Vanessa C. Abílio

Role of hippocampal oxidative stress in memory deficits induced by sleep deprivation in mice.

Numerous animal and clinical studies have described memory deficits following sleep deprivation. There is also evidence that the absence of sleep increases brain oxidative stress. The present study investigates the role of hippocampal oxidative stress in memory deficits induced by sleep deprivation in mice. Mice were sleep deprived for 72 h by the multiple platform method-groups of 4-6 animals were placed in water tanks, containing 12 platforms (3 cm in diameter) surrounded by water up to 1 cm beneath the surface. Mice kept in their home cage or placed onto larger platforms were used as control groups. The results showed that hippocampal oxidized/reduced glutathione ratio as well as lipid peroxidation of sleep-deprived mice was significantly increased compared to control groups. The same procedure of sleep deprivation led to a passive avoidance retention deficit. Both passive avoidance retention deficit and increased hippocampal lipid peroxidation were prevented by repeated treatment (15 consecutive days, i.p.) with the antioxidant agents melatonin (5 mg/kg), N-tert-butyl-alpha-phenylnitrone (200 mg/kg) or vitamin E (40 mg/kg). The results indicate an important role of hippocampal oxidative stress in passive avoidance memory deficits induced by sleep deprivation in mice.

Effects of pre- or post-training paradoxical sleep deprivation on two animal models of learning and memory in mice

The aim of the present study was to verify the effects of pre- or post-training paradoxical sleep (PS) deprivation in mice tested in the passive and the plus-maze discriminative avoidance tasks. Three-month-old Swiss male mice were placed in narrow platforms in a water tank for 72 h to prevent the occurrence of PS. Control animals were kept in the same room, but in their home cages. Before or after this period, the animals were submitted to the training session of one of the behavioral tasks. The test sessions were performed 3 and 10 days after the training. The animals that were PS-deprived before the training session showed retention deficits in the test sessions performed 3 days later in both tasks (decreased latency to enter the dark chamber of the passive avoidance apparatus or increased percent time spent in the aversive arm of the plus-maze discriminative avoidance apparatus). Animals that were PS deprived after the training session showed no differences from control animals in the test sessions performed 3 days after the training in any of the tasks, but showed passive and discriminative avoidance retention deficits in the test performed 10 days after the training. The results suggest that both pre- and post-training paradoxical sleep deprivation produce memory deficits in mice. However, these effects have different temporal characteristics.

Vitamin E attenuates reserpine-induced oral dyskinesia and striatal oxidized glutathione/reduced glutathione ratio (GSSG/GSH) enhancement in rats

The effects of a previous and concomitant treatment with vitamin E (VE) were studied on an animal model of tardive dyskinesia, i.e., the frequency of spontaneous tongue protrusions in rats treated with reserpine (RE). VE (5, 10, 20 or 40 mg/kg administered intraperitoneally, daily, for 19 days) attenuated the increase in tongue protrusion frequency induced by RE (1 mg/kg administered subcutaneously, on Days 16 and 18, 1 h after VE), which was quantified on Day 19. In a second experiment, a similar treatment with 20 mg/kg VE attenuated RE-induced increase in the striatal ratio of oxidized/reduced glutathione (GSSG/GSH), an index of the oxidative stress process. These results support the free radical hypothesis of tardive dyskinesia.

Important role of striatal catalase in aging- and reserpine-induced oral dyskinesia.

Tardive dyskinesia, the most serious iatrogenic movement disorder, has been tentatively associated with nigrostriatal dopaminergic supersensitivity and with oxidative stress. It is also suggested that long-term neuroleptic treatment does not cause oral dyskinesia (OD), but interacts with some substrate of brain aging, resulting in the premature emergence of OD, that can occur spontaneously with aging. In order to investigate a possible role of nigrostriatal dopaminergic supersensitivity and of oxidative stress in aging- and reserpine-induced OD, the stereotyped behavior induced by dopaminergic agonists, a functional index of dopaminergic striatal activity, as well as the striatal antioxidant enzymes glutathione peroxidase and catalase were assessed. We demonstrate that, opposite to normotensive Wistar rats (NWR), spontaneously hypertensive rats (SHR) do not develop aging- or reserpine-OD. There were no differences between NWR and SHR in stereotyped behavior or in striatal glutathione peroxidase activity. Adult and old SHR presented higher striatal catalase activity relative to NWR, and aging increased it only in SHR. The catalase inhibitor aminotriazole reverted the absence of aging- and reserpine-induced OD in SHR. Our results suggest an important role of striatal catalase in the development of reserpine- and aging-induced OD.

Behavioral characterization of morphine effects on motor activity in mice

A biphasic effect of morphine on locomotion has been extensively described. Nevertheless, the effects of this opioid on other behavioral parameters have been overlooked. The aim of the present study was to verify the effects of different doses of morphine on motor behaviors observed in an open-field. Adult female mice were injected with saline or morphine (10, 15 and 20 mg/kg, i.p.) and observed in an open-field for quantification of locomotor and rearing frequencies as well as duration of immobility and grooming. The lowest dose of morphine decreased locomotion (and increased immobility duration) while the highest dose increased it. All doses tested decreased rearing and grooming. Thus, the effects of morphine on locomotion do not parallel to its effects on rearing and grooming. Our results indicate that locomotion not always reflects the effect of drugs on motor activity, which can be better investigated when other behavioral parameters are concomitantly taken into account.

Beneficial effects of vitamin C and vitamin E on reserpine-induced oral dyskinesia in rats: critical role of striatal catalase activity.

Oral dyskinesias are implicated in a series of neuropathologies and have been associated to an increase in oxidative stress. Several antioxidants, including vitamin E, decrease reserpine-induced oral dyskinesia (OD) in rodents and we have described a protective role of striatal catalase against the development of OD. The aim of this study was to verify the effects of vitamin C alone or in combination with vitamin E on reserpine-induced OD as well as to determine a possible role of catalase in the antidyskinetic property of these vitamins. Different doses of vitamin C attenuated reserpine-induced increase in OD. A similar treatment with an effective dose of vitamin C concomitant to an effective dose of vitamin E potentiated the antidyskinetic effect of both vitamins when administered alone. The administration of these vitamins alone produced an increase in striatal catalase activity that likewise was potentiated by their combined administration. In addition, the antidyskinetic property of vitamin E and vitamin C was abolished by a concomitant treatment with the catalase inhibitor aminotriazole. These results indicate a beneficial effect of these vitamins and reinforce the critical role of striatal catalase against the development of oral dyskinesias.

Concomitant development of oral dyskinesia and memory deficits in reserpine-treated male and female mice

It has been suggested that reserpine-induced oral dyskinesia in rats may provide a new animal model of tardive dyskinesia. Both cognitive deficits and gender have been associated with the development of tardive dyskinesia. The aim of the present study was to investigate the effects of reserpine administration on the development of orofacial dyskinesia and on plus-maze discriminative avoidance task (DAT-an animal model of associative learning) in male and female mice. Male and female mice received 1.0 mg/kg reserpine or saline subcutaneously on day 1. On days 3, 6 and 8, the frequency of vacuous chewing movements (VCM) was quantified. On day 6, the DAT conditioning was performed, in a modified elevated plus-maze. In one of the enclosed arms, the animals received aversive stimulation (light and noise). On day 8, a test session was performed and the time spent by the animals in each of the enclosed arms was recorded. Our results showed that reserpine-treated male and female mice presented significantly higher VCM when compared with respective control groups in all observation days. On day 6, reserpine-treated female mice presented significantly higher VCM when compared with male mice injected with this drug. The DAT test performed on day 8 showed that the time spent in the aversive arm by saline-treated mice was significantly lower than the time spent in the non-aversive arm. This difference was not observed for reserpine-treated mice. Our results demonstrate the development of reserpine-induced oral dyskinesia in both male and female mice. While this oral dyskinesia is accompanied by a cognitive deficit in both genders, female mice tended to have more severe oral dyskinesia. It is suggested that reserpine-induced oral dyskinesia may provide a quick, simple and efficient mouse model of tardive dyskinesia.

Neuroleptic drugs revert the contextual fear conditioning deficit presented by spontaneously hypertensive rats: a potential animal model of emotional context processing in schizophrenia?

Schizophrenia, bipolar disorder, and attention deficit/hyperactivity disorder (ADHD) present abnormalities in emotion processing. A previous study showed that the spontaneously hypertensive rats (SHR), a putative animal model of ADHD, present reduced contextual fear conditioning (CFC). The aim of the present study was to characterize the deficit in CFC presented by SHR. Adult male normotensive Wistar rats and SHR were submitted to the CFC task. Sensitivity of the animals to the shock and the CFC performance after repeated exposure to the task were investigated. Pharmacological characterization consisted in the evaluation of the effects of the following drugs administered previously to the acquisition of the CFC: pentylenetetrazole (anxiogenic) and chlordiazepoxide (anxiolytic); methylphenidate and amphetamine (used for ADHD); lamotrigine, carbamazepine, and valproic acid (mood stabilizers); haloperidol, ziprasidone, risperidone, amisulpride, and clozapine (neuroleptic drugs); metoclopramide and SCH 23390 (dopamine antagonists without antipsychotic properties); and ketamine (a psychotomimmetic). The effects of paradoxical sleep deprivation (that worsens psychotic symptoms) and the performance in a latent inhibition protocol (an animal model of schizophrenia) were also verified. No differences in the sensitivity to the shock were observed. The repeated exposure to the CFC task did not modify the deficit in CFC presented by SHR. Considering pharmacological treatments, only the neuroleptic drugs reversed this deficit. This deficit was potentiated by proschizophrenia manipulations. Finally, a deficit in latent inhibition was also presented by SHR. These findings suggest that the deficit in CFC presented by SHR could be a useful animal model to study abnormalities in emotional context processing related to schizophrenia.

The importance of housing conditions on behavioral sensitization and tolerance to ethanol

The differential outcomes of social isolation and crowding environment on the effects of single or repeated administration of ethanol on open-field behavior were examined in female mice. Whereas housing conditions did not alter the increase in locomotor activity induced by ethanol single administration, behavioral sensitization (a progressive increase of a drug effect following repeated drug administration) to the locomotor activating effect of ethanol was significantly greater in crowded mice as compared to isolated and control groups. Single administration of ethanol significantly decreased rearing frequency and increased immobility duration, there being tolerance to these ethanol behavior effects after repeated treatment. Social isolation attenuated the increase in immobility behavior induced by single administration of ethanol and potentiated the tolerance of ethanol-induced rearing decrease, verified after repeated treatment. These results point out that both sensitization and tolerance to the behavioral effects of ethanol can be critically influenced by housing conditions.

Effects of cannabinoid drugs on the deficit of prepulse inhibition of startle in an animal model of schizophrenia: the SHR strain.

Clinical and neurobiological findings suggest that the cannabinoids and the endocannabinoid system may be implicated in the pathophysiology and treatment of schizophrenia. We described that the spontaneously hypertensive rats (SHR) strain presents a schizophrenia behavioral phenotype that is specifically attenuated by antipsychotic drugs, and potentiated by proschizophrenia manipulations. Based on these findings, we have suggested this strain as an animal model of schizophrenia. The aim of this study was to evaluate the effects of cannabinoid drugs on the deficit of prepulse inhibition (PPI) of startle, the main paradigm used to study sensorimotor gating impairment related to schizophrenia, presented by the SHR strain. The following drugs were used: (1) WIN55212,2 (cannabinoid agonist), (2) rimonabant (CB1 antagonist), (3) AM404 (anandamide uptake inhibitor), and (4) cannabidiol (CBD; indirect CB1/CB2 receptor antagonist, among other effects). Wistar rats (WRs) and SHRs were treated with vehicle (VEH) or different doses of WIN55212 (0.3, 1, or 3 mg/kg), rimonabant (0.75, 1.5, or 3 mg/kg), AM404 (1, 5, or 10 mg/kg), or CBD (15, 30, or 60 mg/kg). VEH-treated SHRs showed a decreased PPI when compared to WRs. This PPI deficit was reversed by 1 mg/kg WIN and 30 mg/kg CBD. Conversely, 0.75 mg/kg rimonabant decreased PPI in SHR strain, whereas AM404 did not modify it. Our results reinforce the role of the endocannabinoid system in the sensorimotor gating impairment related to schizophrenia, and point to cannabinoid drugs as potential therapeutic strategies.