Morgana Moretti

Effects of mood stabilizers on mitochondrial respiratory chain activity in brain of rats treated with d-amphetamine.

Bipolar disorder (BD) is a devastating major mental illness associated with high rates of suicide and work loss. There is an emerging body of data suggesting that bipolar disorder is associated with mitochondrial dysfunction. In this context, the present study aims to investigate the effects of mood stabilizers lithium (Li) and valproate (VPT) on mitochondrial respiratory chain activity in brain of rats undergoing treatment with the pro-manic agent d-AMPH d-amphetamine (d-AMPH). In the reversal treatment, Wistar rats were first given d-AMPH or saline for 14 days, and then, between days 8 and 14, rats were treated with Li, VPA or saline (Sal). In the prevention treatment, rats were pretreated with Li, VPA or Sal. Locomotor behavior was assessed using the open-field task and mitochondrial chain activity complexes I, II, III and IV were measured in brain structures (hippocampus, striatum and prefrontal). Li and VPA reversed and prevented d-AMPH-induced hyperactivity. In both experiments, d-AMPH inhibited mitochondrial respiratory chain activity in all analyzed structures. In the reversal treatment, VPA reversed d-AMPH-induced dysfunction in all brain regions analyzed. In the prevention experiment, the effects of Li and VPA on d-AMPH-induced mitochondrial dysfunction were dependent on the brain region analyzed. These findings suggested that dopamine can be an important link for the mitochondrial dysfunction seen in BD and, Li and VPA exert protective effects against this d-AMPH-induced mitochondrial dysfunction, but this effect varies depending on the brain region and the treatment regimen.

Role of oxidative stress in the pathophysiology of bipolar disorder

In this work, we review the studies of oxidative stress markers, showing association with the pathophysiology of bipolar disorder (BD). BD is a prevalent, chronic and highly disabling psychiatric disorder. Several hypotheses have been postulated to explain the exact neurochemical mechanisms underlying the pathophysiology of BD, including a role for monoamines, gamma-amino butyric acid (GABA), glutamate, and second messenger singling pathways. More recently, oxidative stress has been implicated in the pathogenesis of BD. Recent studies have reported increased products of lipid peroxidation and alterations of the major antioxidants enzymes in patients with BD. It has been widely demonstrated that the generation of reactive oxygen species (ROS) plays a critical role in the pathophysiology of several neuropsychiatric disorders, such BD.

Lithium and valproate modulate antioxidant enzymes and prevent ouabain-induced oxidative damage in an animal model of mania

In this study, we assessed the oxidative stress parameters in rats submitted to an animal model of mania induced by ouabain (OUA), which included the use of lithium (Li) and valproate (VPA). Li and VPA treatment reversed and prevented the OUA-induced damage in these structures, however, this effect varies depending on the brain region and treatment regimen. Moreover, the activity of the antioxidant enzymes, namely, superoxide dismutase (SOD) and catalase (CAT) was found to be increased and decreased, respectively, in the brain of OUA-administered rats. Li and VPA modulated SOD and CAT activities in OUA-subjected rats in both experimental models. Our results support the notion that Li and VPA exert antioxidant-like properties in the brain of rats submitted to animal model of mania induced by ouabain.

Effects of mood stabilizers on hippocampus and amygdala BDNF levels in an animal model of mania induced by ouabain

There is a body of evidence suggesting that BDNF is involved in bipolar disorder (BD) pathogenesis. Intracerebroventricular (ICV) injection of ouabain (OUA), a specific Na(+)/K(+) ATPase inhibitor, induces hyperlocomotion in rats, and has been used as an animal model of mania. The present study aims to investigate the effects of the lithium (Li) and valproate (VPT) in an animal model of mania induced by ouabain. In the reversal model, animals received a single ICV injection of OUA or cerebrospinal fluid (aCSF). From the day following the ICV injection, the rats were treated for 6 days with intraperitoneal (IP) injections of saline (SAL), Li or VPT twice a day. In the maintenance treatment (prevention model), the rats received IP injections of Li, VPT, or SAL twice a day for 12 days. In the 7th day of treatment the animals received a single ICV injection of either OUA or aCSF. After the ICV injection, the treatment with the mood stabilizers continued for more 6 days. Locomotor activity was measured using the open-field test and BDNF levels were measured in rat hippocampus and amygdala by sandwich-ELISA. Li and VPT reversed OUA-related hyperactive behavior in the open-field test in both experiments. OUA decreased BDNF levels in first and second experiments in hippocampus and amygdala and Li treatment, but not VPT reversed and prevented the impairment in BDNF expression after OUA administration in these cerebral areas. Our results suggest that the present model fulfills adequate face, construct and predictive validity as an animal model of mania.

Neuropeptide S produces hyperlocomotion and prevents oxidative stress damage in the mouse brain: a comparative study with amphetamine and diazepam.

Neuropeptide S (NPS) is a recently discovered peptide which induces hyperlocomotion, anxiolysis and wakefulness. This study aimed to compare behavioral and biochemical effects of NPS with amphetamine (AMPH), and diazepam (DZP). To this aim, the effects of NPS (0.01, 0.1 and 1 nmol, ICV), AMPH (2 mg/kg, IP) and DZP (1 mg/kg, IP) on locomotion and oxidative stress parameters were assessed in mouse brain structures. The administration of NPS and AMPH, but not DZP, increased locomotion compared to control. Biochemical analyses revealed that AMPH increased carbonylated proteins in striatum, but did not alter lipid peroxidation. DZP increased lipid peroxidation in the cortex and cerebellum, and increased protein carbonyl formation in the striatum. In contrast, NPS reduced carbonylated protein in the cerebellum and striatum, and also lipid peroxidation in the cortex. Additionally, the treatment with AMPH increased superoxide dismutase (SOD) activity in the striatum, while it did not affect catalase (CAT) activity. DZP did not alter SOD and CAT activity. NPS inhibited the increase of SOD activity in the cortex and cerebellum, but little influenced CAT activity. Altogether, this is the first evidence of a putative role of NPS in oxidative stress and brain injury.

Effects of long-term ovariectomy on anxiety and behavioral despair in rats.

Clinical and pre-clinical findings point to the critical role of ovarian hormones in modulating anxiety and depressive symptoms in female. However, few studies investigated the effects of long-term ovarian hormones withdrawal on animal behavior. The current study evaluated the behavioral effects of long-term ovariectomy (performed at 3 months of life) in adult (6 months old) and aged (18 months old) rats subjected to the elevated plus-maze and forced swimming tests. A substantial reduction in the time spent in open arms in adult and aged ovariectomized rats was observed compared to intact animal from the same age. A significant increase in the immobility time was observed in aged rats, ovariectomized or not, compared to adult rats. It should be noted that no alterations in the spontaneous locomotion were detected among groups. In addition, a reduction in serum concentrations of 17beta-estradiol was observed in adult ovariectomized and aged sham and ovariectomized rats compared to adult intact animals. Taken together, these findings suggest that anxiety-related behaviors were affected by ovariectomy, but not aging. However, the depressive-like behavior observed in aged rats seems to be much more influenced by senescence than ovarian hormones withdrawal. The presented results are discussed considering the effects of gradual and abrupt reduction of ovarian steroids concentrations, and the influence of aging on behavior of female rats.

Behavioral and neurochemical effects of sodium butyrate in an animal model of mania.

The present study investigated the effect of the histone deacetylase inhibitor, sodium butyrate (SB), on locomotor behavior and on mitochondrial respiratory-chain complexes activity in the brain of rats subjected to an animal model of mania induced by d-amphetamine (d-AMPH). In the reversal treatment, Wistar rats were first treated with d-AMPH or saline (Sal) for 14 days. Thereafter, between days 8 and 14, rats were administered SB or Sal. In the prevention treatment, rats were treated with SB or Sal for 14 days and received d-AMPH or Sal between days 8 and 14. The d-AMPH treatment increased locomotor behavior in Sal-treated rats under reversion and prevention treatment, and SB reversed and prevented d-AMPH-related hyperactivity. Moreover, d-AMPH decreased the activity of mitochondrial respiratory-chain complexes in Sal-treated rats in the prefrontal cortex, hippocampus, striatum, and amygdala in both experiments, and SB was able to reverse and prevent this impairment. The present study suggests that the mechanism of action of SB involves induction of mitochondrial function in parallel with behavioral changes, reinforcing the need for more studies on histone deacetylase inhibitors as a possible target for new medications for bipolar disorder treatment.

Anti-HIV drugs nevirapine and efavirenz affect anxiety-related behavior and cognitive performance in mice.

Nevirapine (NVP) and efavirenz (EFV) belong to the class of anti-HIV drugs called non-nucleoside reverse transcriptase inhibitors (NNRTIs), commonly used as part of highly active antiretroviral therapy (HAART). Although the HAART is able to bring down viral load to undetectable levels and restore immune function, their prolonged use causes several adverse effects. It has been demonstrated that both NVP and EFV are able to cross the blood–brain barrier, causing important central nervous system-related side effects. Thus, this study investigated the effects of chronic administration of EFV (10xa0mg/kg) and NVP (3.3xa0mg/kg) in mice submitted to two distinct series of experiments, which aimed to evaluate: (1) the emotional behavior (elevated plus-maze, forced swimming, and open-field test) and (2) the cognitive performance (object recognition and inhibitory avoidance test) of mice. Our results demonstrated that EFV, but not NVP, reduced the exploration to open arms in the elevated plus-maze test. Neither NVP nor EFV altered mouse behavior in the forced swimming and open-field tests. Both drugs reduced the recognition index in the object recognition test, but only EFV significantly impaired the aversive memory assessed in the inhibitory avoidance test 24xa0h after training. In conclusion, our findings point to a genuine anxiogenic-like effect to EFV, since it reduced exploration to open arms of elevated plus-maze test without affecting spontaneous locomotion. Additionally, both drugs impaired recognition memory, while only the treatment with EFV impaired significantly aversive memory.

Emotional behavior in middle-aged rats: Implications for geriatric psychopathologies

Clinical findings reveal that middle-aged patients are more susceptible to suffer from psychiatric disorders than older ones. However, little is known about the emotional behavior of aging rodents. This study aimed to investigate behavioral alterations in male middle-aged Wistar rats in the open-field (OF) test (at illuminated and dimly light conditions), elevated plus maze (EPM), forced swimming (FST) and inhibitory avoidance task (IA). In the EPM, middle-aged rats displayed reduced percentages of the time spent in and entries into open arms. The ambulatory activity measured in the OF under dimly light conditions was identical among groups. However, under illuminated conditions, a reduction in the number of crossings was detected in older rats, reinforcing that aged animals display a genuine anxiogenic-like phenotype. Additionally, aged rats showed an increase in the immobility time in the FST, and a reduction in the latency to step down the platform in the IA. A negative correlation was found between the immobility time and latency to step down the platform, suggesting a relationship between depressive-behavior and cognitive impairment in old rats. Altogether, male middle-aged rats are more anxious, depressed, and display aversive memory impairments. These observations contribute to investigate biological mechanisms and therapeutic interventions for geriatric anxiety and depression.

Intracerebroventricular ouabain administration induces oxidative stress in the rat brain.

Intracerebroventricular (ICV) injection of ouabain (a potent Na+/K+‐ATPase inhibitor) in rats resulted in manic‐like effects. There is an emerging body of data indicating that major neuropsychiatric disorders, such as bipolar disorder and schizophrenia, are associated with increased oxidative stress. In this study, we investigated the effects of ICV ouabain injection on oxidative stress parameters in total tissue of rat brain. Our findings demonstrated that ICV injection increased thiobarbituric acid reactive species levels and protein carbonyl generation in the prefrontal cortex and hippocampus of rats. Moreover, the activity of the antioxidants enzymes catalase and superoxide dismutase was altered in several areas of the rat brain and cerebrospinal fluid of ICV ouabain‐subjected rats. These results showed that Na+/K+‐ATPase inhibition can lead to oxidative stress in the brain of rats.