Amelioration of cognition impairments in the valproic acid-induced animal model of autism by ciproxifan, a histamine H3-receptor antagonist.

Autism spectrum disorder is a neurodevelopmental disorder characterized by deficits in social communication and repetitive behavior. Many studies show that the number of cognitive impairmentscan be reduced by antagonists of the histamine H3 receptor (H3R). In this study, the effects of ciproxifan (CPX) (1 and 3 mg/kg, intraperitoneally) on cognitive impairments in rat pups exposed to valproic acid (VPA) (600 mg/kg, intraperitoneally) wereexamined on postnatal day 48-50 (PND 48-50) using marble-burying task (MBT), open field, novel object recognition (NOR), and Passive avoidance tasks. Famotidine (FAM) (10, 20, and 40 mg/kg, intraperitoneally) was also used to determine whether histaminergic neurotransmission exerts its procognitive effects via H2 receptors (H2Rs). Furthermore, a histological investigation was conducted to assess the degree of degeneration of hippocampal neurons. The results revealed that repetitive behaviors increased in VPA-exposed rat offspring in the MBT. In addition, VPA-exposed rat offspring exhibited more anxiety-like behaviors in the open field than saline-treated rats. It was found that VPA-exposed rat offspring showed memory deficits in NOR and Passive avoidance tasks. Our results indicated that 3 mg/kg CPX improved cognitive impairments induced by VPA, while 20 mg/kg FAM attenuated them. We concluded that 3 mg/kg CPX improved VPA-induced cognitive impairments through H3Rs. The histological assessment showed that the number of CA1 neurons decreased in the VPA-exposed rat offspring compared to the saline-exposed rat offspring, but this decrease was not significant. The histological assessment also revealed no significant differences in CA1 neurons in VPA-exposed rat offspring compared to saline-exposed rat offspring. However, CPX3 increased the number of CA1 neurons in the VPA + CPX3 group compared to the VPA + Saline group, but this increase was not significant. This study showed that rats prenatally exposed to VPA exhibit cognitive impairments in the MBT, open field, NOR, and Passive avoidance tests, which are ameliorated by CPX treatment on PND 48-50. In addition, morphological investigations showed that VPA treatment did not lead to neuronal degeneration in the CA1 subfield of the hippocampus in rat pups.

The anxiolytic effect of salicylic acid is mediated via the GABAergic system in the fear potentiated plus maze behavior in rats.

BACKGROUND: Salicylic acid (SA) is a natural phenolic compound in plants with many beneficial effects for humans. The anxiolytic effect of this compound has been reported in animal models, but its mechanism of action remains unclear. In this study, by using the fear potentiated plus maze test, we evaluated the effect of salicylic acid on the gene expression of the main form of GABA (gamma aminobutyric acid) synthesizing enzyme i.e., the enzyme glutamic acid decarboxylase 67 (GAD67) which is called GAD1, in the ventral subiculum of the hippocampus, one of the main brain structures, in anxiety circuits. Also, the hypnotic effect of Salicylic acid was evaluated. METHODS: Animals were divided into the solvent, (SA) and diazepam treated groups (n = 6). For evaluating the anxiolytic effect of Salicylic acid, animals were subjected to 2 h of isolation, before placing them in the elevated plus maze (EPM). Afterward, the ventral part of the hippocampus was removed for evaluating the change in GAD1 gene expression by the reverse transcription-quantitative polymerase chain reaction (RTqPCR) technique. The hypnotic effect of Salicylic acid was evaluated in the ketamine induced sleeping test. RESULTS: Salicylic acid at 10 and 30 (mg/kg) increased time spent and entries to the open arms in the (EPM) (p < 0.05). (RTqPCR) revealed that 30 mg/kg of Salicylic acid increased GAD1 gene expression (p < 0.001). Salicylic acid (30 and 300 mg/kg) also increased the duration of sleep, in ketamine induced sleeping test (p < 0.05). CONCLUSION: Our results showed that Salicylic acid has anxiolytic and hypnotic effects and it exerts its anxiolytic effect partly, via up the regulation of GAD1 in the ventral part of the hippocampus.

The effects of co-administration of pregabalin and vitamin E on neuropathic pain induced by partial sciatic nerve ligation in male rats.

OBJECTIVE: This study was performed to evaluate the effect of pregabalin co-administration with vitamin E in Partial Sciatic Nerve Ligation (PSNL)-induced neuropathic pain in rats. METHODS: Male Wistar rats were randomly allocated as control, sham, and PSNL groups (n = 8). PSNL was induced by tight ligation of the sciatic nerve with a copper wire. On day 14th, the PSNL and sham operated rats received either pregabalin (1, 3, and 30 mg/kg), vitamin E (100 and 200 mg/kg), or their combination intraperitoneally. An antinociceptive effect was evaluated as latency times and Maximum possible Effect Percent (%MPE) using tail-flick test. Locomotor activity was evaluated by open-field test before PSNL surgery and then twice at the 14th days (before and after drug injection). Ligated nerves were removed on the 28th days after surgery for histological examinations. RESULTS: The time course of latency times and %MPE showed significant decrease in PSNL but not in sham and control groups. Pregabalin (3 and 30 mg/kg) and vitamin E (100 and 200 mg/kg) caused significant increases in latency time in PSNL (but not sham) group compared to control group. Vitamin E 200 mg/kg increased significantly %MPE in PSNL group compared to sham group. In addition, the %MPE following combination treatment of pregabalin (30 mg/kg) and vitamin E (100 mg/kg) was significantly higher than both vitamin E and control group. Also combination of pregabalin with 100 mg/kg of vitamin E reversed Wallerian degeneration of sciatic nerve and the inflammatory responses to almost similar to sham group. Pregabalin and vitamin E did not affect locomotor activity. CONCLUSION: Our results showed antinociceptive effects of both vitamin E and pregabalin alone or in combination in PSNL rats and also neuroprotective properties without affecting locomotor activity.

Effects of Subacute Administration of Co-Trimoxazole and Folic Acid on Ovarian Tissue in Adult Female Rats.

BACKGROUND: Previous studies have reported the antifertility activities of sulfonamides. This study was designed to evaluate the effects of co-trimoxazole and its co-administration with folic acid on ovarian tissue in female rats. METHODS: A total of 54 rats were randomly divided into 9 groups (n=6). Group I served as the control and group II (vehicle) received saline. Other groups, III to IX, received co-trimoxazole (30, 60, and 120 mg/kg; i.p.), folic acid (1 mg/kg; i.p.) or their combination for 14 days, respectively. The oocytes were obtained from each group at the end of the 14th days and scored for maturational status as germinal vesicle (GV), metaphase I (MI), or metaphase II (MII). The number of primordial follicle (PrF), primary follicle (PF), and secondary follicle in formalin-fixed ovaries were counted under light microscopy. The data were analyzed by one-way ANOVA followed by post-hoc Dunnet test using SPSS statistical software (version 17.0). Results were considered statistically significant at P<0.05. RESULTS: Co-trimoxazole (60 and 120 mg/kg) treatment for 14 days caused a significant decrease in the number of GV (P=0.02, P<0.001), MI and MII (P=0.03, P<0.001), a significant increase in structural abnormalities, including PrF, PF and secondary follicle (P<0.001) as well as congestion, inflammation and necrosis of ovarian tissue compared to the vehicle group. Folic acid co-administration with co-trimoxazole reversed partially all these parameters compared to the co-trimoxazole group (P<0.001). CONCLUSION: The data showed the adverse effects of co-trimoxazole on the ovarian maturational status and tissue structure which was reversed partially by folic acid co-administration in rats.

Efficacy of Melissa officinalis in suppressing ventricular arrhythmias following ischemia-reperfusion of the heart: a comparison with amiodarone.

OBJECTIVE: We aimed to assess the influence of Melissa officinalis (lemon balm), a well-known herbal drug with numerous applications in traditional and modern medicine, on cardiac conduction and susceptibility to lethal ventricular arrhythmia. MATERIALS AND METHODS: Forty-two male Wistar rats were divided into a control group (CTL), an M. officinalis group that received the aqueous extract of M. officinalis L. intraperitoneally (i.p.) at dosages of 50, 100, 200 and 400 mg/ml/kg, respectively, and an amiodarone group (Amio group) that received 30 mg/ml/kg i.p. of amiodarone. Heart ischemia/reperfusion was induced by the ligation and release of the left anterior descending branch of the left coronary artery. RESULTS: There were no statistical differences between the groups in the basal heart rate and blood pressure. PR, corrected QT (QTc) and QRS intervals increased in the M. officinalis and Amio groups. PR and QTc were statistically significant only in the Amio group and QRS was significant only in the group receiving 400 mg of M. officinalis (M400 group) in comparison with the CTL group. During the reperfusion period, the decrease in ventricular fibrillations was statistically significant in all groups (except the M400 group) when compared with the CTL group. The score of arrhythmia severity also decreased, but was statistically significant only in the Amio group (p < 0.05 vs. CTL group). CONCLUSIONS: Our findings suggest that M. officinalis extract has a mild protective effect against reperfusion-induced lethal ventricular arrhythmias in rats.

Preparation and Evaluation of Preventive Effects of Inhalational and Intraperitoneal Injection of Myrtenol Loaded Nano-Niosomes on Lung Ischemia-Reperfusion Injury in Rats.

INTRODUCTION: Ischemia-reperfusion injury (IRI) is directly related to forming reactive oxygen species, endothelial cell injury, increased vascular permeability, and the activation of neutrophils and cytokines. Niosomes are nanocarriers and an essential part of drug delivery systems. We aimed to investigate the effects of myrtenol's inhaled and intraperitoneal niosomal form, compared to its simple form, on lung ischemia reperfusion injury (LIRI). MATERIAL AND METHOD: Wistar rats were divided into ten groups. Simple and niosomal forms of myrtenol were inhaled or intraperitoneally injected daily for one week prior to LIRI. We evaluated oxidative stress, apoptotic, and inflammatory indices, nitric oxide, inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS) and histopathological indices. RESULTS: Pretreatment with simple and niosomal forms of myrtenol significantly inhibited the indices of pulmonary edema, pro-inflammatory cytokines and proteins, oxidant agents, nitric oxide, iNOS, apoptotic proteins, congestion of capillaries, neutrophil infiltration, and bleeding in the alveoli. Furthermore, myrtenol increased anti-inflammatory cytokines, anti-oxidants agents, eNOS, anti-apoptotic proteins and the survival time of animals. The niosomal form of myrtenol showed a more ameliorative effect than its simple form. CONCLUSION: The results showed the superior protective effect of the inhalation of myrtenol niosomal form against LIRI compared to its simple form and systemic use.

Age-related changes in glutamic acid decarboxylase 1 gene expression in the medial prefrontal cortex and ventral hippocampus of fear-potentiated rats subjected to isolation stress.

Gamma-aminobutyric acid (GABA) plays a crucial role as a neurotransmitter in anxiety circuits, prominently in the hippocampus, amygdala, and prefrontal cortex. The synthesis of GABA in the central nervous system is primarily governed by glutamic acid decarboxylase 67 (GAD67). Aging is associated with emotional alterations, and isolation stress has been linked to increased anxiety. This study aimed to investigate the impact of aging on the gene expression of GAD67 (Gad1) in the medial prefrontal cortex (m PC) and ventral hippocampus (v Hip) of fear-potentiated rats subjected to isolation stress. To conduct the study, Wistar rats of different age groups 21-day-old (immature), 42-day-old (peri-adolescent), and 365-day-old (mature adult) were utilized. Each age level was categorized into four groups: 1) Control group - no pre-stressor, no maze, no drug, 2) Innate fear group (M) - no pre-stressor, maze, no drug, 3) Fear-potentiated group (IM) - isolation pre-stressor for 120 min, maze, no drug, and 4) Diazepam-treated group (IMD) - isolation pre-stressor for 120 min, maze, and diazepam administration. Following the tests, the (m PC) and (v Hip) regions were dissected, and Gad1 gene expression changes were assessed using Real-time PCR technique. The results revealed that, across all age groups, Gad1 expression in both the (m PC) and (v Hip) was significantly higher in the fear-potentiated groups (IM) compared to the control and innate fear (M) groups. Notably, in aged 365-day-old rats from the innate fear group (M), the expression of Gad1 in (v Hip) was also higher than that in the control group. Additionally, aged fear-potentiated rats exhibited elevated Gad1 gene expression in both structures compared to other age groups. These findings suggest that isolation stress before exposure to the elevated plus maze (EPM) can elevate Gad1 gene expression in both the (v Hip) and (m PC), and age may play a role in modulating its expression.

Ameliorating age-dependent effects of resveratrol on VPA-induced social impairments and anxiety-like behaviors in a rat model of neurodevelopmental disorder.

Although anxiety disorders, as well as difficulties in social interaction, are documented in children with autism spectrum disorder (ASD) as a neurodevelopmental disorder, the effectiveness of potential therapeutic procedures considering age and sex differences is under serious discussion. The present study aimed to investigate the effect of resveratrol (RSV) on anxiety-like behaviors and social interaction in juvenile and adult rats of both sex in a valproic acid (VPA)-induced autistic-like model. Prenatal exposure to VPA was associated with increased anxiety, also causing a significant reduction in social interaction in juvenile male subjects. Further administration of RSV attenuated VPA-induced anxiety symptoms in both sexes of adult animals and significantly increased the sociability index in male and female juvenile rats. Taken together, it can be concluded that treatment with RSV can attenuate some of the harsh effects of VPA. This treatment was especially effective on anxiety-like traits in adult subjects of both sexes regarding their performance in open field and EPM. We encourage future research to consider the sex and age-specific mechanisms behind the RSV treatment in the prenatal VPA model of autism.

The quality of prescription drug utilization five years after the 2003 Bam earthquake.

PURPOSE: Few reports considering drug use among earthquake survivors exist. The present study aims to examine the Bam earthquake's impact on prescribing patterns and drug use among residents five years post-disaster. DESIGN/METHODOLOGY/APPROACH: In this study, 297,104 prescriptions, issued by general practitioners in Bam city in 2008, were investigated for drugs/prescriptions, drug name, drug category, using WHO appropriate general practice prescribing indicators. FINDINGS: Mean drugs per prescription was 3.1. Drugs affecting the central nervous system were the most frequently used among Bam residents, representing 25.1 per cent, followed by antimicrobials, respiratory, cardiovascular and gastrointestinal tract drugs. Benzodiazepines were the most frequently used central nervous system drugs (15.8 per cent) followed by narcotic analgesics and tricyclic antidepressants. Penicillins (6.4 per cent) and cephalosporines (2.3 per cent) were the most frequently used antimicrobial drugs. ORIGINALITY/VALUE: Results emphasize increased drug use for psychological disturbances and the need for strategies to improve mental health among disaster survivors.

Effect of mebudipine on oxidative stress and lipid peroxidation in myocardial ischemic-reperfusion injury in male rat.

BACKGROUND: Myocardial infarction (MI) is the acute condition of necrosis in myocardium which occurs as a result of imbalance between coronary blood supply and myocardial demand. The resultant oxidative stress excess leads to worsen the condition. The aim of this study was to investigate the effect of mebudipine, a new dihydropyridine calcium channel blocker, on lipid peroxidation and antioxidant enzymes in myocardial ischemia-reperfusion injury. MATERIALS AND METHODS: Male Wistar rats (250-300 g) were randomly divided to Control-ischemic, mebudipine-ischemic and vehicle (ethanol-ischemic) groups. The hearts of anaesthetized rats were removed and mounted on Langendorff apparatus and perfused by Krebs-Henseleit solution under constant pressure of 75 mmHg at 37°C. Ischemic groups were received 30 min global ischemia and 120 min reperfusion and the mebudipine and vehicle groups received mebudipine (0.1 nM) or ethanol (0.01%)-enriched solution 25 min before global ischemia. Malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase levels of heart tissue samples were determined by commercial specific Kits. RESULTS: Mebudipine significantly reduced the MDA level (2.3 ± 0.07 nmol/mg protein) as the biochemical indicator of oxidative damage and lipid peroxidation product as compared with those of vehicle (4.6 ± 0.01 nmol/mg protein) and control groups (4.8 ± 0.09 nmol/mg protein). Furthermore, antioxidant enzymes SOD (0.1 ± 0.006 in drug vs. 0.037 ± 0.009 U/mg Protein in control), GPX (16 ± 0.009 in drug vs. 0.068 ± 0.01 U/mg Protein in control) and catalase activities (0.075 ± 0.006 in drug vs. 0.028 ± 0.002 U/mg Protein in control), activities of myocardium were significantly increased by mebudipine (P < 0.01). CONCLUSION: Our results showed that mebudipine may have antioxidant activity against myocardial ischemia-reperfusion injury since it decreased oxidative stress by enhancing the enzymatic antioxidant defense and inhibiting the lipid peroxidation. Thus, this drug can reduce the intensity of cardiac ischemic insults.

Histamine H3 receptor antagonist, ciproxifan, alleviates cognition and synaptic plasticity alterations in a valproic acid-induced animal model of autism.

RATIONALE: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication and cognitive behaviors. Histamine H3 receptor (H3R) antagonists are considered as therapeutic factors for treating cognitive impairments. OBJECTIVES: The aim of the present study was to evaluate the effects of the H3R antagonist, ciproxifan (CPX), on cognition impairment especially, spatial learning memory, and synaptic plasticity in the CA1 region of the hippocampus in autistic rats. METHODS: Pregnant rats were injected with either valproic acid (VPA) (600 mg/kg, i.p.) or saline on an embryonic day 12.5 (E12.5). The effects of the H3R antagonist, ciproxifan (CPX) (1, 3 mg/kg, i.p.), were investigated on learning and memory in VPA-exposed rat pups and saline-exposed rat pups using Morris water maze (MWM) and social interaction tasks. The H2R antagonist, famotidine (FAM) (10, 20, 40 mg/kg, i.p.), was used to determine whether brain histaminergic neurotransmission exerted its procognitive effects through the H2R. In addition, synaptic reinforcement was evaluated by in vivo field potential recording. RESULTS: The results showed that VPA-exposed rat pups had significantly lower sociability and social memory performance compared to the saline rats. VPA-exposed rat pups exhibited learning and memory impairments in the MWM task. In addition, VPA caused suppression of long-term potentiation (LTP) in the CA1 area of the hippocampus. Our results demonstrated that CPX 3 mg/kg improved VPA-induced cognitive impairments and FAM 20 mg/kg attenuated cognitive behaviors as well as electrophysiological properties. CONCLUSIONS: CPX 3 mg/kg improved VPA-induced impairments of LTP as well as learning and memory deficits through H2R.

The different role of G-protein-coupled receptor 30 (GPR30) in the interaction effects of marijuana and estradiol on spatial learning and memory at different ages.

Some studies suggest that the effect of cannabis on behavior performance depends on the presence of ovarian hormones and the age of use initiation. Estradiol is the main ovarian hormone that can interact with cannabinoids. It has been suggested that cannabinoids exert some of their effects directly through estrogen receptors (ERs). A novel G-protein-coupled receptor (GPR30) was described as mediating estrogen signaling in various cell lines. Since there are few studies on the interaction of cannabis and ovarian hormones on cognitive behaviors, so, this study evaluated the role of GPR30 in the effects of marijuana (M) and estrogen, alone and in combination, on spatial learning and memory of young (non-ovarian(OVX)) and old female rats. Young (5-7 months) and old (22-24 months) female rats received an intraperitoneal injection (i.p) of 17ß-estradiol (E2), G1 (GPR30 agonist), and G15 (GPR30 antagonist) every four days, and M (every day), either alone or in combination, for 28 days. One hour after the last injection, the Morris water maze (MWM) test was conducted to evaluate of spatial learning and memory. Moreover, hippocampal BDNF level was assessed by the ELISA method. The results showed a positive effect of M on spatial learning in both young and old rats, however, E2 showed beneficial effects on the memory of young, but not old rats. Our results showed that GPR30 does not have any role in the interaction effects of M and E2 in young rats. Although both E2 and M alone showed positive effects on spatial learning and memory in old rats, however, our results showed a negative interaction between marijuana and E2 combined effects on spatial learning and memory in old female rats which is mediated by GPR30. Our results showed that the effects of GPR30 on spatial learning and memory is age dependent. Furthermore, this study showed that hippocampal BDNF does not have any role in the interaction effects of M and E2 on spatial learning and memory in young and old rats.

Choline chloride modulates learning, memory, and synaptic plasticity impairments in maternally separated adolescent male rats.

Maternal separation (MS) is a model to induce permanent alternations in the central nervous system (CNS) and is associated with increased levels of anxiety and cognitive deficiencies. Since methyl donor choline (Ch) has been shown to play a significant role in learning and memory and enhance synaptic plasticity, the authors hypothesized that Ch may attenuate MS-induced impairments in synaptic plasticity and cognitive performance. Rat pups underwent an MS protocol for 180 min/day from postnatal day (PND) 1 to 21. Ch was administered subcutaneously (100 mg/kg, 21 days) to the choline chloride and MS + choline chloride groups from PND 29 to 49. Anxiety-like behaviour, recognition memory, and spatial and passive avoidance learning and memory were measured in the adolescent rats. In addition, evoked field excitatory postsynaptic potentials (fEPSP) were recorded from the CA1 region of the hippocampus. MS induced higher anxiety-like behaviour in the animals. It also impaired learning and memory. However, MS had no effect on locomotor activity. Subcutaneous administration of Ch attenuated MS-induced cognitive deficits and enhanced the learning and memory of MS rats. Ch also decreased anxiety-like behaviour in the open-field test. The present results showed that long-term potentiation (LTP) was induced in all groups except MS and MS + saline animals. However, Ch injection induced LTP and had maintenance in MS + choline chloride, but it was not statistically significant compared with the MS group. In summary, the present findings indicate that MS can interfere with normal animal's cognition and subcutaneous of Ch may be considered an appropriate therapeutic strategy for promoting cognitive dysfunctions in MS animals.

Marijuana and ß-estradiol interactions on spatial learning and memory in young female rats: Lack of role of the G protein-coupled estrogen receptor (GPR30).

It has been shown that 17ß-estradiol (E2) hormone is an essential biological factor for increasing the sensitivity of women to drug abuse. Recent studies have shown a potential overlap between the molecular pathways of cannabinoids and ovarian hormones. The current study evaluated the interference between the marijuana and E2 effect on spatial learning and memory and the role of the G protein-coupled estrogen receptor (GPR30) in young female rats. The animals were separated into two main groups: intact-ovary and ovariectomized (OVX) rats. The latter group received intraperitoneal injections of E2, G-1 (GPR30 agonist), G-15 (GPR30 antagonist), marijuana, and different combinations of these substances for 28 days. Spatial learning and memory were evaluated by the Morris water maze (MWM) test. We also assessed the BDNF (brain-derived neurotrophic factor) concentration and the hippocampal level of GPR30. The results showed a significant reduction of spatial learning and memory in OVX rats compared to intact-ovary rats, which were restored by E2 replacement. Moreover, treatment with G-1 mimicked E2 effects on spatial learning and memory. Marijuana impaired spatial learning and memory in intact-ovary rats, while improved in OVX rats. We also found that treatment with M + E2 induced significant impairment in spatial learning and memory; however, treatment with M + G1 and M + G15 + E2 showed no significant difference. No significant differences in BDNF expression were observed in experimental groups. These results suggest that marijuana and E2 interact in their effect on spatial learning and memory in young female rats, but GPR30 seems to play no role in this interaction.

The intracerebroventricular (ICV) administration of W-7, a calmodulin inhibitor, attenuates the development of morphine tolerance in rats.

The present study was performed to determine the effect of intracerebroventricular (ICV) administration of W-7, a specific calmodulin inhibitor, on the development of tolerance to antinociceptive effect morphine administration. This study was carried out on male wistar rats, weighing 200-250 g. Morphine was administered daily (15 mg/kg for 8 days). The threshold to thermal nociceptive stimuli was measured by tail-flick test. W-7 (0.25, 0.5 and 1 micromol/rat) was injected through ICV. Maximal possible effect percentage (MPE %) was considered as analgesia index. Our result showed that chronic morphine exposure induced tolerance to its antinociceptive effect and administration of W-7 (0.5 and 1 micromol/rat) decreased the development of tolerance to it. In conclusion these data showed that chronic injection of W-7 inhibited the development of morphine tolerance which indicates that calmodulin and its dependent pathways may play a role in the morphine tolerance processes.

Prenatal Pregabalin Exposure Alters Postnatal Pain Sensitivity and Some Behavioral Responses in Adult Offspring Rats.

BACKGROUND: Prenatal antiepileptic drug exposure could demonstrate both congenital malformations and behavioral impairments in offspring. OBJECTIVE: This study was performed to assess the effects of prenatal exposure to pregabalin (PGB) on pain response, anxiety, motor activity and some behavior of adult offspring rats. METHODS: Pregnant Wistar rats received PGB (7.5, 15 and 30 mg/kg/ip) during embryonic days 9.5- 15.5. The pain response, anxiety-like behaviors, locomotor activity, motor balance and coordination and anhedonia of adult offspring were examined by tail-flick and hot plate test, open field test, elevated plus maze (EPM), beam balance test and sucrose preference test in their 60th day of life, respectively. RESULTS: Prenatal exposure to PGB revealed significant dose-dependent reduction in pain sensitivity (increase in pain latency response) in the hot plate test, especially in females, while anxiety-like behavior assessed in EPM and open field significantly reduced in males. In the open field, locomotor activity reduced significantly after exposure to PGB 30 mg/kg and motor coordination decreased dose-dependently, especially in males. Anhedonia, as an indication of sucrose preference or pleasure response, was not changed. CONCLUSION: These findings suggest that prenatal PGB exposure could be associated with significant changes in pain response, anxiety, locomotor activity and coordination in adult offspring rats.

Prenatal pregabalin is associated with sex-dependent alterations in some behavioral parameters in valproic acid-induced autism in rat offspring.

This study was performed to evaluate the effects of prenatal exposure to pregabalin (PGB) on behavioral changes of rat offspring in an animal model of valproic acid (VPA)-induced autism-like symptoms. Pregnant rats received VPA (600 mg/kg/i.p.) once at 12.5 gestational days for autism-like symptom induction in offspring. After the delivery single male and single female offspring from each mother were randomly selected for behavioral test (anxiety, pain response, pleasure, and motor function) at 60th day adulthood (n = 7). Offspring received prenatal PGB (15 & 30 mg/kg/i.p.) during gestational days 9.5 to 15.5 either alone or in combination with VPA (PGB15, PGB30, PGB15 + VPA, and PGB30 + VPA). Control offspring received normal saline during the same period. The result showed that prenatal VPA exposure was associated with autism-like behaviors in rat offspring. PGB treatment during the gestational period revealed significant reduction in sucrose preference test and anxiety in elevated plus maze and open field test in offspring. Also, PGB treatments exhibited a dose-dependent increase in pain threshold in prenatally VPA exposed rats in tail-flick and hot plate test. Also, there was a sex-related significant impairment in motor function in beam balance and open field test, and male rats were affected more than females. However, no significant sex differences in sucrose preference and pain sensitivity were observed in prenatal PGB-treated rat offspring. In conclusion, prenatal exposure to VPA increased the risk of autism-like behaviors in the offspring rats, and PGB treatment during the gestational period was associated with some beneficial effects, including anxiety reduction and motor impairment in autism-like symptoms in rat offspring.

The effects of alone and combination tamoxifen, raloxifene and estrogen on lipid profile and atherogenic index of ovariectomized type 2 diabetic rats.

INTRODUCTION: The cardiovascular dysfunctions in postmenopausal diabetic women increase relative to premenopausal women. In this study we evaluated protective effects of selective estrogen receptor modulators (SERMs), alone and in combination with estrogen (E2) in diabetic rats with menopausal model. METHODS: Female rats groups are included: Sham-Control (CTL), Diabetes (DM), and ovariectomized rats divided to DM, DM + Vehicle (Veh), DM + Tamoxifen (TAM), DM + Raloxifene (RLX), DM + Veh + Oil, DM + Oil, DM + E2, DM + E2 + Veh, DM + TAM + E2, DM + RLX + E2. DM was induced by high fat diet and followed by a light dose of streptozotocin. SERMs and E2 were administrated for four weeks after establishment of type 2 diabetes mellitus (T2DM). RESULTS: Our results depicts that, T2DM increased triglyceride, total cholesterol, low-density lipoprotein, and fasting blood glucose. Also it decreased high-density lipoprotein, which had exacerbated by ovariectomy. These changes were reversed by using SERMs, E2 and SERMs+E2, although combinatory treatment is more effective than individual treatment. Additionally the cardiovascular indices were also significantly disrupted in ovariectomized diabetic rats, but all therapeutic groups equally improved these disturbances, whereas in TAM + E2 group, the atherogenic index was more decreased than TAM group. CONCLUSION: We concluded that SERMs treatment, individual or in combination with E2 in menopausal model can be efficient substitute for E2 replacement therapy. This study suggests cellular mechanisms of SERMs in future studies.

What are the consequences of Methylphenidate exposure for maternally separated rats?

Methylphenidate (MPH) abuse is prevalent among youth. Drug abuse results in pain perception. We sought to investigate whether Maternal separation (MS) prone to MPH addiction. The next question was whether MPH abusers with MS differ in pain perception. We investigated the impact of MS on addiction and drug reward as well as pain perception following 5 days of MPH injection in males and females rats. Initially, rats underwent MS protocol of 3 hr daily for 21 days. Conditioned place preference (CPP) test was an attempt to investigate whether MS rats experience more reward with MPH. The protocol consisted of 10 min habituation on Day 1, conditioning on Day 2-Day 6 (5 mg per kg MPH injection in drug compartment and saline in saline compartment with 4 hr gap between injections) and 10 min test on Day 7. Furthermore, using another group, differences in pain perception were investigated after 5 days of daily MPH injection with 5 mg per kg. Sensory pain sensitivity was tested on PND 39 using tail flick and hotplate in MS and control groups with and without MPH exposure. Results indicated that female rats are equally prone to addiction in CPP. On the other hand, MS males experience a higher reward in CPP. In tail flick test, female MS rats exposed to MPH show a lower sensory pain threshold with similar MPH exposure. Experiencing MPH similarly declined hotplate pain perception in MS and controls in the females. Males, on the other hand, did not show any difference in sensory pain tests. According to results one can argue MS is detrimental. MS males experience more reward with MPH, females are equally addiction prone and MS females experience more pain in tail flick. On the other hand pain threshold can decline in hotplate test for both control and MS females that received MPH.

Sex dependent alterations of resveratrol on social behaviors and nociceptive reactivity in VPA-induced autistic-like model in rats.

INTRODUCTION: The present study was designed to clarify the effects of resveratrol (RSV) on social behavioral alterations and nociceptive reactivity in valproic acid (VPA)-induced autistic-like model in female and male rats. METHODS: Pregnant Wistar rats were randomly divided in five groups. Animals received saline, DMSO, VPA, RSV and RSV + VPA. VPA was administered (600 mg/kg, i. p.) on embryonic day 12.5 (E12.5) and pretreatment by resveratrol (3.6 mg/kg, s. c.) was applied on E6.5 until E18.5. All offspring were weaned on postnatal day 21 and the experiments were done in male and female rats on day 60. Social interaction, hot plate and tail flick tests were set out to assess social deficits and pain threshold, respectively. Sociability index (SI), Social novelty index (SNI) and latency time were calculated as the standard indices of social behaviors and pain threshold, respectively. RESULTS: The results indicated that systemic intraperitoneal administration of VPA (600 mg/kg) significantly decreased SI and SNI in social interaction test (SIT) especially in male rats, indicating the social impairments caused by VPA. RSV (3.6 mg/kg, s. c.) reversed VPA-induced social deficits in male rats, but not in female group. VPA administration resulted in significant increase in latency time in the hot plate and tail flick tests in male rats, whereas it had no such dramatic effect in females. RSV administration in combination with VPA had no significant effect on latency time compared to the valproic acid group in male rats. It is important to note that RSV by itself had no significant effect on SI, SNI and latency time in female and male rats. CONCLUSION: It can be concluded that valproic acid produces autistic-like behaviors and increases pain threshold in male rats which may be ameliorated at least in part by resveratrol administration. Further studies are needed to elucidate the molecular mechanisms involved in valproic acid and resveratrol-induced effects.