Passive Avoidance Task Research Articles

Long-term exercise pre-training attenuates Alzheimer's disease-related pathology in a transgenic rat model of Alzheimer's disease.

Alzheimer'sdisease (AD) is the most common form of dementia. Despite enormous efforts around the world, there remains no effective cure for AD. This study was performed to investigate the effects of long-term exercise pretreatment on the typical pathology of AD in a novel transgenic AD rat model. Male 2-month-old animals were divided into the following groups: wild-type (WT) rats, AD rats, and AD rats with treadmill exercise pretreatment (AD-Exe). After exercise pretreatment, the Barnes maze task, passive avoidance task, and cued fear conditioning test were performed to test learning and memory function. The elevated plus maze, open field test, sucrose preference test, and forced swim test were conducted to measure anxious-depressive-like behavior. Immunofluorescence staining, Golgi staining, transmission electron microscopy, Western blot analysis, F-Jade C staining, TUNEL staining, and related assay kits were conducted to measure Aβ plaques, tau hyperphosphorylation, neuronal damage, neuronal degeneration, dendritic spine density, synapses, synaptic vesicles, mitochondrial morphology, mitochondrial dynamic, oxidative stress, and neuroinflammation. Behavioral tests revealed that long-term exercise pretreatment significantly alleviated learning and memory dysfunction and anxious-depressive-like behaviors in AD animals. In addition, exercise pretreatment attenuated amyloid-β deposition and tau hyperphosphorylation and preserved spine density, synapses, and presynaptic vesicles. Exercise also inhibited neuronal damage, neuronal apoptosis, and neuronal degeneration. Additional studies revealed the imbalance of mitochondrial dynamics was significantly inhibited by exercise pretreatment accompanied by a remarkable suppression of oxidative stress and neuroinflammation. Our findings suggest that long-term exercise pretreatment alleviated behavioral deficits and typical pathologies of the AD rat model, supporting long-term exercise pretreatment as a potential approach to delay the progression of AD.

Effect of Chloroquine on Hyoscine-Induced Memory Impairment in Mice: Possible Involvement of Opioids and Nitric Oxide

Supporting evidence suggests the possible neuroprotective potential of chloroquine, an anti-malaria medication. Moreover, reports indicate that endogenous opioids and nitric oxide (NO) play role of a mediator by chloroquine’s effects. In the present study, the effects of chloroquine on hyoscine-induced memory impairment were assessed. Furthermore, the possible involvements of opioids and NO were evaluated. Chloroquine was administered intraperitoneally (i.p.) at doses of 0.1, 0.5, 1, 3, 10, and 20 mg/kg to hyoscine-treated (1 mg/kg, i.p.) mice, and the spatial and fear memories were evaluated using Y-maze and passive-avoidance tasks, respectively. Also, to provide further evidence about chloroquine’s mechanism of action, the opioid receptors and the NO production were blocked using two nonselective antagonist’s naltrexone and L-NAME, respectively. Chloroquine at doses of 0.5, 10, and 20 mg/kg furtherly damaged the impaired memory of hyoscine-treated mice and at doses of 10 and 20 mg/kg impaired the memory of saline-treated mice in the passive avoidance task. Additionally, chloroquine at doses of 0.5 and 1 mg/kg improved the spatial memory in hyoscine-treated mice in the Y-maze test. In addition, naltrexone (3 mg/kg) reversed the neuroprotective effect of chloroquine (1 mg/kg) in hyoscine-treated mice in the Y-maze task. It could be concluded that chloroquine at low doses may improve cognitive performance by involving the opioid receptors; as a result, blocking the opioid receptors may reverse chloroquine’s neuroprotective effect. Notably, chloroquine at high doses did not improve the memory, and in combination with hyoscine, it caused even more damage to long-term memory.

Effect of caffeine on the anticonvulsant action of pregabalin against electroconvulsions in mice.

Experimental data indicate that caffeine (CAF) can reduce the anticonvulsant activity of antiepileptic drugs (AEDs) in animal models of seizures. The purpose of the current study was to examine the effect of CAF on the protective action of pregabalin (PGB) against electroconvulsions in mice. Maximal electroshock seizure (MES) test was used in the current study. In addition, the combined treatment with CAF and PGB was assessed in the passive avoidance task (long-term memory) and the chimney test (motor coordination). Drugs were injected intraperitoneally (ip) as single injections. CAF was administered at doses reported to compromise the anticonvulsant action of AEDs in mice. CAF at a dose of 23.1mg/kg reduced the anticonvulsant action of PGB in the MES test. The brain concentration of PGB was not significantly changed by CAF and vice versa. In the chimney test, CAF (23.1mg/kg) protected mice against PGB-induced motor coordination impairment. Regarding seizure control, it might be suggested that patients with epilepsy treated with PGB should avoid taking CAF. The estimated total brain concentration of PGB and CAF does not suggest a pharmacokinetic interaction as an explanation for these results.

Beneficial effects of levetiracetam in streptozotocin-induced rat model of Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder among the elderly. In the light of increasing AD prevalence and lack of effective treatment, new strategies to prevent or reverse this condition are needed. Levetiracetam (LEV) is a newer antiepileptic drug that is commonly used to treat certain types of seizures. Researches indicated that LEV has several other pharmacological activities, including improvement of cognitive function. In this study, the recovery effects of chronic (28 days) administration of LEV (50, 100, and 150mg/kg, ip) on cognitive deficits caused by the intracerebroventricular (icv) injection of streptozotocin (STZ), as a model for sporadic AD, were evaluated in rats. We also considered the protective effects of LEV against hippocampal cell loss, oxidative damage, acetylcholinesterase (AChE) activity, neuroinflammation, and tauopathy caused by STZ. LEV (100 and 150mg/kg) significantly attenuated the STZ-induced learning and memory impairments in the passive avoidance and Morris water maze (MWM) tasks. In addition, LEV suppressed STZ-induced hippocampal neuronal loss, while restored alterations in the redox status (lipid peroxides and glutathione), AChE activity, proinflammatory cytokines (IL-1β, IL-6, TNF-α), and hyperphosphorylation of tau linked to STZ administration. In conclusion, our study demonstrated that LEV alleviated hippocampal cell death and memory deficits in STZ-AD rats, through mitigating oxidative damage, suppression of proinflammatory cytokines expression, and inhibition of abnormal tau hyperphosphorylation.

So what'cha want? The impact of individualised rewards on associative learning in psychopathic offenders

Psychopathic individuals typically present with associative learning impairments under explicit learning conditions. The present study aimed to investigate whether the formation of stimulus-outcome associations, as well as updating of these associations after changed contingencies, could be improved by using rewards with sufficiently high subjective values. To this end, 20 psychopathic offenders, 17 non-psychopathic offenders and 18 healthy controls performed a passive avoidance task with a reversal phase under three motivational conditions, using naturalistic rewards. The subjective values of the rewards were assessed a priori for each individual participant using a visual analogue scale. The correspondence of these values to their internal representation was confirmed by analyses of brain potentials. Analyses using both signal detection theory and classical approaches indicated that psychopathic offenders performed worse compared to the other groups during passive avoidance learning. However, using the signal detection approach, we found this deficiency to be present only when a hypothetical reward was used (‘neutral reward’ condition), whereas psychopathic offenders performed similar to the other groups when naturalistic rewards could be obtained (‘low reward’ and ‘high reward’ conditions). Furthermore, traditional analyses suggested that psychopathic offenders had more hits than the other groups during reversal learning, but the signal detection approach indicated that no effects of group or condition were present. Analysis of win-stay and lose-shift behaviour showed that psychopathic offenders were less likely to stay with a rewarded response during passive avoidance learning in the neutral reward condition. In addition, regardless of experimental phase or condition, psychopathic offenders were less likely to stop responding to a particular stimulus after receiving negative feedback. Although the approaches employed did not lead to unequivocal results, our findings suggest that psychopathic offenders do have the ability to adapt their behaviour to environmental contingencies when positive reinforcers with sufficiently high subjective values are used.

Calcitriol supplementation attenuates cisplatin-induced behavioral and cognitive impairments through up-regulation of BDNF in male rats

Chemotherapy-induced cognitive impairment such as memory impairment and concentration problems are now extensively recognized as side effects of chemotherapy. These problems reduce the quality of life in patients. Therefore, the present study aims to examine the effects of calcitriol supplementation (100 ng/kg /day for five weeks) on cognitive impairment, behavioral deficits, and hippocampal brain-derived neurotrophic factor (BDNF) changes following cisplatin treatment (5 mg/kg/ once a week for five weeks). We also determined the impact of cisplatin and calcitriol administration on reaction time against the thermal stimulus and muscle strength. Our findings showed that cisplatin administration resulted in a significant increase in anxiety-like behaviors. Treatment of rats with cisplatin also impaired performance in the passive avoidance and novel object recognition tasks which are indicating cognitive deficits. Co-administration of calcitriol prevented the cisplatin-induced behavioral and cognitive impairments. Cisplatin exposure also resulted in enhanced reaction time to the thermal stimulus and decreased muscle ability. Besides, hippocampal BDNF levels were reduced in cisplatin-treated rats; however, calcitriol alleviated these effects of cisplatin and up-regulated BDNF mRNA in the hippocampus. In addition, calcitriol alone indicated a significant change in BDNF level compared to the control group. We conclude that increased hippocampal BDNF mediates the beneficial effects of calcitriol against neurotoxicity in cisplatin-exposed rats. However, further studies are required to explore the other mechanisms that mediate the beneficial effect of calcitriol

Neuroprotective role of Diosgenin, a NGF stimulator, against Aβ (1-42) induced neurotoxicity in animal model of Alzheimer's disease.

Diosgenin is a neurosteroid derived from the plants and has been previously reported for its numerous health beneficial properties, such as anti-arrhythmic, hypolipidemic, and antiproliferative effects. Although several studies conducted earlier suggested cognition enhancement actions of diosgenin against neurodegenerative disorders, but the molecular mechanisms underlying are not clearly understood. In the present study, we investigated the neuroprotective effect of diosgenin in the Wistar rats that received an intracerebroventricular injection of Amyloid-β (1-42) peptides, representing a rodent model of Alzheimer's disease (AD). Animals were treated with 100 and 200mg/kg/p.o of diosgenin for 28days, followed by Amyloid-β (1-42) peptides infusion. Animals were assessed for the spatial learning and memory by using radial arm maze and passive avoidance task. Subsequently, animals were euthanized and brains were collected for biochemical estimations and histopathological studies. Our results revealed that, diosgenin administration dose dependently improved the spatial learning and memory and protected the animals from Amyloid-β (1-42) peptides induced disrupted cognitive functions. Further, biochemical analysis showed that diosgenin successfully attenuated Amyloid-β (1-42) mediated plaque load, oxidative stress, neuroinflammation and elevated acetylcholinesterase activity. In addition, histopathological evaluation also supported neuroprotective effects of diosgenin in hippocampus of rat brain when assessed using hematoxylin-eosin and Cresyl Violet staining. Thus, the aforementioned effects suggested protective action of diosgenin against Aβ (1-42) induced neuronal damage and thereby can serve as a potential therapeutic candidate for AD.

Paeonol Ameliorates Cuprizone-Induced Hippocampal Demyelination and Cognitive Deficits through Inhibition of Oxidative and Inflammatory Events.

Multiple sclerosis (MS) is a chronic and inflammatory disorder of the central nervous system with autoimmune nature that is typified by varying degrees of demyelination and axonal damage. Paeonol is an active ingredient in some medicinal plants with anti-inflammatory and neuroprotective property. This study was conducted to reveal whether paeonol can alleviate hippocampal demyelination and cognitive deficits in cuprizone-induced murine model of demyelination as a model of MS. C57BL/6 mice received oral cuprizone (400mg/kg) for 6weeks, and paeonol was administered p.o. at two doses of 25 or 100mg/kg, starting from the second week post-cuprizone for 5weeks. After assessment of learning and memory in different tasks, oxidative stress and inflammation were evaluated besides immunohistochemical assessment of hippocampal myelin basic protein (MBP). Paeonol (100mg/kg) properly ameliorated cognitive deficits in Y maze, novel object discrimination (NOD) test, and Barnes maze with no significant improvement of performance in passive avoidance task. In addition, paeonol treatment at the higher dose was also associated with partial restoration of hippocampal level of oxidative stress and inflammatory markers including MDA, ROS, GSH, SOD, catalase, NF-kB, and TNF. Besides, paeonol improved MMP as an index of mitochondrial integrity and health and reduced MPO as a factor of neutrophil infiltration. Furthermore, paeonol treatment prevented hippocampal MBP immunoreactivity, indicating its prevention of demyelination. In conclusion, the current study showed the preventive effect of paeonol against cuprizone-induced demyelination and cognitive deficits through reversing most oxidative stress- and inflammation-related parameters in addition to its improvement of mitochondrial health.

Selenomethionine Ameliorates Cognitive Impairment, Decreases Hippocampal Oxidative Stress and Attenuates Dysbiosis in D-Galactose-Treated Mice.

The prevalence of age-related cognitive impairment is increasing as the proportion of older individuals in the population grows. It is therefore necessary and urgent to find agents to prevent or ameliorate age-related cognitive impairment. Selenomethionine (SeMet) is a natural amino acid occurring in yeast and Brazil nuts. It mitigates cognitive impairment in an Alzheimer’s disease mouse model, however, whether it works on age-related cognitive impairment remains unknown. In this study, SeMet significantly improved the performance of D-galactose-treated mice in the novel object recognition test, passive avoidance task and Morris water maze test. SeMet reversed D-galactose-induced reduction of hippocampal acetylcholine levels, suppression of choline acetyltransferase activity and activation of acetyl cholinesterase. It decreased D-galactose-induced oxidative stress and increased the selenoprotein P levels in the hippocampus. Besides, it attenuated D-galactose-induced dysbiosis by increasing the α-diversity and modulating the taxonomic structure. Correlations between certain taxa and physiological parameters were observed. Our results provide evidence of the effectiveness of SeMet on ameliorating D-galactose-induced cognitive impairment and suggest SeMet has potential to be used in the prevention or adjuvant treatment of age-related cognitive impairment.

The effects of vitamin D on learning and memory of hypothyroid juvenile rats and brain tissue acetylcholinesterase activity and oxidative stress indicators.

Apart from a role as a key regulator of calcium/phosphate homeostasis, vitamin D (Vit D) is suggested to be a potential player in nervous system growth and function. This study aimed to assess the impacts of Vit D administration on memory impairment, oxidative damage, and acetylcholinesterase (AchE) overactivity in hypothyroid juvenile rats. The animals were randomly grouped as (1) Control; (2) Hypothyroid; (3) Hypothyroid-Vit D100, and (4) Hypothyroid-Vit D 500. Propylthiouracil (PTU) was added to their drinking water (0.05%) for 6weeks, and Vit D (100 or 500IU/kg) treatment was performed daily by gavage. Morris water maze (MWM) and passive avoidance (PA) tests were performed. The brains were removed under deep anesthesia, then the hippocampal and cortical tissues were separated to assess biochemical parameters. Hypothyroidism was significantly associated with learning and memory impairment in MWM and PA tests. Hypothyroidism was also accompanied by an elevation in AChE activity and malondialdehyde (MDA) content and a reduced level of thiol content and superoxide dismutase (SOD) activity in the brain. Treatment with Vit D recovered hypothyroidism-induced cognitive impairment and improved memory performance in MWM and PA tasks. On the other hand, Vit D alleviated AChE activity and MDA level, whereas increased SOD activity and thiol content in the hippocampal and cortical tissues. In conclusion, these outcomes suggest an association between the oral administrations of Vit D and learning and memory improvement of hypothyroid rats, which was accompanied by decreasing AChE activity and brain tissue oxidative damage.

Effect of Sanguisorba minor on scopolamine-induced memory loss in rat: involvement of oxidative stress and acetylcholinesterase.

Sanguisorba minor (S. minor) has neuroprotective and antioxidant activities. However, its potential benefits in ameliorating learning and memory functions have been explored in no studies up to now. So, in the current study, rats were treated with S. minor hydro-ethanolic extract (50, 100, and 200mg/kg, intraperitoneal (i.p.)) as well as rivastigmine (0.5mg/kg, i.p.) for 21 consecutive days. Thereafter, their behavioral performance was assessed using Morris water maze (MWM) and passive avoidance (PA) tasks. Notably, 30min before conducting the tasks, scopolamine was injected. Finally, the biochemical assessments were done using the brain tissue. The extract characterization was performed by liquid chromatography-mass spectrometry, which confirmed the presence of quercetin, myricetin, kaempferol, catechin, ellagic acid, and gallic acid derivatives. In the MWM test, the extract reduced both escape latency and the travelled distance, compared to the scopolamine group. Moreover, in the PA test, the latency to enter the dark chamber significantly increased by the extract, compared to the scopolamine group (p < 0.05-p < 0.001). Notably, the beneficial effects of S. minor on cognitive performance of the scopolamine-treated rats appeared to be similar or even better than rivastigmine in behavior performance. Similar to rivastigmine, it was observed that the extract attenuated both AChE activity and oxidative injury in the brain as evidenced by the increased antioxidant enzymes and total thiol content; however, it decreased malondialdehyde level (p < 0.05-p < 0.001). In conclusion, the results suggested the effectiveness of S. minor in preventing cognitive dysfunction induced by scopolamine. Accordingly, these protective effects might be produced by the regulation of cholinergic activity and oxidative stress. S. minor could be considered as a potential alternative therapy in cognition disorders.

Development and Validation of PEG‐PCL Based Nanoformulation of Rosiglitazone and Evaluation of its Brain Selectivity in Mice Model of Alzheimer’s disease

AbstractBackgroundType‐2 Diabetes Mellitus and insulin resistance increases the risk of Alzheimer’s disease (AD). Recent studies highlighted the role of peroxisome proliferator‐activated receptor‐gamma (PPAR‐γ) in modulation of AD. This study was designed to investigate the effect of rosiglitazone alone or in its nanoformulated form for an effective drug delivery in mice model of AD.MethodAD mice model was developed by intracerebroventricular (ICV) administration of streptozotocin (STZ). PEG‐PCL polymer was synthesized using ring opening polymerization of caprolactone with methoxy‐PEG as a macroinitiator and stannousoctoate as catalyst. Nanoformulation of rosiglitazone was developed using emulsion‐diffusion‐solvent evaporation method. Nanoformulation was evaluated by Scanning electron microscopy, particle size analyzer and HPLC method. Cognitive functions were evaluated by passive avoidance task, object recognition task and Morris water maze test. Amyloid beta (Aβ) and phosphorylated tau (p‐tau) level were assessed by ELISA, level of oxidative stress and pro‐inflammatory cytokines like tumor necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6) were measured in hippocampus homogenates and the expression level of CREB, BDNF, GDNF, NGF were assessed by RT‐PCR method.ResultThe rosiglitazone nanoformulation was observed within a range of 70±10 nm in size and the entrapment efficiency of rosiglitazone was 70±5%. The ICV‐STZ mice showed significant features of cognitive abnormalities. The mice treated with rosiglitazone and its formulation improved cognition, attenuated the elevated level of Aβ and p‐tau along with pro‐inflammatory cytokines‐TNF‐α and IL‐6 and oxidative stress was altered when compared with disease control animals. Moreover, these changes occurred concurrently with an increased expression level of BDNF, GDNF and NGF.ConclusionNanoformulation of rosiglitazone imparted significant neuroprotective efficacy with greater amounts being observed in the brain at a lower dose compared to its free form.

Memory improvement effects of Ganoderma mediosinense in mice via its anticholinergic and antioxidant activities

AbstractBackgroundSpecies of the genus Ganoderma are valued both for their medicinal as well as nutritional properties. Traditionally, these are employed in neurological disorders. However, G. mediosinense has not been evaluated for anti‐amnesic effects previously. Therefore the present study is aimed to explore the cognitive improvement effects of the G. mediosinense extract (GME) against mouse model of scopolamine induced amnesia.MethodAnimals were orally administered with GME (200, 400 and 800 mg/kg) for 7 consecutive days and amnesia was induced by scopolamine (1 mg/kg, i.p.) after 30 min of treatment. Cognitive functions were determined by employing passive shock avoidance task and novel object recognition test. Brain AChE and lipid peroxidation were determined to have an insight into the associated neuroprotective mechanism of GME.ResultTreatment with GME showed dose dependent amelioration of cognitive deficit induced by scopolamine in animals. Also, GME reduced the brain AChE activity and oxidative stress.ConclusionThese results indicated the anti‐amnesic effects of GME via decreasing brain cholinergic and oxidative stress.

(R,S)-ketamine and (2R,6R)-hydroxynorketamine differentially affect memory as a function of dosing frequency

A single subanesthetic infusion of ketamine can rapidly alleviate symptoms of treatment-resistant major depression. Since repeated administration is required to sustain symptom remission, it is important to characterize the potential untoward effects of prolonged ketamine exposure. While studies suggest that ketamine can alter cognitive function, it is unclear to what extent these effects are modulated by the frequency or chronicity of treatment. To test this, male and female adolescent (postnatal day [PD] 35) and adult (PD 60) BALB/c mice were treated for four consecutive weeks, either daily or thrice-weekly, with (R,S)-ketamine (30 mg/kg, intraperitoneal) or its biologically active metabolite, (2R,6R)-hydroxynorketamine (HNK; 30 mg/kg, intraperitoneal). Following drug cessation, memory performance was assessed in three operationally distinct tasks: (1) novel object recognition to assess explicit memory, (2) Y-maze to assess working memory, and (3) passive avoidance to assess implicit memory. While drug exposure did not influence working memory performance, thrice-weekly ketamine and daily (2R,6R)-HNK led to explicit memory impairment in novel object recognition independent of sex or age of exposure. Daily (2R,6R)-HNK impaired implicit memory in the passive-avoidance task whereas thrice-weekly (2R,6R)-HNK tended to improve it. These differential effects on explicit and implicit memory possibly reflect the unique mechanisms by which ketamine and (2R,6R)-HNK alter the functional integrity of neural circuits that subserve these distinct cognitive domains, a topic of clinical and mechanistic relevance to their antidepressant actions. Our findings also provide additional support for the importance of dosing frequency in establishing the cognitive effects of repeated ketamine exposure.

Effects of ethanol ingestion on aversive conditioning in honey bees (Apis mellifera L.).

Ethanol consumption has been shown to have many deleterious effects, including behavioral alterations, motor deficits, reduction in inhibition, and alteration of neurochemical expression. These effects occur in the wide variety of species that consume ethanol. Although studies have examined aversive conditioning in honey bees (Apis mellifera), few have examined the role of intoxication on the acquisition of learning in such paradigms. The current study continues a line of research using honey bees as a model to explore the behavioral effects of ethanol toxicity. A passive avoidance task is used to explore how increasing dosages of ethanol affects the ability of honey bees to perform this task. The results show that honey bees exposed to higher concentrations of ethanol have slower passive avoidance acquisition than bees exposed to lower concentrations under the same conditions. Bees not experiencing aversive stimuli displayed no difference from baseline behavior when exposed to varying concentrations of ethanol. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Memantine improves cognitive deficits via KATP channel inhibition in olfactory bulbectomized mice

Patients with Alzheimer's disease (AD) demonstrate severely impaired olfactory systems, which occur in the early stages of the disease. Olfactory bulbectomy (OBX) in mice elicits cognitive deficits, and reduces cholinergic activity in the hippocampus. Here, we confirmed that the novel AD drug memantine rescues cognitive deficits via ATP-sensitive potassium (KATP) channel inhibition in OBX mice. Repeated memantine administration at 1–3 mg/kg p.o. for 14 days starting at 10 days after OBX surgery significantly rescued cognitive deficits in OBX mice, as assessed using Y-maze, novel object recognition, and passive avoidance tasks. Consistent with the rescued cognitive deficits in OBX mice, long-term potentiation (LTP) in the hippocampal cornu ammonis (CA) 1 region was markedly restored with memantine administration. As demonstrated by immunoblotting, the reductions of calcium/calmodulin-dependent protein kinase II (CaMKII) α (Thr-286) autophosphorylation and calcium/calmodulin-dependent protein kinase IV (CaMKIV; Thr-196) phosphorylation in the CA1 region of OBX mice were significantly restored with memantine. Conversely, pre-treatment with pinacidil, a KATP channel opener, failed to reinstate hippocampal LTP and CaMKII/CaMKIV activities in the CA1 region. Finally, improvement of cognitive deficits by memantine treatments was observed in OBX-operated Kir6.1 heterozygous (+/−) mice but not in OBX-operated Kir6.2 heterozygous (+/−) mice. Overall, our study demonstrates that memantine rescues OBX-induced cognitive deficits via Kir6.2 channel inhibition in the CA1 region.

Assessment of drug-drug interactions between moxonidine and antiepileptic drugs in the maximal electroshock seizure test in mice.

Hypertension is a common comorbid condition with epilepsy, and drug interactions between antihypertensive and antiepileptic drugs (AEDs) are likely in patients. Experimental studies showed that centrally active imidazoline compounds belonging to antihypertensive drugs can affect seizure susceptibility. The purpose of this study was to assess the effect of moxonidine, an I1 -imidazoline receptor agonist, on the anticonvulsant efficacy of numerous AEDs (carbamazepine, phenobarbital, valproate, phenytoin, oxcarbazepine, topiramate and lamotrigine) in the mouse model of maximal electroshock. Besides, the combinations of moxonidine and AEDs were investigated for adverse effects in the passive avoidance task and the chimney test. Drugs were administered intraperitoneally (ip). Moxonidine at doses of 1 and 2 mg/kg ip did not affect the convulsive threshold. Among tested AEDs, moxonidine (2 mg/kg) potentiated the protective effect of valproate against maximal electroshock. This interaction could be pharmacodynamic because the brain concentration of valproate was not significantly changed by moxonidine. The antihypertensive drug did not cause adverse effects when combined with AEDs. This study shows that moxonidine may have a neutral or positive effect on the anticonvulsant activity of AEDs in patients with epilepsy. The enhancement of the anticonvulsant action of valproate by moxonidine needs further investigations to elucidate potential mechanisms involved.

Folic acid attenuated learning and memory impairment via inhibition of oxidative damage and acetylcholinesterase activity in hypothyroid rats.

Hypothyroidism has been reported to be associated with cognitive decline. Considering the role of folic acid (FA) in cognitive performance, the present study was designed to investigate the effects of FA on hypothyroidism-induced cognitive impairment, oxidative damage, and alterations in acetylcholinesterase (AChE) activity in rat model of propylthiouracil (PTU)-induced hypothyroidism. In this study, PTU (0.05% in drinking water) and FA (5, 10, and 15mg/kg, oral gavage) were administered for the rats during 7weeks. Then, behavioral performance was tested using Morris water maze (MWM) and passive avoidance (PA) tasks. Finally, oxidative stress indicators and AChE activity were assayed in the brain tissues. The impairing effect of hypothyroidism on cognitive performance was markedly alleviated by FA especially at higher doses. In the MWM test, FA reduced escape latency and travelled distance, compared to the non-treated hypothyroid group. In the PA test, latency to enter dark chamber was significantly enhanced by FA compared to the non-treated hypothyroid group (p < 0.05-p < 0.001). Besides, FA attenuated AChE activity and malondialdehyde level but it increased activity of superoxide dismutase enzyme and total thiol content (p < 0.05-p < 0.001). In conclusion, our findings revealed that FA could improve learning and memory ability in hypothyroid rats. The observed protective effects may have been mediated through regulation of oxidative stress and AChE activity.

Dysfunction in differential reward-punishment responsiveness in conduct disorder relates to severity of callous-unemotional traits but not irritability.

Conduct disorder (CD) has been associated with dysfunction in reinforcement-based decision-making. Two forms of affective traits that reflect the components of CD severity are callous-unemotional (CU; reduced guilt/empathy) traits and irritability. The form of the reinforcement-based decision-making dysfunction with respect to CD and CU traits remains debated and has not been examined with respect to irritability in cases with CD. The goals of the current study were to determine the extent of dysfunction in differential (reward v. punishment) responsiveness in CD, and CU traits and irritability in participants with CD. The study involved 178 adolescents [typically developing (TD; N = 77) and cases with CD (N = 101)]. Participants were scanned with fMRI during a passive avoidance task that required participants to learn to respond to (i.e. approach) stimuli that engender reward and refrain from responding to (i.e. passively avoid) stimuli that engender punishment. Adolescents with CD showed reduced differential reward-punishment responsiveness within the striatum relative to TD adolescents. CU traits, but not irritability, were associated with reduced differential reward-punishment responsiveness within the striatum, rostromedial, and lateral frontal cortices. The results suggest CD is associated with reduced differential reward-punishment responsiveness and the extent of this dysfunction in participants with CD is associated with the severity of CU traits but not irritability.

Prepulse inhibition can predict the motivational effects of cocaine in female mice exposed to maternal separation

The prepulse inhibition (PPI) of the startle response can identify the rodents that are more sensitive to the effects of cocaine. Mice with a lower PPI presented a higher vulnerability to the effects of cocaine and a higher susceptibility to developing a substance use disorder (SUD). Maternal separation with early weaning (MSEW) is a relevant animal model to induce motivational alterations throughout life. Nevertheless, only a few studies on females exist, even though they are more vulnerable to stress- and cocaine-related problems. Hence, the aim of the present study was to evaluate the ability of PPI to identify females with a greater vulnerability to the long-term consequences of early stress on the motivational effects of cocaine. Female mice underwent MSEW and were classified according to their high or low PPI. They were then assessed in the cocaine-induced locomotor sensitization test, the conditioned place preference paradigm or the operant self-administration paradigm. Additionally, they were also evaluated in the passive avoidance task, the tail-suspension and the splash tests. The results revealed that the females with lower PPI presented higher consequences of MSEW on the effects of cocaine and showed an increase in anhedonia-like behaviours. Our findings support that a PPI deficit could represent a biomarker of vulnerability to the effects of cocaine induced by MSEW.