Plus-maze Discriminative Avoidance Task Research Articles

Memory and anxiety-like behavior of rats in the plus-maze discriminative avoidance task: Role of serotonergic transmission in the basolateral amygdala.

Optimal levels of anxiety are critical to memory consolidation, but maladaptive anxiety can disrupt memory acquisition. Serotonergic activity within the amygdala influences both anxiety-like behavior and aversive memory consolidation. To evaluate the effects of serotoninergic manipulations within the basolateral amygdala (BLA) on anxiety-like behavior and aversive memory in rats tested in the plus-maze discriminative avoidance task (PMDAT). The PMDAT investigates aversive memory and anxiety-like behavior simultaneously in rodents. Three-month-old male Wistar rats received bilateral infusions (1 μL per side) of saline, 8-OH-DPAT (5-HT1 agonist; 10 nmol), WAY100135 (5-HT1 antagonist; 0.9 nmol), ketanserine (5-HT 2 antagonist; 10 nmol), or fluoxetine (serotonin reuptake inhibitor; 1.6 nmol) into the BLA and were submitted to PMDAT training session 15 min later. In the test, 24 hr later, animals were re-exposed to the apparatus without the infusion of drugs, and aversive memory was evaluated. (a) 8-OH-DPAT did not affect memory or anxiety, but impaired avoidance behavior toward the aversive arm during training; (b) fluoxetine, WAY100135 and ketanserin impaired memory formation; (c) ketanserin decreased anxiety-like behavior; and (d) none of the treatments induced motor changes. The results showed that an increase in serotonin (5-HT) availability or the blockade of 5HT1A and 5HT2A BLA receptors impaired aversive memory formation. However, only 5HT2A receptor antagonism induced anxiolytic effects. Thus, both memory and anxiety-like behavior can be modified by changes in serotonergic transmission in the basolateral amygdala, but the effects on both phenomena seem to be mediated by different mechanisms related to serotonergic transmission. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Supplemental Material for Memory and Anxiety-Like Behavior of Rats in the Plus-Maze Discriminative Avoidance Task: Role of Serotonergic Transmission in the Basolateral Amygdala

Supplemental Material for Memory and Anxiety-Like Behavior of Rats in the Plus-Maze Discriminative Avoidance Task: Role of Serotonergic Transmission in the Basolateral Amygdala

Prenatal exposure to fluoxetine modulates emotionality and aversive memory in male and female rat offspring.

During pregnancy, women are prone to depression, for which selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, are usually the first-line treatment. However, fluoxetine can cross the placental barrier and affect fetuses, causing changes in serotonin levels early in life. Long-term effects in the brain circuits that control cognitive and emotional behavior are related to early fluoxetine exposure during development. In this study, we aimed to investigate whether fluoxetine exposure (10 mg/kg/day) from the 13th gestational day (GD13) to GD21 may lead to behavioral emotional-cognitive changes in male and female rat offspring approximately 90 days postnatally (~PN90). We have analyzed the performance of individuals in the open field and in the plus-maze discriminative avoidance task, which assesses anxiety and learning/memory processing behaviors. We have found that prenatal (GD13-GD21) exposure to fluoxetine strengthened aversive memory and induced higher anxiety levels in males, and quick extinction of aversive memory in females. Taken together, these results suggest that early exposure to fluoxetine impairs the basal state of anxiety and the cognitive functions of rats during adulthood, which may be in a sex-specific manner because males appear more susceptible than females.

Stress-related impairment of fear memory acquisition and disruption of risk assessment behavior in female but not in male mice

Stress encompasses reactions to stimuli that promote negative and positive effects on cognitive functions, such as learning and memory processes. Herein, we investigate the effect of restraint stress on learning, memory, anxiety levels and locomotor activity of male and female mice. We used the plus-maze discriminative avoidance task (PMDAT), a behavioral task based on the innate exploratory response of rodents to new environments. Moreover, this task is used to simultaneously evaluate learning, memory, anxiety-like behavior and locomotor activity. Male and female mice were tested after repeated daily restraint stress (4 h/day for 3 days). The results showed stress-induced deficits on aversive memory retrieval only in female mice, suggesting a sexual dimorphism on memory acquisition. Furthermore, stressed females exhibited increased anxiety-like behavior and decreased exploratory behavior. Plasma corticosterone levels were similarly increased by restraint stress in both sexes, suggesting that the behavioral outcome was not related to hormonal secretion. Our findings corroborate previous studies, showing a sexually dimorphic effect of restraint stress on cognition. In addition, our study suggests that stress-related acquisition deficit may be the consequence of elevated emotional response in females.

The influence of early exposure to methylphenidate on addiction-related behaviors in mice

Methylphenidate (MET) has a putative cognitive enhancer effect that has led adolescents and young adults to increase and indiscriminate its use aiming to ameliorate their productivity. However, the impacts of MET on addiction-related behaviors, emotional levels, and cognition are still not fully understood. To investigate the influence of chronic treatment with MET during adolescence on addiction-like behaviors, memory, and anxiety in adult mice. Thirty-day-old female mice received i.p. 10 mg/kg MET or Veh injections for 10 consecutive days. Forty days after the treatment (mice were 70-days-old), animals were submitted to the behavioral evaluation under the effects of MET, which included: MET-induced conditioned place preference (CPP), behavioral sensitization, and plus-maze discriminative avoidance task. Pre-exposure to MET during adolescence promoted an early expression of CPP and also facilitated the development of MET-induced behavioral sensitization during adulthood. These addictive-like behaviors were accompanied by anxiogenic effects of MET but not by any memory-enhancing effect. We demonstrated that exposure to MET during adolescence can increase the vulnerability to addiction-like behaviors and anxiety during adulthood. Our results reinforce the necessity of a more efficient system to control MET indiscriminate use, thus avoiding its potential tardive addictive effects.

Impaired discriminative avoidance and increased plasma corticosterone levels induced by vaginal lavage procedure in rats

Historically, females have been neglected in behavioral neuroscience research due to the alleged increased variability caused by hormonal fluctuations. More recently, there has been a tendency to include female subjects in the studies, in a majority of those cases with the condition that the hormonal variation is controlled. In rodent studies, the vaginal lavage procedure is a common method of collecting smears and determining the estrous cycle phase. However, little is known regarding the consequences of the procedure, although stress is often mentioned as a concern. Within the neuroscience field, spatial memory has been a relevant subject in terms of sex differences. The plus-maze discriminative avoidance task (PMDAT) allows for the concomitant evaluation of spatial memory, anxiety-like behavior, and locomotion, as well as possible interactions between these behaviors. The aim of the present study was to investigate the effects of the vaginal lavage procedure (VLP) on the performance of female rats in the PMDAT. We submitted adult female Wistar rats to VLP for 14 straight days and then to training and test sessions in the PMDAT. Additionally, another set of animals was submitted to the VLP procedure for determination of plasma corticosterone levels. Rats submitted to the vaginal lavage procedure did not discriminate the enclosed arms of the PMDAT apparatus, indicating impaired performance, but no anxiety-like alterations were found. VLP also resulted in a higher corticosterone level, suggesting it is a stressful manipulation. As such, the use of this method to control for hormonal variation should be restricted in behavioral studies.

Effects of chronic treatment with new strains ofLactobacillus plantarum on cognitive, anxiety- and depressive-like behaviors in male mice.

Psychobiotics correspond to a class of probiotics, mainly of the genus Lactobacillus and Bifidobacterium, capable of producing neuroactive substances, such as γ-aminobutyric acid (GABA) and serotonin, which exert effects on the brain-gut axis. Evidence suggests that psychobiotics can have a beneficial effect on mood, anxiety and cognition. The present study evaluated the effects of chronic administration of two new strains of Lactobacillus plantarum, L. plantarum 286 (Lp 286) and L. plantarum 81 (Lp 81) isolated from the fermentation of cocoa (Theobroma cacao L.) and cupuaçu (Theobroma grandiflorum), respectively, on cognitive, anxiety- and depressive-like behaviors in male Swiss mice. Different groups of animals were administered (oral gavage) solutions of vehicle (0.85% saline plus 15% skim milk), Lp 286 (109/0.1 ml CFU) or Lp 81 (109/0.1 ml CFU) for 30 days, and animals were tested for general locomotor activity, depressive-like behavior in the forced swim test, and learning/memory and anxiety-like behavior in the plus-maze discriminative avoidance task. Treatment with the strains Lp 286 and Lp 81 did not interfere with locomotor activity or learning and memory. The Lp 286 strain exerted anti-depressant- and anxiolytic-like effects under our experimental conditions. Our findings add to the current body of evidence suggesting that probiotics from the genus Lactobacillus may exert psychobiotic potential and introduce a new strain, Lp 286, as a potential candidate in the prevention or as therapeutic adjuvant in the treatment of mental disorders.

Deleterious effects of chronic mercury exposure on in vitro LTP, memory process, and oxidative stress.

Heavy metal contamination in aquatic environments plays an important role in the exposure of humans to these toxicants. Among these pollutants, mercury (Hg) is one main concern due to its high neurotoxicity and environmental persistence. Even in low concentrations, Hg bioaccumulation is a major threat to human health, with higher impact on populations whose diet has fish as chief consumption. Mercury compounds have high affinity for neuronal receptors and proteins, which gives Hg its cumulative feature and have the ability to cross cell membranes and blood-brain barrier to show their neurotoxicity. Intoxication with Hg increases levels of reactive oxygen species (ROS), thus depleting faster the resource of antioxidant proteins. To evaluate Hg-induced hippocampal ROS production, synaptic plasticity, anxiety, and memory, a total of 11 male Wistar rats were exposed to HgCl2 (Hg30 group) to produce a residual concentration of 8 ng/mL at the end of 30 days. Behavioral tests (plus-maze discriminative avoidance task), in vitro electrophysiology, and ROS assays were performed. Western blot assay showed decreased levels of antioxidant proteins GPx and SOD in Hg30 group. Increased ROS production was observed in the CA1 and CA3 regions in the Hg-exposed group. Plus-maze task detected long-term memory impairment in Hg30 group, linked to poorer in vitro long-term potentiation as compared to control group. Hg intoxication also promoted higher anxiety-like behavior in the exposed animals. In conclusion, our data suggests that low doses of HgCl2 resulted in impaired long-term memory and unbalance between decreased antioxidant protein expression and increased ROS production in the hippocampus.

Differential contribution of H3R antagonism by LINS01 compounds on memory, anxiety-like behaviour and spontaneous locomotor activity in healthy rats

Histamine H3 receptors (H3R) have attracted interest of research groups as drug target to several CNS disorders. Data suggests that H3R antagonists exert neuroprotective, cognitive enhancement and antidepressant effects in rodents. The LINS01 compounds were reported as selective H3R antagonists, but their effects on memory, anxiety-like behaviour and spontaneous locomotor activity were not evaluated to date. Therefore, this study employed the plus-maze discriminative avoidance task (PM-DAT) to assess concomitantly the effects of LINS01 compounds on short- and long-term memory, anxiety-like behaviour and spontaneous locomotor activity. Thirty-eight adult male Wistar rats were divided into five groups (n = 7–8 per group) according to the treatment. The animals were treated with donepezil (1 mg/kg) and clobenpropit (3 mg/kg) (reference compounds), and with two LINS01 compounds at doses of 5 mg/kg (LINS01003 and LINS01004), and then submitted to the PM-DAT protocol. Saline (vehicle) was used as control group. The behavioural data showed that anxiety-like behaviour, spontaneous locomotor activity and memory effects (short- and long-term) were not affected by the treatment with LINS01004 or clobenpropit. Conversely, treatment with LINS01003 and donepezil impaired the maintenance of discriminative avoidance long-term memory, a hippocampal-dependent memory. Donepezil-treated rats also showed decreased spontaneous locomotor activity and anxiolytic-like effects. In summary, considering that hippocampal damage and memory impairment are associated with Alzheimer’s disease (AD), this work brought important findings regarding the contribution of the histamine system to the effects of LINS01 compounds on memory, anxiety and motility, and suggests that H3R antagonism had no effects on anxiety-like behaviour and do not impair discriminative avoidance memory. Furthermore, the findings herein raise new questions about donepezil’s function in an “impaired” system such as AD, since it prevented the long-term memory formation in healthy rats.

Memory impairment induced by different types of prolonged stress is dependent on the phase of the estrous cycle in female rats

A growing body of evidence demonstrates that estrogen and corticosterone (CORT) impact on cognition and emotion. On the one hand, ovarian hormones may have beneficial effects on several neurophysiological processes, including memory. On the other hand, chronic exposure to stressful conditions has negative effects on brain structures related to learning and memory. In the present study, we used the plus-maze discriminative avoidance task (PMDAT) to evaluate the influence of endogenous variations of sex hormones and exposure to different types of prolonged stressors on learning, memory, anxiety-like behavior and locomotion. Female Wistar rats were submitted to seven consecutive days of restraint stress (4 h/day), overcrowding (18 h/day) or social isolation (18 h/day) and tested in different phases of the estrous cycle. The main results showed that: (1) neither stress conditions nor estrous cycle modified PMDAT acquisition; (2) restraint stress and social isolation induced memory impairments; (3) this impairment was observed particularly in females in metestrus/diestrus; (4) stressed females in estrus displayed less risk assessment behavior, suggesting reduced anxiety-like behavior; (5) restraint stress and social isolation, but not overcrowding, elevated corticosterone levels. Taken together, our findings suggest that the phase of the estrous cycle is an important modulatory factor of the cognitive processing disrupted by stress in female rats. Negative effects were observed in metestrus/diestrus, indicating that the peak of sex hormones may protect females against stress-induced memory impairment.

Diabetes Promotes Development of Alzheimer's Disease Through Suppression of Autophagy.

Recent studies suggest that diabetes predisposes patients to develop neurodegenerative Alzheimer's disease (AD), although the underlying mechanisms have yet to be determined. Compromised autophagy of neuronal cells, which occurs in the early stages of AD, has been shown to enhance disease progression. However, autophagic regulation as a mechanism connecting diabetes and AD has not been shown before. Here, we found that streptozotocin (STZ)-induced diabetic rats exhibited poorer performance on the social recognition test, Morris water maze, and plus-maze discriminative avoidance task, compared to PBS-treated normoglycemic control rats, likely resulting from increased brain deposition of amyloid-β peptide aggregates (Aβ) and increased phosphorylation of tau protein, two pathological features of AD. Moreover, diabetes-induced AD-like behavioral and pathological changes were associated with a decrease in neuronal cell autophagy. Furthermore, compromised cell autophagy was recapitulated in vitro in neuronal cells cultured in high glucose conditions. Thus, our data suggest that hyperglycemia in diabetes may directly inhibit neuronal cell autophagy, which subsequently enhances AD-associated pathological progression.

Calpastatin Mediates Development of Alzheimer's Disease in Diabetes.

Aged people have a high chance to develop two prevalent diseases, diabetes and Alzheimer's disease (AD), which are characterized with hyperglycemia and neurodegeneration, respectively. Interestingly, recent evidence suggest that diabetes is a predisposing factor for AD. Nevertheless, the mechanisms underlying the association of diabetes with AD remain poorly defined. Here, we studied the effects of diabetes on AD in mice. The APP-PS1 mouse, an AD-prone strain, was administrated with streptozotocin (STZ) to destroy 75% beta cell mass to induce sustained hyperglycemia. We found that STZ-treated APP-PS1 mice exhibited poorer performance in the social recognition test, Morris water maze, and plus-maze discriminative avoidance task, compared to saline-treated normoglycemic APP-PS1 mice, likely resulting from increases in brain deposition of amyloid-β peptide aggregates (Aβ). Since formation of Aβ is known to be induced by protein hyperphosphorylation mediated by calpain (CAPN)-induced cleavage of p35 into p25, we examined levels of these proteins in mouse brain. We detected not only increased p35-to-p25 conversion, but also enhanced CAPN1 activity via increased protein but not mRNA levels. The internal CAPN1 inhibitor, calpastatin (CAST), was downregulated in STZ-treated APP-PS1 mouse brain, as a basis for the increase in CAPN1. In vitro, a human neuronal cell line, HCN-2, increased CAPN1 activity and downregulated CAST levels when incubated for 8 days in high glucose level, resulting in increased cell apoptosis. Together, these data suggest that chronic hyperglycemia may promote AD development through downregulating CAST.

Role of Post-Transcriptional Control of Calpain by miR-124-3p in the Development of Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disease prevalent in aged people, clinically characterized by progressive memory loss, behavioral and learning dysfunction, and cognitive deficits. The pathogenesis of AD is hallmarked by formation of amyloid-β peptide aggregates (Aβ) and intraneuronal neurofibrillary tangles (NFTs), which are induced by hyperphosphorylation of amyloid-β protein precursor and tau protein, respectively. The hyperphosphorylation is controlled by cyclin-dependent kinase-5 (CDK5), the aberrant activation of which is mediated by calpain (CAPN)-induced cleavage of p35 into p25. However, the regulation of CAPN in AD remains largely unknown. Here, we studied the post-transcriptional control of CAPN1 by microRNAs (miRNAs) in the setting of AD. We found that miR-124-3p, previously reported as a miRNA that was downregulated in AD, was a CAPN1-targeting miRNA that functionally inhibited the protein translation of CAPN1 in a human neural cell line, HCN-2. In vitro, transfection with miR-124-3p reduced the levels of CAPN1 protein, the cleavage of p35 into p25, and cell apoptosis dose-dependently in HCN-2 cells. Moreover, a significant inverse correlation was detected between the levels of miR-124-3p and CAPN1 in AD specimens. Furthermore, intracranial injection of adeno-associated virus expressing miR-124-3p into APP/PS1-AD mice significantly reduced Aβ deposition and significantly improved the AD-mouse behavior in the social recognition test and plus-maze discriminative avoidance task. Together, our data suggest that post-transcriptional control of calpain by miR-124-3p plays an essential role in the development of AD.

Chronic treatment with five vascular risk factors causes cerebral amyloid angiopathy but no Alzheimer pathology in C57BL6 mice

Alzheimer’s disease (AD) is a progressive neurodegenerative brain disorder and the most common form of dementia coming along with cerebral amyloid angiopathy (CAA) in more than 70% of all cases. However, CAA occurs also in pure form without AD pathology. Vascular life style risk factors such as obesity, hypertension, hypercholesterolemia, diabetes, stress or an old age play an important role in the progression of CAA. So far, no animal model for sporadic CAA has been reported, thus the aim of the present study was to create and characterize a new mouse model for sporadic CAA by treatment with different vascular risk factors. Healthy C57BL6 mice were treated with lifestyle vascular risk factors for 35 or 56 weeks: lipopolysaccharide, social stress, streptozotozin, high cholesterol diet and copper in the drinking water. Four behavioral tests (black-white box, classical maze, cheeseboard maze and plus-maze discriminative avoidance task) showed impaired learning, memory and executive functions as well as anxiety with increased age. The treated animals exhibited increased plasma levels of cortisol, insulin, interleukin-1ß, glucose and cholesterol, confirming the effectiveness of the treatment. Confocal microscopy analysis displayed severe vessel damage already after 35 weeks of treatment. IgG positive staining points to a severe blood-brain barrier (BBB) disruption and furthermore, cerebral bleedings were observed in a much higher amount in the treatment group. Importantly, inclusions of beta-amyloid in the vessels indicated the development of CAA, but no deposition of beta-amyloid plaques and tau pathology in the brains were seen. Taken together, we characterized a novel sporadic CAA mouse model, which offers a strategy to study the progression of the disease and therapeutic and diagnostic interventions.

Sevoflurane impairs learning and memory of the developing brain through post-transcriptional inhibition of CCNA2 via microRNA-19-3p.

The molecular mechanisms underlying sevoflurane (SEVO)-induced impairment of learning and memory remain unclear. Specifically, a role of microRNAs (miRNAs) in the control of the neuron proliferation in the developing brain exposed to SEVO has not been reported previously. Here, we studied the effects of SEVO exposure on the neural cell proliferation, and on the learning and memory of neonatal rats. We found that SEVO exposure significantly decreased neuron cell proliferation, reduced BDNF levels in brain, and impaired learning and memory of neonatal rats in Morris water maze test and Plus-Maze discriminative avoidance task (PM-DAT), likely through downregulation of CCNA2 protein. Next, we used bioinformatic tools to predict CCNA2-binding microRNAs (miRNAs), and found that miR-19-3p was upregulated in neurons exposed to SEVO. Moreover, miR-19-3p functionally inhibited the protein translation of CCNA2 in a human neural cell line, HCN-2. Furthermore, intracranial injection of adeno-associated virus carrying antisense of miR-19-3p under a CMV promoter into the neonatal rats significantly alleviated SEVO exposure-induced impairment of neuron cell proliferation, as well as the learning and memory of the rats. Together, our data suggest that SEVO-induced upregulation of miR-19-3p post-transcriptionally inhibits CCNA2, which contributes to the SEVO-associated impairment of learning and memory of the neonatal rats.

Flavones-bound in benzodiazepine site on GABAA receptor: Concomitant anxiolytic-like and cognitive-enhancing effects produced by Isovitexin and 6-C-glycoside-Diosmetin

Increasing evidence suggests that flavones can modulate memory and anxiety-like behaviour. However, these therapeutic effects are inconsistent and induce of adverse effects, which have been associated with interactions at the Benzodiazepine (BZ)-binding site. To improve our understanding of flavone effects on memory and anxiety, we employed a plus-maze discriminative avoidance task. Furthermore, we evaluated the potential of the compounds in modulating GABAA receptors via BZ-binding site using molecular modelling studies. Adult male Wistar rats were treated 30 min before training session with Vicenin-2 (0.1 and 0.25 mg/kg), Vitexin (0.1 and 0.25 mg/kg), Isovitexin (0.1 and 0.25 mg/kg) and 0.1 mg/kg 6-C-glycoside-Diosmetin, vehicle and a GABAA receptor agonist. The analysis of the time spent in the non-aversive vs aversive enclosed arms during the test session and percentage of time in the open arms within the training session revealed that treatment with Isovitexin and 6-C-glycoside-Diosmetin had memory-enhancing and anxiolytic-like effects (P < 0.001). In contrast, treatment with a higher dose of Diazepam impaired short-and long-term memory when it alleviated anxiety level. Docking studies revealed that flavones docked in a very similar way to that observed to the Diazepam, except by a lack of interaction in residue α1His101 in the BZ-binding site on GABAA receptors, which may be related to memory-enhancing effect. The occurrence of the α1His101 interaction could justify the memory-impairing observed following Diazepam treatment. These findings provide the first evidence that Isovitexin and 6-C-glycoside-Diosmetin could exert their memory-enhancing and anxiolytic-like effects via GABAA receptor modulation, which likely occurs via their benzodiazepine-binding site.

Long-term Potentiation Decay and Poor Long-lasting Memory Process in the Wild Rodents Proechimys from Brazil's Amazon Rainforest.

Proechimys are small terrestrial rodents from Amazon rainforest. Each animal species is adapted to a specific environment in which the animal evolved therefore without comparative approaches unique characteristics of distinct species cannot be fully recognized. Laboratory rodents are exceedingly inbred strains dissociated from their native habitats and their fundamental ecological aspects are abstracted. Thus, the employment of exotic non-model species can be informative and complement conventional animal models. With the aim of promoting comparative studies between the exotic wildlife populations in the laboratory and traditional rodent model, we surveyed a type of synaptic plasticity intimately related to memory encoding in animals. Using theta-burst paradigm, in vitro long-term potentiation (LTP) in the CA1 subfield of hippocampal slices was assessed in the Amazon rodents Proechimys and Wistar rats. Memory, learning and anxiety were investigated through the plus-maze discriminative avoidance task (PM-DAT) and object recognition test. In PM-DAT, both animal species were submitted to two test sessions (3-h and 24-h) after the conditioning training. Proechimys exhibited higher anxiety-like behavior in the training session but during test sessions both species exhibited similar patterns of anxiety-related behavior. After 3-h of the training, Proechimys and Wistar spent significantly less time in the aversive enclosed arm than in the non-aversive arm. But, at 24-h after training, Wistar rats remained less time in the aversive closed arm in comparison with the non-aversive one, while Proechimys rodents spent the same amount of time in both enclosed arms. In the object recognition test, both species were evaluated at 24-h after the acquisition session and similar findings than those of the PM-DAT (24-h) were obtained, suggesting that long-term memory duration did not persist for 24-h in the Amazon rodent. Field excitatory post-synaptic potentials recordings revealed that LTP decays rapidly over time reaching basal levels at 90 min after theta-burst stimulation in Proechimys, contrasting to the stable LTP found in the Wistar rats which was observed throughout 3-h recording period. These findings suggest a link between the LTP decay and the lack of 24-h long-lasting memory process in Proechimys. Nevertheless, why early-phase LTP in Proechimys decays very rapidly remains to be elucidated.

Cannabidiol Prevents Motor and Cognitive Impairments Induced by Reserpine in Rats.

Cannabidiol (CBD) is a non-psychotomimetic compound from Cannabis sativa that presents antipsychotic, anxiolytic, anti-inflammatory, and neuroprotective effects. In Parkinson’s disease patients, CBD is able to attenuate the psychotic symptoms induced by L-DOPA and to improve quality of life. Repeated administration of reserpine in rodents induces motor impairments that are accompanied by cognitive deficits, and has been applied to model both tardive dyskinesia and Parkinson’s disease. The present study investigated whether CBD administration would attenuate reserpine-induced motor and cognitive impairments in rats. Male Wistar rats received four injections of CBD (0.5 or 5 mg/kg) or vehicle (days 2–5). On days 3 and 5, animals received also one injection of 1 mg/kg reserpine or vehicle. Locomotor activity, vacuous chewing movements, and catalepsy were assessed from day 1 to day 7. On days 8 and 9, we evaluated animals’ performance on the plus-maze discriminative avoidance task, for learning/memory assessment. CBD (0.5 and 5 mg/kg) attenuated the increase in catalepsy behavior and in oral movements – but not the decrease in locomotion – induced by reserpine. CBD (0.5 mg/kg) also ameliorated the reserpine-induced memory deficit in the discriminative avoidance task. Our data show that CBD is able to attenuate motor and cognitive impairments induced by reserpine, suggesting the use of this compound in the pharmacotherapy of Parkinson’s disease and tardive dyskinesia.

Protective effects of chronic treatment with a standardized extract of Ginkgo biloba L. in the prefrontal cortex and dorsal hippocampus of middle-aged rats

This study assessed the effects of chronic treatment with a standardized extract of Ginkgo biloba L. (EGb) on short-term and long-term memory as well as on anxiety-like and locomotor activity using the plus-maze discriminative avoidance task (PM-DAT). Additionally, we evaluated the antioxidant and neuroprotective effects of EGb on the prefrontal cortex (PFC) and dorsal hippocampus (DH) of middle-aged rats using the comet assay. Twelve-month-old male Wistar rats were administered vehicle or EGb (0.5mgkg−1 or 1.0gkg−1) for 30days. Behavioural data showed that EGb treatment improved short-term memory. Neither an anti-anxiety effect nor a change in locomotor activity was observed. Twenty-four hours after the behavioural tests, the rats were decapitated, and the PFC and DH were quickly dissected out and prepared for the comet assay. The levels of DNA damage in the PFC were significantly lower in rats that were treated with 1.0gkg−1 EGb. Both doses of EGb decreased H2O2-induced DNA breakage in cortical cells, whereas the levels of DNA damage in the EGb-treated animals were significantly lower than those in the control animals. No significant differences in the level of DNA damage in hippocampal cells were observed among the experimental groups. EGb treatment was not able to reduce H2O2-induced DNA damage in hippocampal cells. Altogether, our data provide the first demonstration that chronic EGb treatment improved the short-term memory of middle-aged rats, an effect that could be associated with a reduction in free radical production in the PFC. These data suggest that EGb treatment might increase the survival of cortical neurons and corroborate and extend the view that EGb has protective and therapeutic properties.

Sex and estrous cycle influence diazepam effects on anxiety and memory: Possible role of progesterone

Studies with rodents and humans show the relationship between female sex hormones and cognitive/emotional tasks. However, despite the greater incidence of anxiety disorders in women, the data are still inconclusive regarding the mechanisms related to this phenomenon. We evaluated the effects of a classical anxiolytic/amnestic drug (diazepam; DZP) on female (at different estrous cycle phases) and male rats tested in the plus-maze discriminative avoidance task (PMDAT), that allows the concomitant evaluation of memory and anxiety-like behavior. Further, in order to investigate the role of progesterone and its metabolites in the effects of DZP in the PMDAT, female rats were pre-treated with the progesterone receptor antagonist mifepristone or the 5-alpha-reductase inhibitor finasteride. The main findings were: (1) DZP caused memory impairment and anxiolysis in both sexes, but only the highest dose induced the anxiolytic effect in females; (2) females in proestrus did not present the amnestic and anxiolytic effects of DZP (at 2.0 and 4.0mg/kg, respectively) and (3) the co-administration of mifepristone reestablished both amnestic and anxiolytic effects of DZP, while finasteride reinstated the amnestic effect in proestrus female rats. These results suggest that changes in the endogenous levels of progesterone and its metabolites are important in the modulation of emotional/cognitive behavior in female rats. Based on the influence on different aspects of DZP action, the mechanisms related to this modulation are probably linked to GABAergic transmission, but this point remains to be investigated. Further, the variation in therapeutic and adverse effects of DZP depending on sex and hormonal state is of great relevance considering the higher prevalence of anxiety disorders in women.