Vortioxetine improved schizophrenia-like behavioral deficits in a Poly I:C-induced maternal immune activation model of schizophrenia in rats.

BACKGROUND: Several studies provide clear evidence that exposure to various infections during pregnancy are linked with an increased risk for schizophrenia. In preclinical studies, administration of polyinosinic-polycytidylic acid (Poly I:C) in pregnant rodents can induce maternal immune activation leading to impairments in brain function in the offspring. OBJECTIVES: The aim of this study was to investigate the effect of vortioxetine, a multimodal selective serotonin reuptake inhibitor (SSRI), in the pathophysiology of Poly I:C-induced schizophrenia-like model in rats. METHODS: For this purpose, Poly I:C (8 mg/kg, ip) was injected into pregnant animals 14 days after mating, and tail blood was taken for determination of IL-6 levels after 2 h. At postnatal days 83-86, behavioral tests were performed. RESULTS: Our results revealed that Poly I:C caused impairments in prepulse inhibition, novel object recognition, social interaction, and open-field tests. Chronic administration of vortioxetine (2.5, 5, and 10 mg/kg, ip, postnatal days 69-83) caused significant improvements in these deficits. CONCLUSION: Overall, our findings indicate that vortioxetine may provide new therapeutic approaches for the treatment of schizophrenia. We think that increased serotonergic activity in frontal brain regions may provide the ameliorative effect of vortioxetine, especially on negative and cognitive symptoms. Therefore, it will be useful to determine the efficacy of vortioxetine with combined drugs with further studies.

The effect of magnesium sulfate on memory and anxiety-like behavior in a rat model: an investigation of its neuronal molecular mechanisms.

BACKGROUND: Anxiety is an adaptive response to potentially threatening conditions. Excessive and uncontrolled anxiety responses become nonadaptive and cause anxiety disorders. To better understand the anxiety-modulating effects of Mg sulfate, behavioral test batteries in the assessment of anxiety and learning and memory functions were performed simultaneously over a time period. This study also examines the effects of Mg sulfate compared to diazepam, an anxiolytic drug with amnestic effects on anxiety-like behavior, as well as possible oxidative-nitrosative stress and hippocampal changes in male rats exposed to predator odor. METHODS: Young adult Sprague-Dawley male rats were used. The rats were assessed using a comprehensive neurobehavioral test battery consisting of novel object recognition, open field, and successive alleys tasks. Anxiety was induced by cat odor, and diazepam and Mg were used as study drugs. Of the frontal cortex and hippocampus, the state of total oxidant and antioxidant and NO levels and histological examination of hippocampal CA1, CA2, CA3, and DG regions were performed. RESULTS: Diazepam- and Mg-treated rats showed an improvement in anxiety-related behavior to predator odors. Furthermore, Mg treatment alleviated some of the increasing oxidative stress in the frontal cortex and hippocampus of rats, while diazepam treatment in particular enhanced hippocampal oxidant and antioxidant activity. In addition, brain NO increase induced by animal odor exposure or diazepam treatment was ameliorated by Mg administration. CONCLUSIONS: Overall, our work suggests that Mg had a partial anxiolytic effect on anxiety-like behaviors, although not as much as diazepam, and this effect varied depending on the dose. Mg treatment might counteract increased oxidative stress and elevated NO levels in the brain.

The long-lasting effects of aceclofenac, a COX-2 inhibitor, in a Poly I:C-Induced maternal immune activation model of schizophrenia in rats.

It is well established that rats exposed to inflammation during pregnancy or the perinatal period have an increased chance of developing schizophrenia-like symptoms and behaviors, and people with schizophrenia also have raised levels of inflammatory markers. Therefore, there is evidence supporting the idea that anti-inflammatory drugs may have therapeutic benefits. Aceclofenac is a nonsteroidal anti-inflammatory drug that has anti-inflammatory properties and is used clinically to treat inflammatory and painful processes such as osteoarthritis and rheumatoid arthritis, making it a potential candidate for preventive or adjunctive therapy in schizophrenia. This study therefore examined the effect of aceclofenac in a maternal immune activation model of schizophrenia, in which polyinosinic-polycytidylic acid (Poly I:C) (8 mg/kg, i.p.) was administered to pregnant rat dams. Young female rat pups received daily aceclofenac (5, 10, and 20 mg/kg, i.p., n = 10) between postnatal day 56 and 76. The effects of aceclofenac were compared with assessment of behavioral tests and ELISA results. During the postnatal days (PNDs) 73-76, behavioral tests were conducted in rats, and on PND 76, ELISA tests were performed to examine the changes in Tumor necrosis factor alpha (TNF-α), Interleukin-1ß (IL-1ß), Brain-derived neurotrophic factor (BDNF), and nestin levels. Aceclofenac treatment reversed deficits in prepulse inhibition, novel object recognition, social interaction, and locomotor activity tests. In addition, aceclofenac administration decreased TNF-α and IL-1ß expression in the prefrontal cortex and hippocampus. In contrast, BDNF and nestin levels did not change significantly during treatment with aceclofenac. Taken together, these results suggest that aceclofenac may be an alternative therapeutic adjunctive strategy to improve the clinical expression of schizophrenia in the further studies.

Group I mGluRs positive allosteric modulators improved schizophrenia-related behavioral and molecular deficits in the Poly I:C rat model.

RATIONALE: Maternal polyinosinic-polycytidylic acid (Poly I:C) exposure leads to an increase in various proinflammatory cytokines and causes schizophrenia-like symptoms in offspring. In recent years, group I metabotropic glutamate receptors (mGluRs) have emerged as a potential target in the pathophysiology of schizophrenia. OBJECTIVES: The aim of our study was to investigate the behavioral and molecular changes by using the mGlu1 receptor positive allosteric modulator (PAM) agent RO 67-7476, and the negative allosteric modulator (NAM) agent JNJ 16259685 and the mGlu5 receptor PAM agent VU-29, and NAM agent fenobam in the Poly I:C-induced schizophrenia model in rats. METHODS: Female Wistar albino rats were treated with Poly I:C on day 14 of gestation after mating. On the postnatal day (PND) 34-35, 56-57 and 83-84, behavioral tests were performed in the male offspring. On the PND84, brain tissue was collected and the level of proinflammatory cytokines was determined by ELISA method. RESULTS: Poly I:C caused impairments in all behavioral tests and increased the levels of proinflammatory cytokines. While PAM agents caused significant improvements in prepulse inhibition (PPI), novel object recognition (NOR), spontaneous alternation and reference memory tests, they brought the levels of proinflammatory cytokines closer to the control group. NAM agents were ineffective on behavioral tests. It was observed that PAM agents significantly improved Poly I:C-induced disruption in behavioral and molecular analyses. CONCLUSIONS: These results suggest that PAM agents, particularly the mGlu5 receptor VU-29, are also promising and could be a potential target in schizophrenia.

Investigation of antinociceptive effects of vitamin D and EB1089 in rats.

OBJECTIVES: The aim of this study is to investigate the effect of vitamin D on pain threshold in rats. In addition, to examine, whether EB1089, which is a vitamin D receptor agonist, can contribute to this mechanism by increasing the effects of the receptor. METHODS: In the study, 24 male Wistar Albino rats of 3 months, an average of 240-260 g, were used. The animals were randomly divided into three groups, eight animals in each group. Groups; control, vitamin D (10 µg/kg), and EB1089 (10 µg/kg). Tail flick and hot plate tests were used to evaluate the antinociceptive effect. Measurements were taken at 0 min before drug administration and at 30, 60, and 90 min after drug administration and times were recorded in seconds. Serotonin levels were also analyzed by ELISA method in plasma obtained from intracardiac blood samples taken at the end of the experiment. RESULTS: Vitamin D and EB1089 significantly increased the time to endure pain in the tail flick test compared to the control group (p<0.05). In the hot plate test, EB1089 group significantly extended the pain threshold compared to the control group (p<0.05), while the vitamin D group did not create a significant difference, although it had a higher latency than the control group (p>0.05). There was no significant difference between the groups in terms of serotonin levels (p>0.05). CONCLUSION: As a result of our study, the administration of vitamin D and EB1089 increased the pain threshold in animals and increased pain resistance.

Effects of post-learning REM sleep deprivation on hippocampal plasticity-related genes and microRNA in mice.

Sleep is essential for memory consolidation that stabilizes a memory trace. Memory consolidation includes waves of new gene expression and protein synthesis. Recently, microRNAs (miRNAs) have emerged as critical regulators of memory processes. Previous studies demonstrated that rapid eye movement (REM) sleep deprivation (REM SD) during specific time windows after training in the Morris water maze (MWM) task impairs memory consolidation. Here, we showed that the post-learning REM sleep, extending from 3 to 6 h after last training, is critical for spatial learning in the MWM task. Further, we found that the REM SD after training significantly changes the hippocampal expression of brain-derived neurotrophic factor (BDNF) mRNA; however, it causes minimal difference in the hippocampal expressions of calcium-calmodulin-dependent protein kinase II (CAMKII) and cAMP response-element-binding (CREB). In addition, it considerably affected the hippocampal expressions of miR-132, miR-182, and miR-124. In conclusion, after the MWM task, the post-learning REM sleep during specific time windows can modulate spatial memory consolidation, and its deprivation can impact the hippocampal transcriptional processes including memory-related miRNAs and mRNAs.

Effects of age and anxiety on learning and memory.

This study aims to investigate the effects of age and anxiety on behavior, learning and memory in rats. Before and after the anxiety and learning tests, locomotor activity, exploratory activity and autonomic functions of the rats were tested in open field area. At the beginning and at the end of behavior tests, urines were collected so as to determine 5-hydroxyindolaceticacid (5-HIAA) levels. Following these tests, rats were anesthetized and their serum corticosteron (CORT) levels were analyzed. After anxiety, except for defecation, all parameters in open field such as line crossing, rearing, sitting and number of grooming were decreased in both young and aged animals. 5-Hydroxyindolaceticacid levels were decreased and serum CORT levels were increased, it is supported that especially the aged rats were much more affected from anxiety compared to the young ones. Elevated T-maze results show that emotional learning did not change while conditioned performance was tested in the closed arm and unconditioned performance was tested in the open arm. Nevertheless, it is observed that aging leaded to extensions in avoidance responses and thus caused difficulty in learning. In water maze test, rats showed higher performance in reaching the platform in repetitive trials; this demonstrates that they have learned by environmental cues. Experimental group had not better performance in reaching the platform according to control group, so this supports that anxiety affects spatial learning. As a conclusion, it could be stated that especially in aged rats, anxiety that is created by elevated T-maze and cat odor and supported with 5-hydroxyindoleacetic acid and serum corticosterone, causes difficulty in emotional and spatial learning.

Effect of hyperglycemia on electrodermal activity in diabetic rats.

This study investigated the relationship between hyperglycemia and electrodermal activity (EDA) parameters in streptozotocin (STZ) induced diabetic rats. The article evaluates the course of development of neurophysiological alterations in the peripheral nervous system in diabetic rats through EDA. Rats were made diabetic using a moderate dose of STZ (DI) and high dose (DII). The placebo group (P) was injected with physiological saline. EDA was recorded 1 h before the injection (beginning, 0, day), 1st day (one day after the injection) and 10th day. Skin conductance level (SCL) was lower in DII than P on the 1st and the 10th days. The SCL and SC fluctuation rate (SCFr) of DI were significantly lower on the 10th day compared to their first record. SC response rate (SCRr) was lower on the 10th day compared to the 1st day, in the DI. In the DI, SCL, SC fluctuation rate (SCFr) and SC response rate (SCRr) were lower on the 10th day compared to the 1st day. The DII was statistically higher in electrodermal non-responsiveness compared to other groups on the 1st day. The results obtained show that hyperglycemia affects the peripheral nervous system, and EDA parameters are affected by blood glucose level. It is suggested that EDA is a simple and non-invasive electrophysiological method in early diagnosis of diabetic neuropathy.

Ketamine reduces lidocaine-induced seizures in mice.

Systemic toxic reactions to local anesthetics are brought about by absolute overdosage, and, most commonly, inadvertent intravascular injections. The anti-convulsant action of ketamine has been studied. However, the effect of ketamine on lidocaine-induced convulsions has not been reported. This study investigated the effect of ketamine on lidocaine-induced seizures in mice. Mice (32-41 g) were divided into 2 groups, 15 in each group, and were pretreated with intraperitoneal normal saline solution or intraperitenoeal (ip) ketamine before lidocaine. Group 1 (N = 15) received 75 mg kg ip lidocaine; Group 2 (N = 15) received 20 mg kg ketamin ip; 5 min later 75 mg kg lidokaine ip were applied. Clinical features, incidences, latencies, durations, and mortality rate of convulsions were recorded. After 75 mg kg lidocaine injection, ataxia, loss of righting reflex, and generalized tonic-clonic convulsions were seen within 2-5 min in Group 1. Generalized tonic-clonic convulsions were seen in 8 mice and deep sedation was seen in 7 mice in Group 2 (p < .05). Generalized status epilepticus occurred in one mouse in both groups. Three mice from Group l and one mouse from Group 2 died during convulsions. There were no differences between the two groups with regard to the onset and duration of seizures (p > .05). It was concluded that ketamine significantly prevented lidocaine-induced generalized tonic-clonic seizures; on the other hand, the lethality of lidocaine was least reduced by ketamine.

Effects of pentylenetetrazole-induced status epilepticus on behavior, emotional memory and learning in immature rats.

Status epilepticus (SE) can be harmful to the developing brain. Our knowledge of the emotional and behavioral consequences of generalized SE in developing animals remains limited. Therefore, we investigated the short- and long-term effects of pentylenetetrazole (PTZ)-induced SE on emotional memory and learning and behavioral parameters in immature rats. SE was induced in 16- to 20-day-old rats (P16-P20) using intraperitoneal injections of PTZ (n=21); control rats received saline (n=10). All animals were tested using an elevated T-maze and open-field test 2, 14, 30, and 180 days after SE, to evaluate emotional memory and learning and behavior. Anxiety levels decreased 2 and 14 days after SE, and conditioned learning of PTZ-treated immature rats was better than that of the control rats. These results indicate that a decreased anxiety level facilitates conditioned learning. Behavioral changes are transient, and no emotional memory or learning deficits occur following PTZ-induced SE in immature rats.

Sex-related differences in time estimation and the role of expectancy.

In this study, using auditory sequences, the authors designed an examination with three phases of stimulus-driven attention that is based on the possibility that involuntarily time shifts of attention are caused by nonunique stimulus properties. The purpose was to investigate whether attending and temporal expectancies are influenced by stimulus's properties and by sex. In each phase, an auditory stimulus train was presented, and the participant was asked to tap rhythmically in order to anticipate every fifth stimulus (or, in the third phase, the lack of it). The time between button pressing and stimulus onset was measured using a computer. Time estimation was accepted as a false response if the subject responded before 150 ms or 150 ms later from onset stimulus time. Error numbers were greater in Phase 3 and there was no significant difference between the male and female subjects for any of the phases when error numbers were compared. On the other hand, males pressed the button more accurately than females. Time estimation performance was affected by sex and expectancy-related motor responses are very important for time estimation.

The effects of pentylenetetrazole-induced status epilepticus on behavior, emotional memory, and learning in rats.

Status epilepticus (SE) can cause spatial learning, memory, and behavioral deficits; however, little information is available, especially regarding the effects of such seizures on emotional memory and learning functions. We investigated the effects of SE on emotional memory, learning, and behavior in mature rats over short and long periods. SE was induced in 50- to 60-day-old rats (P50-P60) using intraperitoneal injections of pentylenetetrazole (PTZ, n = 20); control rats received saline (n = 10). All animals were tested with elevated T-maze and open-field tests on the 1st, 7th, 14th, and 180th days after SE to evaluate emotional memory, learning, and behavior. The number of fecal boli increased, and one-way escape latency was long in a short period after SE. PTZ-induced SE causes transient memory deficits, which is related to unconditioned fear, but it did not cause any persistent abnormalities of behavior, emotional memory, and learning in mature rats.

Effects of cigarette smoking on cognitive processing.

Several previous studies have reported that cigarette smoking enhances performance of cognitive processing. These enhancements are generally attributed to the pharmacological effects of nicotine, while there is some debate whether the effects of smoking/nicotine are a result of recovery from abstinence. Evoked potentials (EPs) and event related potentials (ERPs) of the brain have been applied as an index of information processing in a wide variety of normal and cognitive impaired subjects. This study was carried out on 20 healthy students (23 +/- 2.3 years old) from the medical faculty of City University. Study population comprised ten chronic cigarette smokers consuming an average of 14 +/- 4.2 cigarettes per day, with a history of smoking for more than one year. Ten non -smokers served as control. Standard oddball paradigm was presented, and EEG activity was recorded at the Fz, Cz, Pz electrode sites. Twenty responses to target stimuli were averaged at each location. N1, P2, N2, and P300 components were evaluated in these recordings. Amplitudes were measured relative to prestimulus baseline, and peak latencies were defined as the time point of maximum amplitude. It was found that there were no significant differences between either N1, P2, N2, P300 amplitudes or peak latency values of cigarette smokers and non smokers. As a result, chronic cigarette smoking generally does not improve cognitive processing.

Evaluation of auditory evoked potentials from the inferior colliculus in rat.

This study aimed to investigate the usefulness of auditory evoked potentials (AEPs) in rats. To this end, N1, P2 latencies, and the N1-P2 amplitude of responses to different acoustic stimuli from rats, which were implanted with permanent electrodes in the inferior colliculus (IC), were evaluated and used to demonstrate the frequency characteristics of IC region. Permanent electrodes were implanted in IC regions of 7 male albino rats by the stereotaxic method. The animals were exposed to five tones series of stimuli (1000 Hz, 2000 Hz, 4000 Hz, 6000 Hz, and 8000 Hz tones with 1500 ms interstimulus intervals) of 70 dB with a duration of 1000 ms. AEPs) were recorded and analyzed with the Brain-Data Acquisition system. There were no statistically significant differences in N1, P2 latencies, and the N1-P2 amplitude of AEPs from IC regions of rats as a result of changes in the frequency of stimulus. It was determined that the dominant frequency activity of the IC to acoustic stimulus was theta-alpha band, with theta as the peak frequency.