Mariana Bendlin Calzavara

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.

Paradoxical sleep deprivation impairs acquisition, consolidation, and retrieval of a discriminative avoidance task in rats

The aim of the present study was to investigate the effects of paradoxical sleep deprivation (PSD) for 96 h on the learning/memory processes in rats submitted to the plus-maze discriminative avoidance task (PM-DAT), which simultaneously evaluates learning, memory, anxiety and motor function. Four experiments were performed in which rats were submitted to: (1) post-training and pre-test PSD; (2) post-training or pre-test PSD; (3) pre-training PSD or pre-training paradoxical sleep (PS) rebound (24 h) and (4) pre-test PSD rebound. Concerning Experiment I, post-training and pre-test PSD induced memory deficits, an anxiolytic-like behavior and an increase in locomotor activity. In Experiment II, both post-training PS-deprived and pre-test PS-deprived groups showed memory deficits per se. However, only the pre-test PS-deprived animals presented anxiolytic-like behavior and increased locomotor activity. In Experiment III, pre-training PS-deprived rats showed learning and memory deficits, anxiolytic-like behavior and increased locomotor activity. A 24h-sleep recovery period after the PSD abolished the learning and memory deficits but not anxiety and locomotor alterations. Finally, sleep rebound did not modify acquisition (Experiment III) and retrieval (Experiment IV). This study strengthened the critical role of paradoxical sleep (but not sleep rebound) in all the phases of learning and memory formation. In addition, it suggests that PSD effects on acquisition and consolidation do not seem to be related to other behavioral alterations induced by this procedure.

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.

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.

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.

Spontaneously Hypertensive Rats (SHR) present deficits in prepulse inhibition of startle specifically reverted by clozapine.

Deficits in an operational measure of sensorimotor gating - the prepulse inhibition of startle (PPI) - are presented in psychiatric disorders such as schizophrenia, bipolar disorder, and attention deficit/hyperactivity disorder (ADHD). Some previous studies showed that the spontaneously hypertensive rats (SHR) present PPI deficit. Although SHR is suggested as an animal model to study ADHD, we have suggested that the behavioral phenotype of this strain mimics some aspects of schizophrenia. The aim of this study was to characterize the PPI response in SHR. Pharmacological characterization consisted in the evaluation of the effects of the following drugs administered to adult Wistar rats (WR) and SHR previously to the PPI test: amphetamine (used for ADHD and also a psychotomimetic drug), haloperidol and clozapine (antipsychotic drugs), metoclopramide (dopamine antagonist without antipsychotic properties) and carbamazepine (mood stabilizer). Our results showed that SHR presented reduced PPI. This deficit was similar to that induced by amphetamine in WR. Only the atypical antipsychotic clozapine improved the PPI deficit observed in SHR. These findings reinforce the SHR strain as an animal model to study several aspects of schizophrenia, including the abnormalities in sensorimotor gating associated with this disease.

Cannabidiol exhibits anxiolytic but not antipsychotic property evaluated in the social interaction test.

Cannabidiol (CBD), a non-psychotomimetic compound of the Cannabis sativa, has been reported to have central therapeutic actions, such as antipsychotic and anxiolytic effects. We have recently reported that Spontaneously Hypertensive Rats (SHRs) present a deficit in social interaction that is ameliorated by atypical antipsychotics. In addition, SHRs present a hyperlocomotion that is reverted by typical and atypical antipsychotics, suggesting that this strain could be useful to study negative symptoms (modeled by a decrease in social interaction) and positive symptoms (modeled by hyperlocomotion) of schizophrenia as well as the effects of potential antipsychotics drugs. At the same time, an increase in social interaction in control animals similar to that induced by benzodiazepines is used to screen potential anxiolytic drugs. The aim of this study was to investigate the effects of CBD on social interaction presented by control animals (Wistar) and SHRs. The lowest dose of CBD (1mg/kg) increased passive and total social interaction of Wistar rats. However, the hyperlocomotion and the deficit in social interaction displayed by SHRs were not altered by any dose of CBD. Our results do not support an antipsychotic property of cannabidiol on symptoms-like behaviors in SHRs but reinforce the anxiolytic profile of this compound in control rats.

Effects of antipsychotics and amphetamine on social behaviors in spontaneously hypertensive rats.

We have recently reported that spontaneously hypertensive rats (SHRs) exhibit a deficit in contextual fear conditioning that is specifically reversed by antipsychotic and potentiated by psychostimulants and other manipulations thought to produce schizophrenia-like states in rodents. Based on these findings, we suggested that this deficit in fear conditioning could be used as an experimental model of emotional processing impairments observed in schizophrenia. This strain has also been suggested as a model by which to study attention deficit/hyperactivity disorder (ADHD). Considering that schizophrenia and ADHD are both characterized by poor social function, this study aimed to investigate possible behavioral deficits of SHRs in a social context. Furthermore, we sought to examine the effects of typical and atypical antipsychotics (used for the treatment of schizophrenia) and a psychostimulant (used to treat ADHD) on these behaviors. Pairs of unfamiliar rats of the same or different (i.e., Wistar) strains were treated with one of the aforementioned drugs and placed in an open-field for 10min. During this time, social behaviors, locomotion and rearing frequencies were scored. Atypical antipsychotics increased social interaction in Wistar rats (WRs) and improved the deficit in social interaction exhibited by SHRs. In addition, the SHR group displayed hyperlocomotion that was attenuated by all antipsychotics (quetiapine and clozapine also decreased locomotion in WRs) and potentiated by amphetamine (which also increased locomotion in WRs). Our results reveal that the behavioral profile of the SHR group demonstrates that this strain can be a useful animal model to study several aspects of schizophrenia.

Adolescent mice are more vulnerable than adults to single injection-induced behavioral sensitization to amphetamine.

Drug-induced behavioral sensitization in rodents has enhanced our understanding of why drugs acquire increasing motivational and incentive value. Compared to adults, human adolescents have accelerated dependence courses with shorter times from first exposure to dependence. We compared adolescent and adult mice in their ability to develop behavioral sensitization to amphetamine following a single injection. Adult (90-day-old) and adolescent (45-day-old) male Swiss mice received an acute intraperitoneal injection of saline or amphetamine (1.0, 2.0 or 4.0 mg/kg). Seven days later, half of the mice from the saline group received a second injection of saline. The remaining animals were challenged with 2.0 mg/kg amphetamine. Following all of the injections, mice were placed in activity chambers and locomotion was quantified for 45 min. The magnitude of both the acute and sensitized locomotor stimulatory effect of amphetamine was higher in the adolescent mice. Previous experience with the test environment inhibited the acute amphetamine stimulation in both adolescent and adult mice, but facilitated the detection of elevated spontaneous locomotion in adolescent animals. These results support the notion that the adolescent period is associated with an increased risk for development of drug abuse. Additionally, they indicate a complex interaction between the environmental novelty, adolescence and amphetamine.

Higher striatal dopamine transporter density in PTSD: an in vivo SPECT study with [ 99m Tc]TRODAT-1

RationaleSome evidence suggests a hyperdopaminergic state in posttraumatic stress disorder (PTSD). The 9-repetition allele (9R) located in the 3′ untranslated region of the dopamine transporter (DAT) gene (SLC6A3) is more frequent among PTSD patients. In vivo molecular imaging studies have shown that healthy 9R carriers have increased striatal DAT binding. However, no prior study evaluated in vivo striatal DAT density in PTSD.ObjectivesThe objective of this study was to evaluate in vivo striatal DAT density in PTSD.MethodsTwenty-one PTSD subjects and 21 control subjects, who were traumatized but asymptomatic, closely matched comparison subjects evaluated with the Clinician-Administered PTSD Scale underwent a single-photon emission computed tomography scan with [99mTC]-TRODAT-1. DAT binding potential (DAT-BP) was calculated using the striatum as the region of the interest and the occipital cortex as a reference region.ResultsPTSD patients had greater bilateral striatal DAT-BP (mean ± SD; left, 1.80 ± 0.42; right, 1.78 ± 0.40) than traumatized control subjects (left, 1.62 ± 0.32; right, 1.61 ± 0.31; p = 0.039 for the left striatum and p = 0.032 for the right striatum).ConclusionsThese results provide the first in vivo evidence for increased DAT density in PTSD. Increases in DAT density may reflect higher dopamine turnover in PTSD, which could contribute to the perpetuation and potentiation of exaggerated fear responses to a given event associated with the traumatic experience. Situations that resemble the traumatic event turn to be interpreted as highly salient (driving attention, arousal, and motivation) in detriment of other daily situations.