Neuroscience Letters - Behavioral changes and brain energy metabolism dysfunction in rats treated with methamphetamine or dextroamphetamine
Gustavo Feier, Samira Valvassori, Jessica Lopes-Borges, Roger Varela, Daniele Bavaresco, Giselli Scaini, Meline Morais, Mônica Levy Andersen, Emilio Streck e João Quevedo
Studies have demonstrated that AMPHs produce long-term damage to the brain dopaminergic, serotoninergic and glutamatergic regions. Prefrontal cortex, amygdala, hippocampus and striatum appear to be involved in the toxicity and behavioral changes induced by AMPHs. A single dose of AMPH causes mitochondrial dysfunction and oxidative stress in rat brain. The goal of the present study was thus to investigate the potency of two amphetamines, dextroamphetamine (d-AMPH) and methamphetamine (m-AMPH), on the behaviour and energetic dysfunction in the brain of rats. d-AMPH and m-AMPH increased the crossing and rearing behaviours. The numbers of visits to the centre were increased by d-AMPH and m-AMPH only at 2mg/kg. Likewise, at a high dose (2mg/kg), the injection of m-AMPH increased the amount of sniffing. The AMPHs significantly decreased the activities of Krebs cycle enzymes (citrate synthase and succinate dehydrogenase) and mitochondrial respiratory chain complexes (I, II, III, IV); nevertheless, this effect varied depending on the brain region evaluated. In summary, this study demonstrated that at high doses, m-AMPH, increased stereotyped (sniffing) behaviour in rats, but d-AMPH did not. However, this study shows that d-AMPH and m-AMPH seem to have similar effects on the brains energetic metabolism.
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Journal of Psychiatric Research - Evaluation of behavioral and neurochemical changes induced by ketamine in rats: Implications as an animal model of mania
Fernando V. Ghedim, Daiane Fraga, Pedro Deroza, Marcos Roberto Oliveira, Samira Valvassori, Amanda Steckert, Josiane Budni, Felipe Dal-Pizzol, João Quevedo e Alexandra Zugno
Bipolar disorder (BD) is a chronic, prevalent, and highly debilitating psychiatric illness characterized by recurrent manic and depressive episodes. Mood stabilizing agents such as lithium and valproate are two primary drugs used to treat BD. To develop a novel animal model of mania (hallmark of BD), it is important to assess the therapeutic and prophylactic effect of these mood stabilizers on the new candidate target animal model. The present work investigates the therapeutic and prophylactic value of lithium and valproate in a novel preclinical animal model of mania, induced by ketamine. In the prevention protocol, wistar rats were pretreated with lithium (47.5 mg/kg, i.p., twice a day), valproate (200 mg/kg, i.p., twice a day), or saline (i.p., twice a day) for 14 days. Between days 8 and 14, the rats were treated with ketamine (25 mg/kg, i.p.) or saline. In the reversal protocol, rats first received ketamine (25 mg/kg, i.p.) or saline. After, the administration of lithium, valproate, or saline was carried out for seven days. Our results indicated that lithium and valproate reversed and prevented ketamine-induced hyperlocomotion. Moreover, lithium and valproate reversed (prefrontal cortex, hippocampus, and striatum) and prevented (prefrontal cortex, hippocampus, striatum, and amygdala) the increase of the TBARS level induced by ketamine. The protein carbonyl formation, induced by ketamine, was reversed by lithium and valproate in the prefrontal cortex, hippocampus, and striatum, and prevented only in the amygdala. These findings support the notion that the administration of ketamine might be a promising pharmacological animal model of mania, which could play a role in the pathophysiology of BD.
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Journal of Neural Transmission - Early life stress exacerbates cognitive dysfunction induced by D-amphetamine: amelioration by valproic acid
Rose Mary Carvalho Pinheiro, Maria Noêmia Martins de Lima, Gabriel Rodrigo Fries, Vanessa Athaíde Garcia, Juliana Presti-Torres, Luis Henrique Hallmenschlager, Luisa Azambuja Alcalde, Rafael Roesler, Mônica Levi Andersen, João Quevedo, Flávio Kapczinski e Nadja Schröder
It has been demonstrated that experiences taking place early in life have a profound influence on brain development, interacting with the genetic background and determining differences in the vulnerability to the onset of bipolar disorder when the individual is exposed to a second adverse event later in life. Here, we investigated the effects of exposure to an early adverse life event (maternal deprivation) and to a later adverse life event [D-amphetamine (AMPH)] on cognition in an animal model of mania. We have previously demonstrated that that repeated AMPH exposure produces severe and persistent cognitive impairment, which was more pronounced when the animals were maternal deprived, suggesting that the early adverse life event could be potentiating the effects of the exposure to the second adverse life event later in life. Here, we show that valproic acid ameliorated the cognitive deficits induced by AMPH, but it was not effective when the animals were exposed to both stressors: maternal deprivation and AMPH treatment.
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Journal of Neural Transmission - Imipramine reverses depressive-like parameters in pneumococcal meningitis survivor rats
Tatiane Barichello, Graziele Milioli, Jaqueline S. Generoso, Andreza L. Cipriano, Caroline Silva da Costa, Ana Paula Moreira, Márcia C. Vilela, Clarissa Comim, Antonio Lucio Teixeira e João Quevedo
Pneumococcal meningitis is a severe infectious disease of the central nervous system, associated with acute inflammation and might cause damage to the host, such as deafness, blindness, seizure, and learning deficits. However, infectious diseases can play a significant role in the etiology of neuropsychiatric disturbances. In this context, we evaluated depressive-like parameters; corticosterone and ACTH levels in pneumococcal meningitis surviving rats. Wistar rats underwent a magna cistern tap receiving either 10 μL sterile saline or a Streptococcus pneumoniae suspension at the concentration of 5 × 10(9) cfu/mL. After 3 days of meningitis induction procedure, the animals were treated with imipramine at 10 mg/kg or saline for 14 days (3rd-17th day). The consumption of sweet food was measured for 7 days (10th-17th day). The meningitis group decreased the sucrose intake and increased the levels of corticosterone and ACTH levels in the serum and TNF-α in the cortex; however, the treatment with imipramine reverted the reduction of sweet food consumption, normalized hormonal levels and TNF-α in the cortex. Our results supported the hypothesis that the pneumococcal meningitis surviving rats showed depressive-like behavior and alterations in the hypothalamus-pituitary-adrenal axis.
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Metabolic Brain Disease - Memantine treatment reverses anhedonia, normalizes corticosterone levels and increases BDNF levels in the prefrontal cortex induced by chronic mild stress in rats
Gislaine Z. Réus, Helena Mendes Abelaira, Roberto B. Stringari Gabriel Rodrigo Fries, Flávio Kapczinski e João Quevedo
Memantine is a N-methyl-D-aspartate (NMDA) receptor antagonist and several studies have pointed to the NMDA receptor antagonists as a potential therapeutic target for the treatment of depression. The present study was aimed to evaluate the behavioral and physiological effects of administration of memantine in rats exposed to the chronic mild stress (CMS) model. To this aim, after 40 days of exposure to CMS procedure, rats were treated with memantine (20 mg/kg) for 7 days. In this study, sweet food consumption, adrenal gland weight, corticosterone levels, and brain-derived-neurotrophic factor (BDNF) protein levels in the prefrontal cortex, hippocampus and amygdala were assessed. Our results demonstrated that chronic stressful situations induced anhedonia, hypertrophy of adrenal gland weight, and an increase of corticosterone levels in rats, but did not alter BDNF protein levels in the rat brain. Memantine treatment reversed anhedonia and the increase of adrenal gland weight, normalized corticosterone levels and increased BDNF protein levels in the prefrontal cortex in stressed rats. Finally, these findings further support the hypothesis that NMDA receptor antagonists such as memantine could be helpful in the pharmacological treatment of depression.
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