A single dose of clothianidin exposure induces varying sex-specific behavioral changes in adulthood depending on the developmental stage of its administration.

Clothianidin (CLO), a neonicotinoid that is widely used in forests and agricultural areas, was recently reported to cause toxicity in mammals. Although sensitivity to chemicals varies between sexes and developmental stages, studies that comprehensively evaluate both males and females are limited. Therefore, in this study we utilized murine models to compare the sex-specific differences in behavioral effects following CLO exposure at different developmental stages. We orally administered CLO to male and female mice as a single high-dose solution (80 mg/kg) during the postnatal period (2-week-old), adolescence (6-week-old), or maturity (10-week-old), and subsequently evaluated higher brain function. The behavioral battery test consisted of open field, light/dark transition, and contextual/cued fear conditioning tests conducted at three and seven months of age. After the behavioral test, the brains were dissected and prepared for immunohistochemical staining. We observed behavioral abnormalities in anxiety, spatial memory, and cued memory only in female mice. Moreover, the immunohistochemical analysis showed a reduction in astrocytes within the hippocampus of female mice with behavioral abnormalities. The behavioral abnormalities observed in female CLO-treated mice were consistent with the typical behavioral abnormalities associated with hippocampal astrocyte dysfunction. It is therefore possible that the CLO-induced behavioral abnormalities are at least in part related to a reduction in astrocyte numbers. The results of this study highlight the differences in behavioral effects following CLO exposure between sexes and developmental stages.

Protective effects of selegiline against amyloid beta-induced anxiety-like behavior and memory impairment.

BACKGROUND: Alzheimer's disease (AD) is a complex and common neurodegenerative disorder. The present study aimed to investigate the potential effects of selegiline (SEL) on various aspects of memory performance, anxiety, and oxidative stress in an AD rat model induced by intracerebroventricular injection of amyloid beta1-42 (Aß1-42). METHODS: Oral administration of SEL at a dose of 0.5 mg/kg/day was performed for 30 consecutive days. Following the 30 days, several tests, including the open-field, elevated plus-maze, novel object recognition, Morris water maze, and passive avoidance learning were conducted to assess locomotor activity, anxiety-like behavior, recognition memory, spatial memory, and passive avoidance memory, respectively. RESULTS: The results indicate that the induction of AD in rats led to recognition memory, spatial memory, and passive avoidance memory impairments, as well as increased anxiety. Additionally, the AD rats exhibited a decrease in total antioxidant capacity and an increase in total oxidant status levels, suggesting an imbalance in oxidative-antioxidant status. However, the administration of SEL improved memory performance, reduced anxiety, and modulated oxidative-antioxidant status in AD rats. CONCLUSIONS: These findings provide evidence that SEL may alleviate anxiety-like behavior and cognitive deficits induced by Aß through modulation of oxidative-antioxidant status.

Exposure to 1-nitropyrene after weaning induces anxiety-like behavior partially by inhibiting steroid hormone synthesis in prefrontal cortex.

1-Nitropyrene (1-NP) is a neurodevelopmental toxicant. This study was to evaluate the impact of exposure to 1-NP after weaning on anxiety-like behavior. Five-week-old mice were administered with 1-NP (0.1 or 1 mg/kg) daily for 4 weeks. Anxiety-like behaviour was measured using elevated-plus maze (EPM) and open field test (OFT). In EPM test, time spending in open arm and times entering open arm were reduced in 1-NP-treated mice. In OFT test, time spent in the center region and times entering the center region were diminished in 1-NP-treated mice. Prefrontal dendritic length and number of dendrite branches were decreased in 1-NP-treated mice. Prefrontal PSD95, an excitatory postsynaptic membrane protein, and gephyrin, an inhibitory postsynaptic membrane protein, were downregulated in 1-NP-treated mice. Further analysis showed that peripheral steroid hormones, including serum testosterone (T) and estradiol (E2), testicular T, and ovarian E2, were decreased in 1-NP-treated mice. Interestingly, T and E2 were diminished in 1-NP-treated prefrontal cortex. Prefrontal T and E2 synthases were diminished in 1-NP-treated mice. Mechanistically, GCN2-eIF2α, a critical pathway that regulates ribosomal protein translation, was activated in 1-NP-treated prefrontal cortex. These results indicate that exposure to 1-NP after weaning induces anxiety-like behaviour partially by inhibiting steroid hormone synthesis in prefrontal cortex.

The lateral septum partakes the regulation of propofol-induced anxiety-like behavior.

Repeated exposure to propofol during early brain development is associated with anxiety disorders in adulthood, yet the mechanisms underlying propofol-induced susceptibility to anxiety disorders remain elusive. The lateral septum (LS), primarily composed of γ-aminobutyric acidergic (GABAergic) neurons, serves as a key brain region in the regulation of anxiety. However, it remains unclear whether LS GABAergic neurons are implicated in propofol-induced anxiety. Therefore, we conducted c-Fos immunostaining of whole-brain slices from mice exposed to propofol during early life. Our findings indicate that propofol exposure activates GABAergic neurons in the LS. Selective activation of LS GABAergic neurons resulted in increased anxiety-like behavior, while selective inhibition of these neurons reduced such behaviors. These results suggest that the LS is a critical brain region involved in propofol-induced anxiety. Furthermore, we investigated the molecular mechanism of propofol-induced anxiety in the LS. Microglia activation underlies the development of anxiety. Immunofluorescence staining and Western blot analysis of LS revealed activated microglia and significantly elevated levels of phospho-NF-κB p65 protein. Additionally, a decrease in the number of neuronal spines was observed. Our study highlights the crucial role of the LS in the development of anxiety-like behavior in adulthood following childhood propofol exposure, accompanied by the activation of inflammatory pathways.

Intraperitoneal administration of arginine vasotocin (AVT) induces anorexigenic and anxiogenic actions via the brain V1a receptor-signaling pathway in the tiger puffer, Takifugu rubripes.

Arginine vasotocin (AVT) is produced mainly in the hypothalamus and as a neurohypophyseal hormone peripherally regulates water-mineral balance in sub-mammals. In addition, AVT-containing neurons innervate several areas of the brain, and AVT also acts centrally as both an anorexigenic and anxiogenic factor in goldfish. However, it is unclear whether these central effects operate in fish in general. In the present study, therefore, we investigated AVT-like immunoreactivity in the brain of the tiger puffer, a cultured fish with a high market value in Japan and also a representative marine teleost species, focusing particularly on whether AVT affects food intake and psychomotor activity. AVT-like immunoreactivity was distributed higher in the ventral region of the telencephalon, the hypothalamus and midbrain. Intraperitoneal (IP) administration of AVT at 100 pmol g-1 body weight (BW) increased the immunoreactivity of phosphorylated ribosomal proteinS6 (RPS6), a neuronal activation marker, in the telencephalon and diencephalon, decreased food consumption and enhanced thigmotaxis. AVT-induced anorexigenic and anxiogenic actions were blocked by IP co-injection of a V1a receptor (V1aR) antagonist, Manning compound (MC) at 300 pmol g-1 BW. These results suggest that AVT acts as an anorexigenic and anxiogenic factor via the V1aR-signaling pathway in the tiger puffer brain.

cGAS/STING signaling pathway-mediated microglial activation in the PFC underlies chronic ethanol exposure-induced anxiety-like behaviors in mice.

Chronic ethanol consumption is a prevalent condition in contemporary society and exacerbates anxiety symptoms in healthy individuals. The activation of microglia, leading to neuroinflammatory responses, may serve as a significant precipitating factor; however, the precise molecular mechanisms underlying this phenomenon remain elusive. In this study, we initially confirmed that chronic ethanol exposure (CEE) induces anxiety-like behaviors in mice through open field test and elevated plus maze test. The cGAS/STING signaling pathway has been confirmed to exhibits a significant association with inflammatory signaling responses in both peripheral and central systems. Western blot analysis confirmed alterations in the cGAS/STING signaling pathway during CEE, including the upregulation of p-TBK1 and p-IRF3 proteins. Moreover, we observed microglial activation in the prefrontal cortex (PFC) of CEE mice, characterized by significant alterations in branching morphology and an increase in cell body size. Additionally, we observed that administration of CEE resulted in mitochondrial dysfunction within the PFC of mice, accompanied by a significant elevation in cytosolic mitochondrial DNA (mtDNA) levels. Furthermore, our findings revealed that the inhibition of STING by H-151 effectively alleviated anxiety-like behavior and suppressed microglial activation induced by CEE. Our study unveiled a significant association between anxiety-like behavior, microglial activation, inflammation, and mitochondria dysfunction during CEE.

Sex Differences in Withdrawal-Induced Anxiety in Rats After Exposure to Tobacco Smoke.

Nicotine, a component of cigarettes, possesses strong reinforcing properties and improves cognitive function, which can lead to dependence. Upon cigarette smoking cessation, withdrawal symptoms occur and may cause an individual to relapse. Affective withdrawal symptoms, such as anxiety, is of great concern as studies have shown its ability to cause relapse in men and women. In this in vivo study, anxiety resulting from smoking cessation after 2-day smoke-free intervals per week for the duration of 4 weeks was investigated in 8 male and 8 female rats after their exposure to cigarette smoke compared to unexposed control rats (8 males and 8 female rats). The anxiety in rats during smoke-free intervals was investigated using an elevated plus-maze (EPM), open-field (OF), and light/dark test (LD). In all tests male rats exhibited significantly higher anxiety symptoms compared to female rats during nicotine withdrawal, despite control rats showing no differences. In the EPM, male rats spent less time in open arm as well having as lower number of crossings than female rats. As for the OFT, the amount of time spent in the center of the open field was also lower in male rats than female rats. In the LD test, the time spent in the light chamber and the latency (delay) to enter the dark chamber was lower in male rats compared to female rats. Our study showed that male rats show greater nicotine withdrawal effects, in terms of anxiety-like behavior than female rats.

The alpha1A antagonist tamsulosin impairs memory acquisition, consolidation and retrieval in a novel object recognition task in mice.

Tamsulosin is an α1-adrenoceptor antagonist used to treat benign prostatic hyperplasia. This drug exhibits high affinity for α1A- and α1D-adrenoceptor subtypes, which are also expressed in the brain. While dementia symptoms have been reported after administration of tamsulosin in humans, studies on its effects on the rodent brain are still rare. The present study investigated the effects of tamsulosin (and biperiden, an amnesic drug) on cognitive performance in the object recognition task (ORT). Tamsulosin (0.001-0.01 mg/kg) was orally administrated in mice at three distinct time points: pre-training, post-training and pre-test session. Tamsulosin 0.01 mg/kg impaired object recognition regardless of when it was injected, whereas at lower doses did not affect mouse performance in the ORT. Biperiden also impaired acquisition and consolidation of object recognition in mice. Furthermore, the effects of tamsulosin on locomotion, motivation and anxiety were excluded as potential confounding factors. At all doses tested, tamsulosin did not alter distance moved, time spent exploring objects in the ORT, and anxiety-related behaviors in the elevated plus-maze test. By contrast, diazepam evoked a significant reduction of anxiety-like behaviours. In conclusion, tamsulosin impaired memory acquisition, consolidation and retrieval in an object recognition task in mice, thus affecting memory performance in a non-specific phase manner. These findings contribute to our understanding of the potential adverse effects of tamsulosin, and shed light on the role played by α1-adrenoceptors, particularly α1A- subtype, in cognitive processes.

The neuroprotective effect of Diosgenin in the rat Valproic acid model of autism.

BACKGROUND AND AIM: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with two core behavioral symptoms restricted/repetitive behavior and social-communication deficit. The unknown etiology of ASD makes it difficult to identify potential treatments. Valproic acid (VPA) is an anticonvulsant drug with teratogenic effects during pregnancy in humans and rodents. Prenatal exposure to VPA induces autism-like behavior in both humans and rodents. This study aimed to investigate the protective effects of Diosgenin in prenatal Valproic acid-induced autism in rats. METHOD: pregnant Wister female rats were given a single intraperitoneal injection of VPA (600 mg/kg, i.p.) on gestational day 12.5. The male offspring were given oral Dios (40 mg/kg, p.o.) or Carboxymethyl cellulose (5 mg/kg, p.o.) for 30 days starting from postnatal day 23. On postnatal day 52, behavioral tests were done. Additionally, biochemical assessments for oxidative stress markers were carried out on postnatal day 60. Further, histological evaluations were performed on the prefrontal tissue by Nissl staining and Immunohistofluorescence. RESULTS: The VPA-exposed rats showed increased anxiety-like behavior in the elevated plus maze (EPM). They also demonstrated repetitive and grooming behaviors in the marble burying test (MBT) and self-grooming test. Social interaction was reduced, and they had difficulty detecting the novel object in the novel object recognition (NOR) test. Also, VPA-treated rats have shown higher levels of oxidative stress malondialdehyde (MDA) and lower GPX, TAC, and superoxide dismutase (SOD) levels. Furthermore, the number of neurons decreased and the ERK signaling pathway upregulated in the prefrontal cortex (PFC). On the other hand, treatment with Dios restored the behavioral consequences, lowered oxidative stress, and death of neurons, and rescued the overly activated ERK1/2 signaling in the prefrontal cortex. CONCLUSION: Chronic treatment with Dios restored the behavioral, biochemical, and histological abnormalities caused by prenatal VPA exposure.

Administration of Atosiban, an oxytocin receptor antagonist, ameliorates autistic-like behaviors in a female rat model of valproic acid-induced autism.

Autism spectrum disorder (ASD) is a pervasive developmental disorder with gender differences. Oxytocin (OXT) is currently an important candidate drug for autism, but the lack of data on female autism is a big issue. It has been reported that the effect of OXT is likely to be different between male and female ASD patients. In the study, we specifically explored the role of the OXT signaling pathway in a VPA-induced female rat's model of autism. The data showed that there was an increase of either oxytocin or its receptor expressions in both the hippocampus and the prefrontal cortex of VPA-induced female offspring. To determine if the excess of OXT signaling contributed to autism symptoms in female rats, exogenous oxytocin and oxytocin receptor antagonists Atosiban were used in the experiment. It was found that exogenous oxytocin triggered autism-like behaviors in wild-type female rats by intranasal administration. More interestingly, several autism-like deficits including social interaction, anxiety, and repeat stereotypical sexual behavior in the VPA female offspring were significantly attenuated by oxytocin receptor antagonists Atosiban. Moreover, Atosiban also effectively improved the synaptic plasticity impairment induced by VPA in female offspring. Our results suggest that oxytocin receptor antagonists significantly improve autistic-like behaviors in a female rat model of valproic acid-induced autism.

Role of brain monoamines in acetamiprid-induced anxiety-like behavior.

Neonicotinoid (NN) pesticides have been linked to increased brain dysfunction in mammals, such as anxiety-like behavior; this is thought to involve monoamines (MA), neurotransmitters that control behavior, memory, and learning. However, the mechanism by which NNs affect the central nervous system is not fully understood. In this study, we aimed to investigate whether MAs affect NNs-induced anxiety-like behavior. Mice were orally administered acetamiprid (ACE), an NN, at the no observed adverse effect level (NOAEL) of mouse (20 mg/kg body mass) set by the Food Safety Commission of Japan, and the elevated zero-maze (EZM) test was performed 30 min after administration. After behavioral analysis, levels of four MA (dopamine, 3-MT, serotonin, and histamine) in selected brain regions were determined by liquid chromatography mass spectrometry (LC/MS/MS). In the exposed group, a trend toward increased anxiety-like behavior was observed, and at least one MA concentration was significantly increased in each region. Further, significant correlations were found between behavioral test results and hippocampal serotonin and striatal dopamine concentrations, as well as between dopamine and serotonin concentrations, in the exposed group. As anxiety can influence activity in the behavioral tests, the activity of neurons in the raphe nuclei (RN), a brain region greatly involved in anxiety via the serotonergic system, was examined by staining with anti-serotonin antibodies, and increased serotonergic activity was observed. Taken together, these results suggest that ACE regulates MA levels, notably serotonin levels in the hippocampus and that RN plays an important role in ACE-induced anxiety-like behavior.

1,2-Dichloroethane causes anxiety and cognitive dysfunction in mice by disturbing GABA metabolism and inhibiting the cAMP-PKA-CREB signaling pathway.

1,2-Dichloroethane (1,2-DCE) is a powerfully toxic neurotoxin, which is a common environmental pollutant. Studies have indicated that 1,2-DCE long-term exposure can result in adverse effects. Nevertheless, the precise mechanism remains unknown. In this study, behavioral results revealed that 1,2-DCE long-term exposure could cause anxiety and learning and memory ability impairment in mice. The contents of γ-aminobutyric acid (GABA) and glutamine (Gln) in mice's prefrontal cortex decreased, whereas that of glutamate (Glu) increased. With the increase in dose, the activities of glutamate decarboxylase (GAD) decreased and those of GABA transaminase (GABA-T) increased. The protein and mRNA expressions of GABA transporter-3 (GAT-3), vesicular GABA transporter (VGAT), GABA A receptor α2 (GABAARα2), GABAARγ2, K-Cl cotransporter isoform 2 (KCC2), GABA B receptor 1 (GABABR1), GABABR2, protein kinase A (PKA), cAMP-response element binding protein (CREB), p-CREB, brain-derived neurotrophic factor (BDNF), c-fos, c-Jun and the protein of glutamate dehydrogenase (GDH) and PKA-C were decreased, while the expression levels of GABA transporter-1 (GAT-1) and Na-K-2Cl cotransporter isoform 1 (NKCC1) were increased. However, there was no significant change in the protein content of succinic semialdehyde dehydrogenase (SSADH). The expressions of adenylate cyclase (AC) and cyclic adenosine monophosphate (cAMP) contents were also reduced. In conclusion, the results of this study show that exposure to 1,2-DCE could lead to anxiety and cognitive impairment in mice, which may be related to the disturbance of GABA metabolism and its receptors along with the cAMP-PKA-CREB pathway.

Sex-dependent behavioral effects of chronic nicotine during adolescence evaluated in young adult rats tested in Hole-Board.

As one of the leading causes of death and serious illnesses, tobacco smoking remains a significant issue in modern societies. Many individuals smoke during adolescence, a trend that has been exacerbated by the prevalence of vaping among young people. In this context, studying the behavioral effects induced by nicotine administration in male and female rats, during the adolescent period, assumes great importance because it can help to better understand the dynamics underlying tobacco use in the two sexes. For this purpose, we employed 4 groups of rats, 2 male and 2 female groups, chronically treated with saline or nicotine 3 mg/kg i.p. for 30 days, spanning from postnatal day 30 to postnatal day 60. Utilizing quantitative analyses and T-pattern detection and analysis, our findings revealed a complex and multifaceted behavioral reorganization in adolescent rats subjected to chronic nicotine administration. Specifically, we observed an increase of anxiety in males and a reduction in females. The distinctive structural changes, induced by chronic nicotine in both sexes, have significant implications, from a translational perspective, for studies on nicotine dependence disorders.

Early-life inflammation increases ethanol consumption in adolescent male mice.

Recent studies have demonstrated that stress during the critical windows of development can evoke a cascade of neurological changes that can result in neuropsychiatric disorders later in life. In this study, we examined the effect of early-life inflammation on ethanol consumption in adolescent mice. C57BL/6J mice were assigned to either the control or Lipopolysaccharide (LPS) group on postnatal day 14 (P14). In the latter group, LPS at a dose of 50 µg/kg was injected intraperitoneally. The mice were weaned at P21, and behavior tests were performed at P45. Ethanol consumption was assessed using a two-bottle choice drinking paradigm. Anxiety-like behaviors were assessed by marble burying test (MBT), open field (OF), and elevated plus maze (EPM). Ethanol-induced loss of righting reflex (LORR), hypothermia and ethanol metabolism were assessed to evaluate ethanol intoxication. P14 LPS-injected adolescent male mice exhibited significantly increased ethanol preference and consumption, with a similar taste preference for saccharin and avoidance of quinine. The adolescent male mice showed increased anxiety-like behaviors in the OF and EPM tests, and an increased duration of LORR, without affecting the hypothermic effects of ethanol and ethanol metabolism. Interestingly, these behavioral changes were not obvious in female mice. In conclusion, our data indicate that early-life inflammation may be a risk factor for ethanol consumption in adolescents with greater changes observed in male mice. SIGNIFICANCE STATEMENT: Our study is the first preclinical model to report the enhancement effect of early-life inflammation on ethanol consumption in adolescent male mice and our findings provide a valuable mouse model to examine the neurobiological mechanisms mediating the long-lasting effects of early-life inflammation on alcohol use disorders vulnerability.

Pesticide-Induced Alterations in Locomotor Activity, Anxiety, and Depression-like Behavior Are Mediated through Oxidative Stress-Related Autophagy: A Persistent Developmental Study in Mice.

Chlorpyrifos (CPF), dichlorvos (DDV), and cypermethrin (CP), as commonly used pesticides, have been implicated in inducing neuropsychiatric disorders, such as anxiety, depression-like behaviors, and locomotor activity impairment. However, the exact molecular mechanisms of these adverse effects, particularly in both sexes and their next-generation effects, remain unclear. In this study, we conducted behavioral analysis, along with cellular assays (monodansylcadaverine staining) and molecular investigations (qRT-PCR and western blotting of mTOR, P62, and Beclin-1) to clear the potential role of autophagy in pesticide-induced behavioral alterations. For this purpose, 42 adult female and 21 male inbred ICR mice (F0) were distributed into seven groups. Maternal mice (F0) and 112 F1 offspring were exposed to 0.5 and 1 ppm of CPF, DDV, and CP through drinking water. F1 male and female animals were studied to assess the sex-specific effects of pesticides on brain tissue. Our findings revealed pronounced anxiogenic effects and impaired locomotor activity in mice. F1 males exposed to CPF (1 ppm) exhibited significantly elevated depression-like behaviors compared to other groups. Moreover, pesticide exposure reduced mTOR and P62 levels, while enhancing the Beclin-1 gene and protein expression. These changes in autophagy signaling pathways, coupled with oxidative and neurogenic damage in the cerebral cortex and hippocampus, potentially contribute to heightened locomotor activity, anxiety, and depression-like behaviors following pesticide exposure. This study underscores the substantial impact of pesticides on both physiological and behavioral aspects, emphasizing the necessity for comprehensive assessments and regulatory considerations for pesticide use. Additionally, the identification of sex-specific responses presents a crucial dimension for pharmaceutical sciences, highlighting the need for tailored therapeutic interventions and further research in this field.

Impact of chronic lithium treatment on brain oxidative stress and anxiety-like behaviors in rats: Dose-dependent effects.

Lithium (Li) is a mood-stabilizing drug. Although one of the potential mechanisms underlying the neuroprotective effects of lithium is related to its antioxidative effect, its mechanisms of action are not fully understood. Herein we aimed to investigate the impact of varied dosages of long-term lithium therapy on oxidative stress parameters in the brains of healthy rats, and on anxiety-like behaviors, and whether any changes in behavior can be attributed to modifications in oxidative stress levels within the brain. Thirty-two adult Wistar albino male rats were randomly assigned to four treatment groups. While the control (C) group was fed with a standard diet, low Li (1.4 g/kg/diet), moderate Li (1.8 g/kg/diet), and high Li (2.2 g/kg/diet) groups were fed with lithium bicarbonate (Li2CO3) for 30 days. Malondialdehyde increased, while superoxide dismutase and catalase levels decreased in the brains of the high Li group animals. In addition, anxiety-like behaviors of animals increased in the high Li group considering fewer entries to and less time spent in the open arms of the elevated plus maze test. Our findings underscore the potential adverse effects of prolonged lithium treatment, especially at doses approaching the upper therapeutic range. The induction of toxicity, manifested through heightened oxidative stress, appears to be a key mechanism contributing to the observed increase in anxiety-like behaviors. Consequently, caution is warranted when considering extended lithium therapy at higher doses, emphasizing the need for further research to delineate the precise mechanisms underlying these effects and to inform safer therapeutic practices.

Neuro-protective effect of pre-treatment with Sorghum bicolor and vitamin C on tramadol induced brain oxidative stress and anxiety-like behaviour in male albino rats.

The study focused on the neuroprotective role of Sorghum bicolor and vitamin C in the amelioration of oxidative stress and anxiety-like behavoiur induced by tramadol in male albino rats. The study design involved 7 groups and a control group with 5 male albino rats in each group. Tramadol (40 mg/kg) treatment was administered for 21 days. Tramadol 40mg/kg was administered in all groups. Pretreatment with varying doses of Sorghum bicolor and Vitamin C was done in three of the groups. Behavioral assessment of anxiety and locomotors actions of the groups were compared using Elevated Plus Maze (EPM) and Open Field Test (OFT). In conclusion, Sorghum bicolor and Vitamin C tramadol ameliorated oxidative stress and anxiety-like behaviour induced by tramadol. Pretreatment with Sorghum bicolor or vitamin C (100mg) can also reduced anxiogenic responses in male albino rats that are induced by chronic tramadol use.

Daidzein ameliorates nonmotor symptoms of manganese-induced Parkinsonism in zebrafish model: Behavioural and biochemical approach.

BACKGROUND AND PURPOSE: Parkinson's disease (PD) is a prevalent neurodegenerative movement disorder characterized by motor dysfunction. Environmental factors, especially manganese (Mn), contribute significantly to PD. Existing therapies are focused on motor coordination, whereas nonmotor features such as neuropsychiatric symptoms are often neglected. Daidzein (DZ), a phytoestrogen, has piqued interest due to its antioxidant, anti-inflammatory, and anxiolytic properties. Therefore, we anticipate that DZ might be an effective drug to alleviate the nonmotor symptoms of Mn-induced Parkinsonism. EXPERIMENTAL APPROACH: Naïve zebrafish were exposed to 2 mM of Mn for 21 days and intervened with DZ. Nonmotor symptoms such as anxiety, social behaviour, and olfactory function were assessed. Acetylcholinesterase (AChE) activity and antioxidant enzyme status were measured from brain tissue through biochemical assays. Dopamine levels and histology were performed to elucidate neuroprotective mechanism of DZ. KEY RESULTS: DZ exhibited anxiolytic effects in a novel environment and also improved intra and inter fish social behaviour. DZ improved the olfactory function and response to amino acid stimuli in Mn-induced Parkinsonism. DZ reduced brain oxidative stress and AChE activity and prevented neuronal damage. DZ increased DA level in the brain, collectively contributing to neuroprotection. CONCLUSION AND IMPLICATIONS: DZ demonstrated a promising effect on alleviating nonmotor symptoms such as anxiety and olfactory dysfunction, through the mitigation of cellular damage. These findings underscore the therapeutic potential of DZ in addressing nonmotor neurotoxicity induced by heavy metals, particularly in the context of Mn-induced Parkinsonism.

Placebo Effects Are Small on Average in the 7.5% CO2 Inhalational Model of Generalized Anxiety.

BACKGROUND: Anxiety disorders are highly prevalent and socio-economically costly. Novel pharmacological treatments for these disorders are needed because many patients do not respond to current agents or experience unwanted side effects. However, a barrier to treatment development is the variable and large placebo response rate seen in trials of novel anxiolytics. Despite this, the mechanisms that drive placebo responses in anxiety disorders have been little investigated, possibly due to low availability of convenient experimental paradigms. We aimed to develop and test a novel protocol for inducing placebo anxiolysis in the 7.5% CO2 inhalational model of generalized anxiety in healthy volunteers. METHODS: Following a baseline 20-minute CO2 challenge, 32 healthy volunteers were administered a placebo intranasal spray labelled as either the anxiolytic "lorazepam" or "saline." Following this, participants surreptitiously underwent a 20-minute inhalation of normal air. Post-conditioning, a second dose of the placebo was administered, after which participants completed another CO2 challenge. RESULTS: Participants administered sham "lorazepam" reported significant positive expectations of reduced anxiety (P = .001), but there was no group-level placebo effect on anxiety following CO2 challenge post-conditioning (Ps > .350). Surprisingly, we found many participants exhibited unexpected worsening of anxiety, despite positive expectations. CONCLUSIONS: Contrary to our hypothesis, our novel paradigm did not induce a placebo response, on average. It is possible that effects of 7.5% CO2 inhalation on prefrontal cortex function or behavior in line with a Bayesian predictive coding framework attenuated the effect of expectations on subsequent placebo response. Future studies are needed to explore these possibilities.

Cyclooxygenase-2 inhibitors alleviated depressive and anxious-like behaviors in mice exposed to lipopolysaccharide: Involvement of oxidative stress and neuroinflammation.

Depression and anxiety disorders have their pathophysiologies linked to inflammation and oxidative stress. In this context, celecoxib (CLX) and etoricoxib (ETR) inhibit cyclooxygenase 2 (COX-2), an enzyme expressed by cells involved in the inflammatory process and found in the brain. Studies have been using CLX as a possible drug in the treatment of depression, although its mechanisms at the central nervous system level are not fully elucidated. In this study, the effects of CLX and ETR on behavioral, oxidative, and inflammatory changes induced by systemic exposure to Escherichia coli lipopolysaccharide (LPS) were evaluated in adult male swiss mice. For ten days, the animals received intraperitoneal injections of LPS at 0.5 mg/kg. From the sixth to the tenth day, one hour after LPS exposure, they were treated orally with CLX (15 mg/kg), ETR (10 mg/kg), or fluoxetine (FLU) (20 mg/kg). Twenty-four hours after the last oral administration, the animals underwent evaluation of locomotor activity (open field test), predictive tests for depressive-like behavior (forced swim and tail suspension tests), and anxiolytic-like effect (elevated plus maze and hole board tests). Subsequently, the hippocampus, prefrontal cortex and striatum were dissected for the measurement of oxidative and nitrosative parameters (malondialdehyde, nitrite, and glutathione) and quantification of pro-inflammatory cytokines (IL-1ß and IL-6). LPS induced depressive and anxious-like behavior, and treatment with CLX or ETR was able to reverse most of the behavioral changes. It was evidenced that nitrosative stress and the degree of lipid peroxidation induced by LPS were reduced in different brain areas after treatment with the drugs, as well as the endogenous defense system against free radicals was strengthened. CLX and ETR also significantly reduced LPS-induced cytokine levels. These data are expected to expand information on the role of inflammation in depression and anxiety and provide insights into possible mechanisms of COX-2 inhibitors in psychiatric disorders with a neurobiological basis in inflammation and oxidative stress.