Correlation between desynchrony of hippocampal neural activity and hyperlocomotion in the model mice of schizophrenia and therapeutic effects of aripiprazole.

AIMS: The hippocampus has been reported to be morphologically and neurochemically altered in schizophrenia (SZ). Hyperlocomotion is a characteristic SZ-associated behavioral phenotype, which is associated with dysregulated dopamine system function induced by hippocampal hyperactivity. However, the neural mechanism of hippocampus underlying hyperlocomotion remains largely unclear. METHODS: Mouse pups were injected with N-methyl-D-aspartate receptor antagonist (MK-801) or vehicle twice daily on postnatal days (PND) 7-11. In the adulthood phase, one cohort of mice underwent electrode implantation in field CA1 of the hippocampus for the recording local field potentials and spike activity. A separate cohort of mice underwent surgery to allow for calcium imaging of the hippocampus while monitoring the locomotion. Lastly, the effects of atypical antipsychotic (aripiprazole, ARI) were evaluated on hippocampal neural activity. RESULTS: We found that the hippocampal theta oscillations were enhanced in MK-801-treated mice, but the correlation coefficient between the hippocampal spiking activity and theta oscillation was reduced. Consistently, although the rate and amplitude of calcium transients of hippocampal neurons were increased, their synchrony and correlation to locomotion speed were disrupted. ARI ameliorated perturbations produced by the postnatal MK-801 treatment. CONCLUSIONS: These results suggest that the disruption of neural coordination may underly the neuropathological mechanism for hyperlocomotion of SZ.

Recognizing the opponent: The consolidation of long-term social memory in zebrafish males.

Recognizing and remembering another individual in a social context could be beneficial for individual fitness. Especially in agonistic encounters, remembering an opponent and the previous fight could allow for avoiding new conflicts. Considering this, we hypothesized that this type of social interaction forms a long-term recognition memory lasting several days. It has been shown that a second encounter 24 h later between the same pair of zebrafish males is resolved with lower levels of aggression. Here, we evaluated if this behavioral change could last for longer intervals and a putative mechanism associated with memory storage: the recruitment of NMDA receptors. We found that if a pair of zebrafish males fight and fight again 48 or 72 h later, they resolve the second encounter with lower levels of aggression. However, if opponents were exposed to MK-801 (NMDA receptor antagonist) immediately after the first encounter, they solved the second one with the same levels of aggression: that is, no reduction in aggressive behaviors was observed. These amnesic effect suggest the formation of a long-term social memory related to recognizing a particular opponent and/or the outcome and features of a previous fight.

GLP-1-directed NMDA receptor antagonism for obesity treatment.

The N-methyl-D-aspartate (NMDA) receptor is a glutamate-activated cation channel that is critical to many processes in the brain. Genome-wide association studies suggest that glutamatergic neurotransmission and NMDA receptor-mediated synaptic plasticity are important for body weight homeostasis1. Here we report the engineering and preclinical development of a bimodal molecule that integrates NMDA receptor antagonism with glucagon-like peptide-1 (GLP-1) receptor agonism to effectively reverse obesity, hyperglycaemia and dyslipidaemia in rodent models of metabolic disease. GLP-1-directed delivery of the NMDA receptor antagonist MK-801 affects neuroplasticity in the hypothalamus and brainstem. Importantly, targeting of MK-801 to GLP-1 receptor-expressing brain regions circumvents adverse physiological and behavioural effects associated with MK-801 monotherapy. In summary, our approach demonstrates the feasibility of using peptide-mediated targeting to achieve cell-specific ionotropic receptor modulation and highlights the therapeutic potential of unimolecular mixed GLP-1 receptor agonism and NMDA receptor antagonism for safe and effective obesity treatment.

Long-term effects of Preweaning environmental impoverishment on neurobehavioral and neurocognitive outcomes in Sprague Dawley rats: An early environmental stress model.

Developmental stress, including low socioeconomic status (SES), can induce dysregulation of the hypothalamic-pituitary-adrenal axis and result in long-term changes in stress reactivity. Children in lower SES conditions often experience more stress than those in other SES groups. There are multiple model systems of early environmental stress (EES), one of which is reduced cage bedding. Here we tested the effects of both prenatal and lactational EES in rats on a range of long-term behavioral and cognitive outcomes. There were persistent reductions in body weight in the EES rats in both sexes. The behavioral results showed no effects on learning and memory using tests of spatial learning or cognitive flexibility in the Morris water maze, egocentric learning in the Cincinnati water maze, or working memory in the radial-arm maze. There were no effects on basic open-field activity, elevated zero-maze, or forced swim test, but EES rats had reduced time in the dark side of the light/dark test. When rats were drug challenged in the open-field with d-amphetamine or MK-801, there were no differential responses to d-amphetamine, but the EES group under responded compared with the drug-induced hyperactivity in the control group in both males and females. The objective was to establish a developmental stress model that induced cognitive deficits and to the extent that this method did not cause such effects it was not the model we sought. However, the data showed several long-term effects of EES, including the reduced response to the irreversible NMDA antagonist MK-801. This effect merits further investigation.

Particulate matter (PM10) exacerbates on MK-801-induced schizophrenia-like behaviors through the inhibition of ERK-CREB-BDNF signaling pathway.

Particulate matter (PM), released into the air by a variety of natural and human activities, is a key indicator of air pollution. Although PM is known as the extensive health hazard to affect a variety of illness, few studies have specifically investigated the effects of PM10 exposure on schizophrenic development. In the present study, we aimed to investigate the impact of PM10 on MK-801, N-methyl-D-aspartate (NMDA) receptor antagonist, induced schizophrenia-like behaviors in C57BL/6 mouse. Preadolescent mice were exposed PM10 to 3.2 mg/m3 concentration for 4 h/day for 2 weeks through a compartmentalized whole-body inhalation chamber. After PM10 exposure, we conducted behavioral tests during adolescence and adulthood to investigate longitudinal development of schizophrenia. We found that PM10 exacerbated schizophrenia-like behavior, such as psychomotor agitation, social interaction deficits and cognitive deficits at adulthood in MK-801-induced schizophrenia animal model. Furthermore, the reduced expression levels of brain-derived neurotrophic factor (BDNF) and the phosphorylation of BDNF related signaling molecules, extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB), were exacerbated by PM10 exposure in the adult hippocampus of MK-801-treated mice. Thus, our present study demonstrates that exposure to PM10 in preadolescence exacerbates the cognitive impairment in animal model of schizophrenia, which are considered to be facilitated by the decreased level of BDNF through reduced ERK-CREB expression.

N-methyl-D-aspartate receptors and thymoquinone induce apoptosis and alteration in mitochondria in colorectal cancer cells.

Colon cancer is on the rise in both men and women. In addition to traditional treatment methods, herbal treatments from complementary and alternative medicine are actively followed. Naturally derived from plants, thymoquinone (TQ) has drawn a lot of attention in the field of cancer treatment. MK-801, an N-methyl-D-aspartate agonist, is used to improve memory and plasticity, but it has also lately been explored as a potential cancer treatment. This study aimed to determine the roles of N-Methyl-D-Aspartate agonists and Thymoquinone on mitochondria and apoptosis. HT-29 cells were treated with different TQ and MK-801 concentrations. We analyzed cell viability, apoptosis, and alteration of mitochondria. Cell viability significantly decreased depending on doses of TQ and MK-801. Apoptosis and mitochondrial dysfunctions induced by low and high doses of TQ and MK-801. Our study emphasizes the need for further safety evaluation of MK-801 due to the potential toxicity risk of TQ and MK-801. Optimal and toxic doses of TQ and MK-801 were determined for the treatment of colon cancer. It should be considered as a possibility that colon cancer can be treated with TQ and MK-801.

Disruption of NMDA receptor-mediated regulation of PPI in the maternal immune activation model of schizophrenia is restored by 17ß-estradiol and raloxifene.

Maternal immune activation (MIA) during pregnancy is known to increase the risk of development of schizophrenia in the offspring. Sex steroid hormone analogues have been proposed as potential antipsychotic treatments but the mechanisms of action involved remain unclear. Estrogen has been shown to alter N-methyl-d-aspartate (NMDA) receptor binding in the brain. We therefore studied the effect of chronic treatment with 17ß-estradiol, its isomer, 17α-estradiol, and the selective estrogen receptor modulator, raloxifene, on MIA-induced psychosis-like behaviour and the effect of the NMDA receptor antagonist, MK-801. Pregnant rats were treated with saline or the viral mimetic, poly(I:C), on gestational day 15. Adult female offspring were tested for changes in baseline prepulse inhibition (PPI) and the effects of acute treatment with MK-801 on PPI and locomotor activity. Poly(I:C) offspring had significantly lower baseline PPI compared to control offspring, and this effect was prevented by 17ß-estradiol and raloxifene, but not 17α-estradiol. MK-801 reduced PPI in control offspring but had no effect in poly(I:C) offspring treated with vehicle. Chronic treatment with 17ß-estradiol and raloxifene restored the effect of MK-801 on PPI. There were no effects of MIA or estrogenic treatment on MK-801 induced locomotor hyperactivity. These results show that MIA affects baseline PPI as well as NMDA receptor-mediated regulation of PPI in female rats, and strengthen the view that estrogenic treatment may have antipsychotic effects.

Differential impact of intermittent versus continuous treatment with clozapine on fatty acid metabolism in the brain of an MK-801-induced mouse model of schizophrenia.

Continuous antipsychotic treatment is often recommended to prevent relapse in schizophrenia. However, the efficacy of antipsychotic treatment appears to diminish in patients with relapsed schizophrenia and the underlying mechanisms are still unknown. Moreover, though the findings are inconclusive, several recent studies suggest that intermittent versus continuous treatment may not significantly differ in recurrence risk and therapeutic efficacy but potentially reduce the drug dose and side effects. Notably, disturbances in fatty acid (FA) metabolism are linked to the onset/relapse of schizophrenia, and patients with multi-episode schizophrenia have been reported to have reduced FA biosynthesis. We thus utilized an MK-801-induced animal model of schizophrenia to evaluate whether two treatment strategies of clozapine would affect drug response and FA metabolism differently in the brain. Schizophrenia-related behaviors were assessed through open field test (OFT) and prepulse inhibition (PPI) test, and FA profiles of prefrontal cortex (PFC) and hippocampus were analyzed by gas chromatography-mass spectrometry. Additionally, we measured gene expression levels of enzymes involved in FA synthesis. Both intermittent and continuous clozapine treatment reversed hypermotion and deficits in PPI in mice. Continuous treatment decreased total polyunsaturated fatty acids (PUFAs), saturated fatty acids (SFAs) and FAs in the PFC, whereas the intermittent administration increased n-6 PUFAs, SFAs and FAs compared to continuous administration. Meanwhile, continuous treatment reduced the expression of Fads1 and Elovl2, while intermittent treatment significantly upregulated them. This study discloses the novel findings that there was no significant difference in clozapine efficacy between continuous and intermittent administration, but intermittent treatment showed certain protective effects on phospholipid metabolism in the PFC.

Function and mechanism exploring of icariin in schizophrenia through network pharmacology.

This study aims to explore the therapeutic effect and possible mechanisms of icariin in schizophrenia. SD rats were divided into five groups, a control group, a MK801-induced schizophrenia model group, and three icariin treatment groups, with twelve rats in each group. Morris water maze and open field were used to observe the spatial learning and memory ability of rats. Compared with the control group, rats in the MK801-induced model group showed an increase in stereotypic behavior score, distance of spontaneous activities, escape latency, malondialdehyde (MDA) content, and IL-6, IL-1ß, TNF-α expression, but a decrease in platform crossing times and superoxide dismutase (SOD) activity (P < 0.05). Furthermore, all the above changes of the model group were reversed after icariin treatment in a dose-dependent manner (P < 0.05). Network pharmacology found that icariin can exert anti-schizophrenic effects through some signaling pathways, such as relaxin, estrogen, and TNF signaling pathways. MAPK1, MAPK3, FOS, RELA, TNF, and JUN were the key targets of icariin on schizophrenia, and their expression was detected in animal models, which was consistent with the predicted results of network pharmacology. Icariin treatment may improve the spatial learning and memory ability of schizophrenic rats through TNF signaling pathway.

Acute MK-801 increases measures of both sign-tracking and goal-tracking in male Sprague-Dawley rats.

Sign-tracking is a Pavlovian conditioned approach behavior thought to be important in understanding cue-driven relapse to drug use, and strategies for reducing sign-tracking may have some benefit in preventing relapse. A previous study successfully employed the NMDA receptor antagonist MK-801 in preventing the development of sign-tracking (but not goal-tracking) in a conditioned approach task. In this study, we focused on whether MK-801 would have similar effects on previously established sign-tracking behavior. MK-801 was administered after training in a standard sign-/goal-tracking task using a retractable lever as a conditioned stimulus and a sucrose pellet as unconditioned stimulus. It was found that MK-801 increased measures of both sign- and goal-tracking in subjects who had previously learned the task. The NMDA receptor appears to play a complex role in governing behavior related to sign-tracking.

Chronic MK-801 administration provokes persistent deficits in social memory in the prairie vole (Microtus ochrogaster): A potential animal model for social deficits of schizophrenia.

The prairie vole (Microtus ochrogaster) is a rodent species that has been used extensively to study biological aspects of human social bonding. Nevertheless, this species has not been studied in the context of modeling social deficits characteristic of schizophrenia. Building on studies in rodents that show that sub-chronic administration of an NMDA receptor antagonist induces persistent behavioral and neurological characteristics of schizophrenia, we administered MK-801 (0.2 mg/kg, daily, for 7 days) or physiological saline to young adult (45 days old) virgin male voles. At 69 days of age, we paired these males with virgin females. 24 h later, we assessed the males' social investigation of each female across the first 5 min of a three-hour preference test, and side-by-side contact with each female during the last hour of the test. Unlike saline-treated males, MK-801-treated males did not preferentially investigate the unfamiliar female, indicating a deficit in social memory. Although males of both groups preferentially spent time with their female partner, regression analysis revealed that deficits in social memory predicted lower partner preference in MK-801-treated males. We interpret these results in the context of recent studies of the natural history of the prairie vole as well as in the context of cognitive deficits in schizophrenia and propose that the social component of episodic memory might influence an individual's capacity to form and maintain long-term social bonds.

Suppressive effect of Yokukansan on glutamate released from canine keratinocytes.

Background: Canine atopic dermatitis (CAD) is caused by skin barrier dysfunction due to allergen exposure. Excessive glutamate release in the skin is associated with delayed skin barrier function recovery and epidermal thickening and lichenification. Treatment with Yokukansan (YKS), a traditional Japanese medicine, reduces dermatitis severity and scratching behavior in NC/Nga mice by decreasing epidermal glutamate levels. However, the association between canine keratinocytes and glutamate and the mechanism by which YKS inhibits glutamate release from keratinocytes remains unknown. Aim: We aimed to investigate glutamate release from canine progenitor epidermal keratinocytes (CPEKs) and the inhibitory effect of YKS on this release. We also explored the underlying mechanism of YKS to enable its application in CAD treatment. Methods: Glutamate produced from CPEKs in the medium at 24 hours was measured. The measurement conditions varied in terms of cell density and YKS concentration. CPEKs were treated with a glutamate receptor antagonist (MK-801), a glutamate transporter antagonist (THA), and a glutamate dehydrogenase inhibitor (epigallocatechin gallate; EGCG), and the inhibitory effect of YKS, YKS + THA, MK-801, and EGCG on this release was determined. MK-801 and glutamate dehydrogenase inhibitor were tested alone, and THA was tested in combination with YKS. Finally, glutamine incorporated into CPEKs at 24 hours was measured using radioisotope labeling. Results: CPEKs released glutamate in a cell density-dependent manner, inhibited by YKS in a concentration-dependent manner. Moreover, YKS reduced the intracellular uptake of radioisotope-labeled glutamine in a concentration-dependent manner. No involvement of glutamate receptor antagonism or activation of glutamate transporters was found, as suggested by previous studies. In addition, EGCG could inhibit glutamate release from CPEKs. Conclusion: Our findings indicated that glutamate release from CPEKs could be effectively inhibited by YKS, suggesting the utility of YKS in maintaining skin barrier function during CAD. In addition, CPEKs are appropriate for analyzing the mechanism of YKS. However, we found that the mechanism of action of YKS differs from that reported in previous studies, suggesting that it may have had a similar effect to EGCG in this study. Further research is warranted to understand the exact mechanism and clinical efficacy in treating CAD.

Prevention of MK-801-induced amnestic effect with combined activation of 5-HT1A and muscarinic receptors in mice.

BACKGROUND: Muscarinic or 5-HT1A receptors are crucial in learning and memory processes, and their expression is evident in the brain areas involved in cognition. The administration of the activators of these receptors prevents the development of cognitive dysfunctions in animal models of schizophrenia induced by MK-801 (N-methyl-d-aspartate receptor antagonist) administration. GABAergic dysfunction is considered as one of the most important causes of MK-801-induced spatial learning deficits. METHODS: Novel object recognition (NOR) and Morris water maze (MWM) tests were used to study the anti-amnestic effect of the biased 5-HT1A receptor agonist (F15599) alone or in combinations with VU0357017 (M1 receptor allosteric agonist), VU0152100 (M4 receptor positive allosteric modulator), and VU0238429 (M5 receptor positive allosteric modulator) on MK-801-induced dysfunctions. The compounds were administered for 5 consecutive days. Animals tested with the MWM underwent 5-day training. Western blotting was used to study the expressions of 5-HT1A receptors and the level of GAD65 in the frontal cortices (FCs) and hippocampi of the animals. RESULTS: F15599 prevented the amnestic effect induced by MK-801 in the MWM at a dose of 0.1 mg/kg. The co-administration of the compound with muscarinic receptors activators had no synergistic effect. The additive effect of the combinations was evident in the prevention of declarative memory dysfunctions investigated in NOR. The administration of MK-801 impaired 5-HT1A expression in the hippocampi and decreased GAD65 levels in both the FCs and hippocampi. The administration of muscarinic ligands prevented these MK-801-induced deficits only in the hippocampi of MWM-trained animals. No effects of the compounds were observed in untrained mice. CONCLUSION: Our results indicate that F15599 prevents schizophrenia-related spatial learning deficits in the MWM; however, the activity of the compound is not intensified with muscarinic receptors activators. In contrast, the combined administration of the ligands is effective in the NOR model of declarative memory. The muscarinic receptors activators reversed MK-801-induced 5-HT1A and GAD65 dysfunctions in the hippocampi of MWM-trained mice, but not in untrained mice.

NMDA glutamate receptor antagonist MK-801 induces proteome changes in adult human brain slices which are partially counteracted by haloperidol and clozapine.

Deciphering the molecular pathways associated with N-methyl-D-aspartate receptor (NMDAr) hypofunction and its interaction with antipsychotics is necessary to advance our understanding of the basis of schizophrenia, as well as our capacity to treat this disease. In this regard, the development of human brain-derived models that are amenable to studying the neurobiology of schizophrenia may contribute to filling the gaps left by the widely employed animal models. Here, we assessed the proteomic changes induced by the NMDA glutamate receptor antagonist MK-801 on human brain slice cultures obtained from adult donors submitted to respective neurosurgery. Initially, we demonstrated that MK-801 diminishes NMDA glutamate receptor signaling in human brain slices in culture. Next, using mass-spectrometry-based proteomics and systems biology in silico analyses, we found that MK-801 led to alterations in proteins related to several pathways previously associated with schizophrenia pathophysiology, including ephrin, opioid, melatonin, sirtuin signaling, interleukin 8, endocannabinoid, and synaptic vesicle cycle. We also evaluated the impact of both typical and atypical antipsychotics on MK-801-induced proteome changes. Interestingly, the atypical antipsychotic clozapine showed a more significant capacity to counteract the protein alterations induced by NMDAr hypofunction than haloperidol. Finally, using our dataset, we identified potential modulators of the MK-801-induced proteome changes, which may be considered promising targets to treat NMDAr hypofunction in schizophrenia. This dataset is publicly available and may be helpful in further studies aimed at evaluating the effects of MK-801 and antipsychotics in the human brain.

The Impact of LY487379 or CDPPB on eNOS Expression in the Mouse Brain and the Effect of Joint Administration of Compounds with NO• Releasers on MK-801- or Scopolamine-Driven Cognitive Dysfunction in Mice.

The role of endothelial nitric oxide synthase (eNOS) in the regulation of a variety of biological processes is well established, and its dysfunction contributes to brain pathologies, including schizophrenia or Alzheimer's disease (AD). Positive allosteric modulators (PAMs) of metabotropic glutamate (mGlu) receptors were shown to be effective procognitive compounds, but little is known about their impact on eNOS expression and stability. Here, we investigated the influence of the acute and chronic administration of LY487379 or CDPPB (mGlu2 and mGlu5 PAMs), on eNOS expression in the mouse brain and the effect of the joint administration of the ligands with nitric oxide (NO) releasers, spermineNONOate or DETANONOate, in different combinations of doses, on MK-801- or scopolamine-induced amnesia in the novel object recognition (NOR) test. Our results indicate that both compounds provoked eNOS monomer formation, and CDPPB at a dose of 5 mg/kg exaggerated the effect of MK-801 or scopolamine. The coadministration of spermineNONOate or DETANONOate enhanced the antiamnesic effect of CDPPB or LY487379. The best activity was observed for ineffective or moderate dose combinations. The results indicate that treatment with mGluR2 and mGluR5 PAMs may be burdened with the risk of promoting eNOS uncoupling through the induction of dimer dissociation. Administration of the lowest possible doses of the compounds with NO• donors, which themselves have procognitive efficacy, may be proposed for the treatment of schizophrenia or AD.

Bioenergetic and excitotoxic determinants of cofilactin rod formation.

Cofilactin rods (CARs), which are 1:1 aggregates of cofilin-1 and actin, lead to neurite loss in ischemic stroke and other disorders. The biochemical pathways driving CAR formation are well-established, but how these pathways are engaged under ischemic conditions is less clear. Brain ischemia produces both ATP depletion and glutamate excitotoxicity, both of which have been shown to drive CAR formation in other settings. Here, we show that CARs are formed in cultured neurons exposed to ischemia-like conditions: oxygen-glucose deprivation (OGD), glutamate, or oxidative stress. Of these conditions, only OGD produced significant ATP depletion, showing that ATP depletion is not required for CAR formation. Moreover, the OGD-induced CAR formation was blocked by the glutamate receptor antagonists MK-801 and kynurenic acid; the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors GSK2795039 and apocynin; as well as an ROS scavenger. The findings identify a biochemical pathway leading from OGD to CAR formation in which the glutamate release induced by energy failure leads to activation of neuronal glutamate receptors, which in turn activates NADPH oxidase to generate oxidative stress and CARs.

Effect of intermittent subchronic MK-801 administration on dopamine synthesis capacity and responsiveness in the prefrontal cortex.

AIM: The therapeutic potential of N-methyl-D-aspartate glutamate receptor (NMDAR) antagonists, particularly ketamine, in mood disorders, is linked to their modulation of dopamine dynamics in the medial prefrontal cortex (mPFC). However, conflicting effects of distinct NMDAR antagonists, like ketamine and phencyclidine, on mPFC dopamine levels stem from variances in their receptor affinity profiles. This study investigates the impact of intermittent subchronic administration of an NMDAR antagonist on dopamine synthesis capacity and responsiveness within the mPFC, focusing on Dizocilpine (MK-801), a highly selective NMDAR antagonist. METHODS: In vivo microdialysis and high-performance liquid chromatography assessed extracellular dopamine levels in the mPFC following subchronic MK-801 treatment. Locomotor activity was measured using a computed video tracking system. RESULTS: Intermittent subchronic MK-801 administration, followed by a 24-h withdrawal, preserved both dopamine synthesis capacity and responsiveness to MK-801 challenge in the mPFC. However, altered locomotor activity was observed, deviating from previous findings indicating impaired dopamine synthesis and responsiveness in the mPFC with twice-daily subchronic NMDAR antagonist treatment. CONCLUSION: These findings offer crucial biochemical insights into the diverse impacts of NMDAR antagonists on dopamine dynamics and the distinct therapeutic mechanisms associated with ketamine in depression treatment. However, further investigation is imperative to pinpoint potential inconsistencies stemming from variances in drug type, dosage, or administration frequency.

Therapeutic-like activity of cannabidiolic acid methyl ester in the MK-801 mouse model of schizophrenia: Role for cannabinoid CB1 and serotonin-1A receptors.

Schizophrenia is a psychotic disorder with an increasing prevalence and incidence over the last two decades. The condition presents with a diverse array of positive, negative, and cognitive impairments. Conventional treatments often yield unsatisfactory outcomes, especially with negative symptoms. We investigated the role of prefrontocortical (PFC) N-methyl-D-aspartate receptors (NMDARs) in the pathophysiology and development of schizophrenia. We explored the potential therapeutic effects of cannabidiolic acid (CBDA) methyl ester (HU-580), an analogue of CBDA known to act as an agonist of the serotonin-1A receptor (5-HT1AR) and an antagonist of cannabinoid type 1 receptor (CB1R). C57BL/6 mice were intraperitoneally administered the NMDAR antagonist, dizocilpine (MK-801, .3 mg/kg) once daily for 17 days. After 7 days, they were concurrently given HU-580 (.01 or .05 µg/kg) for 10 days. Behavioural deficits were assessed at two time points. We conducted enzyme-linked immunosorbent assays to measure the concentration of PFC 5-HT1AR and CB1R. We found that MK-801 effectively induced schizophrenia-related behaviours including hyperactivity, social withdrawal, increased forced swim immobility, and cognitive deficits. We discovered that low-dose HU-580 (.01 µg/kg), but not the high dose (.05 µg/kg), attenuated hyperactivity, forced swim immobility and cognitive deficits, particularly in female mice. Our results revealed that MK-801 downregulated both CB1R and 5-HT1AR, an effect that was blocked by both low- and high-dose HU-580. This study sheds light on the potential antipsychotic properties of HU-580, particularly in the context of NMDAR-induced dysfunction. Our findings could contribute significantly to our understanding of schizophrenia pathophysiology and offer a promising avenue for exploring the therapeutic potential of HU-580 and related compounds in alleviating symptoms.

Distinct spatiotemporal patterns of cortical thinning in Alzheimer's disease-type cognitive impairment and subcortical vascular cognitive impairment.

Previous studies on Alzheimer's disease-type cognitive impairment (ADCI) and subcortical vascular cognitive impairment (SVCI) has rarely explored spatiotemporal heterogeneity. This study aims to identify distinct spatiotemporal cortical atrophy patterns in ADCI and SVCI. 1,338 participants (713 ADCI, 208 SVCI, and 417 cognitively unimpaired elders) underwent brain magnetic resonance imaging (MRI), amyloid positron emission tomography, and neuropsychological tests. Using MRI, this study measures cortical thickness in five brain regions (medial temporal, inferior temporal, posterior medial parietal, lateral parietal, and frontal areas) and utilizes the Subtype and Stage Inference (SuStaIn) model to predict the most probable subtype and stage for each participant. SuStaIn identifies two distinct cortical thinning patterns in ADCI (medial temporal: 65.8%, diffuse: 34.2%) and SVCI (frontotemporal: 47.1%, parietal: 52.9%) patients. The medial temporal subtype of ADCI shows a faster decline in attention, visuospatial, visual memory, and frontal/executive domains than the diffuse subtype (p-value < 0.01). However, there are no significant differences in longitudinal cognitive outcomes between the two subtypes of SVCI. Our study provides valuable insights into the distinct spatiotemporal patterns of cortical thinning in patients with ADCI and SVCI, suggesting the potential for individualized therapeutic and preventive strategies to improve clinical outcomes.

Radix Bupleuri aqueous extract attenuates MK801-induced schizophrenia-like symptoms in mice: Participation of intestinal flora.

Schizophrenia (SCZ) is a psychotic mental disorder characterized by cognitive, behavioral, and social impairments. However, current pharmacological treatment regimens are subpar in terms of effectiveness. This study aimed to investigate the function of Radix Bupleuri aqueous extract in SCZ in mouse models. The SCZ mouse model was established by MK-801 injection and feeding of Radix Bupleuri aqueous extract or combined antibiotics. Radix Bupleuri aqueous extract significantly improved the aberrant behaviors and neuronal damage in SCZ mice, upregulated SYP and PSD-95 expression and BDNF levels in hippocampal homogenates, down-regulated DA and 5-HT levels, and suppressed microglial activation in SCZ mice. Moreover, Radix Bupleuri aqueous extract improved the integrity of the intestinal tract barrier. The 16 S rRNA sequencing of feces showed that Radix Bupleuri extract modulated the composition of gut flora. Lactobacillus abundance was decreased in SCZ mice and reversed by Radix Bupleuri aqueous extract administration which exhibited a significant negative correlation with IL-6, IL-1ß, DA, and 5-HT, and a significant positive correlation with BDNF levels in hippocampal tissues. The abundance of Parabacteroides and Alloprevotella was increased in SCZ mice. It was reversed by Radix Bupleuri aqueous extract administration, which exhibited a positive correlation with IL-6, IL-1ß, and 5-HT and a negative correlation with BDNF. In conclusion, Radix Bupleuri aqueous extract attenuates the inflammatory response in hippocampal tissues and modulates neurotransmitter levels, exerting its neuroprotective effect in SCZ. Meanwhile, the alteration of intestinal flora may be involved in this process, which is expected to be an underlying therapeutic option in treating SCZ.