability, which may be related to its antimanic effect. Therapeutic concentrations of this drug practically do not present psychotropic effects in normal individuals, not behaving as a sedative, depressant, or euphoric, a characteristic that distinguishes it from other psychotropics (Ghedim et al., 2012; Chaves et al., 2020).

We also evaluated the enzymatic activity of the TCA cycle (MDH and SDH), and the results demonstrated that Ket induced an increase in the activity of these enzymes. Ket is involved in behavioral and biochemical changes, such as increased mobility, oxidative stress associated with mitochondrial dysfunction, and changes in brain-derived neurotrophic factor levels observed in BD patients. Feier et al. (2011) showed that the administration of m-amphetamine, an animal model of mania, causes increased Citrate Synthase (CS) and SDH in the prefrontal cortex, amygdala, hippocampus, and striatum, and Li and valproate were able to reverse this effect. Ket induces an animal model of schizophrenia (Canever et al., 2010; De Oliveira et al., 2011). In addition, a study has shown in the post-mortem brain of schizophrenic patients the activity of increased SDH and MDH (Bubber et al., 2011). Although Li reverses these effects by altering the transport of cations across cell membranes and in nerve and muscle cells. Furthermore, due to its similarity with other elements (such as sodium and potassium), lithium can influence the reuptake of serotonin and/or norepinephrine and allows it to inhibit the second messenger systems involved in the phosphatidylinositol cycle (Freitas et al., 2010; Valvassori et al., 2014).

The animal models of disorders in humans must meet three sets of criteria, such as construct, face and predictive validity BD is accompanied by recurrent manic and depressive episodes (Goodwin and Jamison, 2003). Manic episodes are characterized by irritable mood, psychomotor activation, reduced sleep requirements, and excessive involvement in potentially problematic behavior (El-Mallakh et al., 2003). One of the few symptoms of this disorder that can be reproduced in animal models is hyperactivity, which was observed in this study. In addition, Li was used to test the efficacy of the anti-manic treatment in this animal model, and we observed that Li completely reversed the hyper-compliance induced by Ket. Therefore, the results found in this study showed that the animal model of mania presented in this study may induce behavioral changes and response to Li treatment, showing similarities to BD, indicating that this animal model induced by Ket presents face and face validity predictive.

In this work, the activity of the complexes I, II, II-III, and IV of the mitochondrial respiratory chain in this animal model was also evaluated. The results indicate that Ket increased the activity of all mitochondrial complexes. Pre-clinical studies show that the activity of these complexes is decreased in animal models of mania induced by m-AMPH and d-AMPH in the hippocampus, striatum, and prefrontal cortex, and Li was able to reverse these effects (Valvassori et al., 2010; Feier et al., 2013). Some preclinical and clinical studies agree with the results of this study. Freitas et al. (2011) showed that intracerebroventricular administration of ouabain, an animal model of mania, induces the increased activity of mitochondrial complexes I, II, II-III, and IV in the prefrontal cortex of rats. A clinical study also corroborates these data, as it shows increased mRNA levels of the mitochondrial I complex in the parieto-occipital cortex of patients with BD (Ben-Shachar and Karry, 2008). A possible explanation for these results would be that increased mitochondrial complex activity occurs as a compensatory effect for ATP reduction observed in BD.

Results showed that Li was able to revert the increased activity of mitochondrial complexes I, II, II-III, but not the increase of IV complex activity. This may have occurred due to the fact that Li can act in a specific way in each brain region (Valvassori et al., 2010), and the response can be differentiated mainly as a function of the type of animal model induced (Frey et al., 2006), in this case, an animal model of the glutamatergic type (Ghedim et al., 2012).

These results suggest that this animal model of mania induced by Ket may have good face validity (induces hyperlocomotion in animals), predictive (Li reverses these effects), but may fail or have a limitation as to construct validity, since it does not the role of energy metabolism in the pathophysiology of BD is very well elucidated. Another study by Venâncio et al. (2015) showed that Ket increases mitochondrial nitric oxide synthase (mitNOS) by interfering with the function of mitochondrial complex I, thereby increasing NO and superoxide anion (O2.−) levels. Ket also increases apoptosis and ROS production in human neurons (Bai et al., 2013). An important factor in the pathogenesis of BD is a disorder of the glutamatergic system, and Li, as a mood stabilizer, can prevent behavioral and biochemical changes caused by KET in animals (Gazal et al. 2014; Saljoughi et al., 2023).

It is important to emphasize the vantage of this animal model in relation to other models of mania, which is a reproduction of glutamatergic changes induced by Ket, such as those found in the phase of mania in BD. In the post-mortem brains of patients with BD, there was an increase in the glutamate/glutamine ratios and a decrease in the levels of N-methyl-D-aspartate (NMDA) receptor subunits (Hashimoto et al., 2007; Rao et al., 2012). In addition, a study by (Dickerson et al., 2012) demonstrated increased levels of antibodies to a subunit of NR2 (NMDA receptor subunits) during an acute phase of patient mania. Therefore, this model may be more relevant to mimic a glutamatergic alteration than a change in energy metabolism (Saljoughi et al., 2023).

In conclusion, our study shows the increase in mitochondrial respiratory capacity in a glutamatergic animal model of mania. Therefore, we suggest an interaction between glutamate, which is involved in the pathophysiology of BD, and mitochondrial dysfunction. We have also shown that Li can reverse Ket-induced mitochondrial dysfunction. However, the protective effect of Li was not observed in all respiratory chain complexes. Future studies may better elucidate the relationship between treatment with Li and the relationship with mitochondrial and glutamatergic dysfunction in animal models of BD using Ket.

Competing Interests

Conflicts of interest: There are no conflict of interests between the authors.

Funding: This work was supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES-001), Fundação de Âmparo à Pesquisa e Inovação de Santa Catarina (FAPESC), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Universidade do Extremo Sul Catarinense (UNESC).

Financial interest: The authors have no relevant financial or non-financial interests to disclose.

Authors contribution: All authors have worked together in this work. Josiane Budni has worked on all the steps of the article. Also, Eduarda Behenck Medeiros, Gustavo de Bem Silveira, Adrielly Vargas Lidio, Gabriel Casagrande Zabot, and Karolina V. Freitas made substantial contributions with the acquisition, analysis, and interpretation of the data. Wilson R. Resende, Gustavo C. Dal-Pont, Amanda L. Maciel, Jaqueline S. Generoso, Cinara L. Gonçalvez, Emilio L. Streck, João Quevedo, and Samira S. Valvassori have drafted the work and revised it critically many times until its conclusion. Josiane Budni and Jaqueline S. Generoso have also worked on the translation of the article and revision of the English language. All the authors approved the version to be published and agreed to be accountable for all aspects of the work to ensure that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Data viability: The datasets generated during and/or analyzed during the current study are not publicly available to protect the privacy of all data and to maintain ethical standards and the integrity of the research process but are available from the corresponding author upon reasonable request.

Ethics approval: This project was accepted by the Ethics Committee for the Use of Animals (CEUA) of the Universidade do Extremo Sul Catarinense – UNESC, having all procedures in accordance with the Brazilian guidelines for the use of animals for scientific and didactic purposes (Law 11,794, DOU 5/27/13, MCTI, p.7). All animal experiments comply with the ARRIVE guidelines.

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Table 1 is available in the Supplementary Files section.

No competing interests reported.

Table1.jpg
Table 1. Effect of Li in male rats subjected to an animal model of mania induced by ket on the open-field test. Values were expressed by Mean ± Standard deviation, n=15. Data were analyzed by two-way ANOVA, following Tukey post-hoc test. *p < 0,01 as compared Sal+Sal group.

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Lithium modulates energy metabolism in the frontal cortex of rats treated with ketamine

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Abstract

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Introduction

Materials and Methods

Behavioral assessment

Open field test

Biochemical analysis

Tissue and Homogenate Preparation

Malate Dehydrogenase Activity

Succinate dehydrogenase activity

Activities of mitochondrial respiratory chain enzymes

Statistical analysis

Results

Discussion

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References

Tables

Additional Declarations

Supplementary Files

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