Nadja Schröder

Cannabidiol Reduces the Anxiety Induced by Simulated Public Speaking in Treatment-Naïve Social Phobia Patients

Generalized Social Anxiety Disorder (SAD) is one of the most common anxiety conditions with impairment in social life. Cannabidiol (CBD), one major non-psychotomimetic compound of the cannabis sativa plant, has shown anxiolytic effects both in humans and in animals. This preliminary study aimed to compare the effects of a simulation public speaking test (SPST) on healthy control (HC) patients and treatment-naïve SAD patients who received a single dose of CBD or placebo. A total of 24 never-treated patients with SAD were allocated to receive either CBD (600u2009mg; n=12) or placebo (placebo; n=12) in a double-blind randomized design 1u2009h and a half before the test. The same number of HC (n=12) performed the SPST without receiving any medication. Each volunteer participated in only one experimental session in a double-blind procedure. Subjective ratings on the Visual Analogue Mood Scale (VAMS) and Negative Self-Statement scale (SSPS-N) and physiological measures (blood pressure, heart rate, and skin conductance) were measured at six different time points during the SPST. The results were submitted to a repeated-measures analysis of variance. Pretreatment with CBD significantly reduced anxiety, cognitive impairment and discomfort in their speech performance, and significantly decreased alert in their anticipatory speech. The placebo group presented higher anxiety, cognitive impairment, discomfort, and alert levels when compared with the control group as assessed with the VAMS. The SSPS-N scores evidenced significant increases during the testing of placebo group that was almost abolished in the CBD group. No significant differences were observed between CBD and HC in SSPS-N scores or in the cognitive impairment, discomfort, and alert factors of VAMS. The increase in anxiety induced by the SPST on subjects with SAD was reduced with the use of CBD, resulting in a similar response as the HC.

Haloperidol- and clozapine-induced oxidative stress in the rat brain.

Haloperidol (HAL) is a typical neuroleptic that acts primarily as a D2 dopamine receptor antagonist. It has been proposed that reactive oxygen species play a causative role in neurotoxic effects induced by HAL. Adult male Wistar rats received daily injections of HAL (1.5 mg/kg) or clozapine (CLO, 25 mg/kg), an atypical neuroleptic, for 28 days. Control animals were given saline (SAL; NaCl 0.9%). Oxidative parameters in the brain were measured in the striatum (ST), hippocampus (HP) and cortex (CX). Thiobarbituric acid (TBA) reactive substances (TBAR) levels were increased by HAL treatment in the ST and decreased in CX of both of the HAL- and CLO-treated rats. Protein carbonyls were significantly increased by both HAL and CLO in the HP. The nonenzymatic antioxidant potential was decreased in the HP, and superoxide production was significantly increased in the ST following treatment with HAL. CLO induced an increase in superoxide production in the HP. Neither HAL nor CLO affected catalase (CAT) and superoxide dismutase (SOD) activities. The findings suggest that HAL and CLO can induce oxidative damage to the ST and HP in rats.

Differential involvement of hippocampal and amygdalar NMDA receptors in contextual and aversive aspects of inhibitory avoidance memory in rats

Adult male rats bilaterally implanted with guide canullae aimed either at the dorsal hippocampus (dHIP) or the basolateral nucleus of the amygdala (BLA) were trained in a step-down inhibitory avoidance task (IA) and tested for retention 24 h after training. Immediately after training, animals were given a bilateral infusion of the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist D,L-2-amino-5-phosphonopentanoic acid (AP5) (5.0 microg) into the dHIP or the BLA. Both intrahippocampal and intraamygdala infusions of AP5 blocked IA retention. Preexposure to the training box, but not to a different environment 24 h prior to training prevented the impairing effect of intrahippocampal infusion of AP5 on retention. Preexposure did not affect the retention impairment induced by intraamygdala infusion of AP5. These data suggest that hippocampal NMDA receptors might be involved in the contextual and spatial aspects, while amygdalar NMDA receptors might be involved in the aversive aspects of memory for IA.

Recognition memory impairment and brain oxidative stress induced by postnatal iron administration.

Iron accumulation in the brain has been implicated in the pathogenesis of neurodegenerative disorders. It is known that iron catalyses the formation of highly reactive hydroxyl radicals. Recent studies have implicated oxidative damage in memory deficits in rats and humans. The purpose of the present study was to investigate the long‐term effects of iron treatment in four different phases of the neonatal period on recognition memory in rats. Additionally, parameters of oxidative stress in cerebral regions related to memory formation were evaluated. Male Wistar rats received vehicle or 10.0u2003mg/kg of Fe2+ orally at postnatal days 5–7, 12–14, 19–21 or 30–32. Animals given iron at any phase of the neonatal period showed impairments in long‐term retention of object recognition memory, although only the group given iron from postnatal days 12–14 showed a complete memory blockade. Iron treatment induced oxidative damage in the brain as assessed by the thiobarbituric acid reactive species assay. Moreover, iron administration increased superoxide production in submitochondrial particles, suggesting impaired mitochondrial function; and there was an increase in superoxide dismutase activity in brain regions susceptible to iron administration. The results show that iron load in the early stages of life induces cognitive impairment possibly by inducing oxidative damage in the brain. These findings are consistent with the view that oxidative stress may be related to the cognitive decline observed in normal ageing.

Selegiline protects against recognition memory impairment induced by neonatal iron treatment.

Excess of iron in the brain has been implicated in the pathogenesis of several human neurodegenerative diseases, for example Alzheimers disease and Parkinsons disease. It has been shown that the neonatal period is critical for the establishment of normal iron content in the adult brain. Moreover, it is known that aging alters the cerebral distribution of this metal. We have recently described that neonatal administration of iron severely impaired novel object recognition memory in rats. The aim of the present study was to determine whether selegiline, a monoamine oxidase (MAO) inhibitor known for its neuroprotective properties, could protect rats against cognitive impairment induced by neonatal administration of iron. In the first experiment, male Wistar rats received vehicle (5% sorbitol in water) or iron (10.0 mg/kg) orally from postnatal days 12 to 14 and saline (0.9% NaCl) or selegiline (1.0 or 10.0 mg/kg) intraperitoneally for 21 days, starting 24 h before the first iron dosing. In the second experiment, rats were given either vehicle or iron (10.0 mg/kg) orally from postnatal days 12 to 14 followed by saline or selegiline (1.0 or 10.0 mg/kg) intraperitoneally for 21 days, starting when rats reached adulthood (50th day after birth). Iron-treated rats given selegiline in both doses showed no deficits in recognition memory. Rats receiving iron but no selegiline presented memory deficits. This is the first study reporting the reversion of iron-induced memory impairment, supporting the view that our model can be considered as a useful tool in the search for new drugs with neuroprotective and/or memory enhancing properties.

Differential neurobehavioral deficits induced by apomorphine and its oxidation product, 8-oxo-apomorphine-semiquinone, in rats.

Apomorphine is a potent dopamine receptor agonist, which has been used in the therapy of Parkinsons disease. It has been proposed that apomorphine and other dopamine receptor agonists might induce neurotoxicity mediated by their quinone and semiquinone oxidation derivatives. The aim of the present study was to evaluate the possible neurobehavioral effects of apomorphine and its oxidation derivative, 8-oxo-apomorphine-semiquinone (8-OASQ). Adult female Wistar rats were treated with a systemic injection of apomorphine (0.05 or 0.5 mg/kg) or 8-OASQ (0.05 or 0.5 mg/kg) 20 min before behavioral testing. Apomorphine and 8-OASQ induced differential impairing effects on short- and long-term retention of an inhibitory avoidance task. Apomorphine, but not 8-OASQ, dose-dependently impaired habituation to a novel environment. The memory-impairing effects could not be attributed to reduced nociception or other nonspecific behavioral alterations, since neither apomorphine nor 8-OASQ affected footshock reactivity or behavior during exploration of an open field. The results suggest that oxidation products of dopamine or dopamine receptor agonists might induce cognitive deficits.

National Science and Technology Institute for Translational Medicine (INCT-TM): advancing the field of translational medicine and mental health

OBJECTIVEnTranslational medicine has been described as the integrated application of innovative pharmacology tools, biomarkers, clinical methods, clinical technologies and study designs to improve the understanding of medical disorders. In medicine, translational research offers an opportunity for applying the findings obtained from basic research to every-day clinical applications. The National Science and Technology Institute for Translational Medicine is comprised of six member institutions (Universidade Federal do Rio Grande do Sul, Universidade de São Paulo-Ribeirão Preto, Universidade Federal do Rio de Janeiro, Pontifícia Universidade Católica do Rio Grande do Sul, Universidade Estadual de Santa Catarina and a core facility that serves all centers). The objectives of the project are divided into four areas: Institutional, Research, Human Resources and Technology for the Community and Productive Sector.nnnMETHODnIn this manuscript, we describe some of the approaches used to attain the main objectives of the National Science and Technology Institute for Translational Medicine, which include the development of 1) animal models for bipolar disorder; 2) strategies to investigate neurobehavioral function and cognitive dysfunction associated with brain disorders; 3) experimental models of brain function and behavior, neuropsychiatric disorders, cell proliferation, and cancer; 4) Simulated Public Speaking and 5) Virtual reality simulation for inducing panic disorder and agoraphobia.nnnCONCLUSIONnThe main focus of the National Science and Technology Institute for Translational Medicine is the development of more useful methods that allow for a better application of basic research-based knowledge to the medical field.

Antioxidant Effects of SelegilIne in Oxidative Stress Induced by Iron Neonatal Treatment in Rats

Increased levels of iron in specific brain regions have been reported in neurodegenerative disorders. It has been postulated that iron exerts its deleterious effects on the nervous system by inducing oxidative damage. In a previous study, we have shown that iron administered during a particular period of the neonatal life induces oxidative damage in brain regions in adult rats. The aim of the present study was to evaluate the possible protective effect of selegiline, a monoamino-oxidase B (MAO-B) inhibitor used in pharmacotherapy of Parkinson’s disease, against iron-induced oxidative stress in the brain. Results have shown that selegiline (1.0 and 10.0xa0mg/kg), when administered early in life was able to protect the substantia nigra as well as the hippocampus against iron-induced oxidative stress, without affecting striatum. When selegiline (10.0xa0mg/kg) was administered in the adult life to iron-treated rats, oxidative stress was reduced only in the substantia nigra.

Iron exposure modifies acetylcholinesterase activity in zebrafish (Danio rerio) tissues: distinct susceptibility of tissues to iron overload.

Iron is one the most abundant metals on the earth being essential for living organisms even though its free form can be toxic. The overload of this metal may be related with some disorders, like Alzheimer and Parkinson diseases, and hemochromatosis in the liver. The aim of the present study was to evaluate the effects of iron on acetylcholinesterase (AChE) activity in brain and liver of zebrafish and to investigate the possible correlation with the iron content in these tissues. Different corresponding concentrations of iron were tested using in vitro (0.018, 0.268, and 2.6xa0mM) and in vivo (1, 15, and 150xa0mg/l) assays. The in vitro studies showed that iron promoted a significant increase in AChE activity in brain (52%) and liver (53%) at the higher concentration (2.6xa0mM). In the in vivo assays, a significant increase in this enzyme activity was observed in the presence of 15xa0mg/l in both, brain (62%) and liver tissue (70%). Semiquantitative RT-PCR did not reveal significant changes in acetylthiocholinesterase mRNA levels. Moreover, we observed that iron content was significantly increased in liver tissue when exposed to 15 (226%) and 150xa0mg/l (200%). These results indicate that iron can promote significant alterations in AChE activity which probably is not directly related to the iron content in zebrafish tissues.

Maternal separation induces hippocampal changes in cadherin-1 (CDH-1) mRNA and recognition memory impairment in adolescent mice

HIGHLIGHTSMS early in life was able to produce a marked deficit in recognition memory in late adolescent BALB/c mice.Female mice submitted to MS had lower CDH‐1 mRNA levels in the hippocampus.CDH‐1 mRNA levels of the hippocampal female mice were correlated with recognition memory.MS induced higher hippocampal CDH‐2 mRNA levels in the hippocampus.MS produced sex‐dependent type II CDH and &bgr;‐Cat mRNA changes in both MS male and female offspring. ABSTRACT In rodents, disruption of mother‐infant attachment induced by maternal separation (MS) is associated with recognition memory impairment and long‐term neurobiological consequences. Particularly stress‐induced modifications have been associated to disruption of cadherin (CDH) adhesion function, which plays an important role in remodeling of neuronal connection and synaptic plasticity. This study investigated the sex‐dependent effect of MS on recognition memory and mRNA levels of classical type I and type II CDH and the related &bgr; ‐catenin (&bgr; ‐Cat) in the hippocampus and prefrontal cortex of late adolescent mice. We provided evidence that the BALB/c mice exposed to MS present deficit in recognition memory, especially females. Postnatal MS induced higher hippocampal CDH‐2 and CDH‐8 mRNA levels, as well as an upregulation of CDH‐1 in the prefrontal cortex in both males and females. MS‐reared female mice presented lower CDH‐1 mRNA levels in the hippocampus. In addition, hippocampal CDH‐1 mRNA levels were positively correlated with recognition memory performance in females. MS‐reared male mice exhibited higher &bgr; ‐Cat mRNA levels in the hippocampus. Considering sex‐specific effects on CDH mRNA levels, it has been demonstrated mRNA changes in CDH‐1, &bgr; ‐Cat, and CDH‐6 in the hippocampus, as well as CDH‐1, CDH‐8 and CDH‐11 in the prefrontal cortex. Overall, these findings suggest a complex interplay among MS, CDH mRNA expression, and sex differences in the PFC and hippocampus of adolescent mice.