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National Science Review Nov 2023Oculomotor behavior has been shown to be correlated with mental disorders in clinics, making it promising for disease diagnosis. Here we developed a thorough oculomotor...
Oculomotor behavior has been shown to be correlated with mental disorders in clinics, making it promising for disease diagnosis. Here we developed a thorough oculomotor test toolkit, involving saccade, smooth pursuit, and fixation, allowing the examination of multiple oculomotor parameters in monkey models induced by psychoactive drugs. Eye movements were recorded after daily injections of phencyclidine (PCP) (3.0 mg/kg), ketamine (0.8 mg/kg) or controlled saline in two macaque monkeys. Both drugs led to robust reduction in accuracy and increment in reaction time during high cognitive-demanding tasks. Saccades, smooth pursuit, and fixation stability were also significantly impaired. During fixation, the involuntary microsaccades exhibited increased amplitudes and were biased toward the lower visual field. Pupillary response was reduced during cognitive tasks. Both drugs also increased sensitivity to auditory cues as reflected in auditory evoked potentials (AEPs). Thus, our animal model induced by psychoactive drugs produced largely similar abnormalities to that in patients with schizophrenia. Importantly, a classifier based on dimension reduction and machine learning could reliably identify altered states induced by different drugs (PCP, ketamine and saline, accuracy = 93%). The high performance of the classifier was reserved even when data from one monkey were used for training and testing the other subject (averaged classification accuracy = 90%). Thus, despite heterogeneity in baseline oculomotor behavior between the two monkeys, our model allows data transferability across individuals, which could be beneficial for future evaluation of pharmaceutical or physical therapy validity.
PubMed: 38046372
DOI: 10.1093/nsr/nwad255 -
Scientific Reports Feb 2024KPNA1 is a mediator of nucleocytoplasmic transport that is abundantly expressed in the mammalian brain and regulates neuronal differentiation and synaptic function. De...
KPNA1 is a mediator of nucleocytoplasmic transport that is abundantly expressed in the mammalian brain and regulates neuronal differentiation and synaptic function. De novo mutations in Kpna1 have been identified using genome-wide association studies in humans with schizophrenia; however, it remains unclear how KPNA1 contributes to schizophrenia pathogenesis. Recent studies have suggested a complex combination of genetic and environmental factors that are closely related to psychiatric disorders. Here, we found that subchronic administration of phencyclidine, a psychotropic drug, induced vulnerability and behavioral abnormalities consistent with the symptoms of schizophrenia in Kpna1-deficient mice. Microarray assessment revealed that the expression levels of dopamine d1/d2 receptors, an RNA editing enzyme, and a cytoplasmic dynein component were significantly altered in the nucleus accumbens brain region in a gene-environment (G × E) interaction-dependent manner. Our findings demonstrate that Kpna1-deficient mice may be useful as a G × E interaction mouse model for psychiatric disorders and for further investigation into the pathogenesis of such diseases and disorders.
Topics: Humans; Mice; Animals; Schizophrenia; Gene-Environment Interaction; Genome-Wide Association Study; Psychotropic Drugs; Phencyclidine; Nucleus Accumbens; Mammals; alpha Karyopherins
PubMed: 38336912
DOI: 10.1038/s41598-024-53237-3 -
IScience Sep 2023ATP-gated P2X7 receptors (P2X7Rs) play a crucial role in brain disorders. However, how they affect normal and pathological synaptic transmission is still largely...
ATP-gated P2X7 receptors (P2X7Rs) play a crucial role in brain disorders. However, how they affect normal and pathological synaptic transmission is still largely unclear. Here, by using whole-cell patch-clamp technique to record AMPA- and NMDA receptor-mediated excitatory postsynaptic currents (s/mEPSCs) in dentate gyrus granule cells (DG GCs), we revealed a modulation by P2X7Rs of presynaptic sites, especially originated from entorhinal cortex (EC)-GC path but not the mossy cell (MC)-GC path. The involvement of P2X7Rs was confirmed using a pharmacological approach. Additionally, the acute activation of P2X7Rs directly elevated calcium influx from EC-GC terminals. In postnatal phencyclidine (PCP)-induced mouse model of schizophrenia, we observed that P2X7R deficiency restored the EC-GC synapse alteration and alleviated PCP-induced symptoms. To summarize, P2X7Rs participate in the modulation of GC excitatory neurotransmission in the DG via EC-GC pathway, contributing to pathological alterations of neuronal functions leading to neurodevelopmental disorders.
PubMed: 37649698
DOI: 10.1016/j.isci.2023.107560 -
Molecular Imaging and Biology Aug 2023NMDA receptors (NMDARs) dysfunction plays a central role in the physiopathology of psychiatric and neurodegenerative disorders whose mechanisms are still poorly...
PURPOSE
NMDA receptors (NMDARs) dysfunction plays a central role in the physiopathology of psychiatric and neurodegenerative disorders whose mechanisms are still poorly understood. The development of a PET (positron emission tomography) tracer able to selectively bind to the NMDARs intra-channel PCP site may make it possible to visualize NMDARs in an open and active state. We describe the in vitro pharmacological characterization of [F]-fluoroethylnormemantine ([F]-FNM) and evaluate its ability to localize activated NMDA receptors in a rat preclinical model of excitotoxicity.
PROCEDURES
The affinity of the non-radioactive analog for the intra-channel PCP site was determined in a radioligand competition assay using [H]TCP ([H]N-(1-[thienyl]cyclohexyl)piperidine) on rat brain homogenates. Selectivity was also investigated by the displacement of specific radioligands targeting various cerebral receptors. In vivo brain lesions were performed using stereotaxic quinolinic acid (QA) injections in the left motor area (M1) of seven Sprague Dawley rats. Each rat was imaged with a microPET/CT camera, 40 min after receiving a dose of 30 MBq + / - 20 of [F]-FNM, 24 and 72 h after injury. Nine non-injured rats were also imaged using the same protocol.
RESULTS
FNM displayed IC value of 13.0 ± 8.9 µM in rat forebrain homogenates but also showed significant bindings on opioid receptors. In the frontal and left somatosensory areas, [F]FNM PET detected a mean of 37% and 41% increase in [F]FNM uptake (p < 0,0001) 24 and 72 h after QA stereotaxic injection, respectively, compared to the control group.
CONCLUSIONS
In spite of FNM's poor affinity for NMDAR PCP site, this study supports the ability of this tracer to track massive activation of NMDARs in neurological diseases.
Topics: Rats; Animals; Receptors, N-Methyl-D-Aspartate; Rats, Sprague-Dawley; Phencyclidine; Brain Injuries; Positron-Emission Tomography; Brain
PubMed: 36944798
DOI: 10.1007/s11307-023-01811-y -
International Journal of Molecular... Sep 2023Tobacco misuse as a comorbidity of schizophrenia is frequently established during adolescence. However, comorbidity markers are still missing. Here, the method of...
Nicotine Exposure in a Phencyclidine-Induced Mice Model of Schizophrenia: Sex-Selective Medial Prefrontal Cortex Protein Markers of the Combined Insults in Adolescent Mice.
Tobacco misuse as a comorbidity of schizophrenia is frequently established during adolescence. However, comorbidity markers are still missing. Here, the method of label-free proteomics was used to identify deregulated proteins in the medial prefrontal cortex (prelimbic and infralimbic) of male and female mice modelled to schizophrenia with a history of nicotine exposure during adolescence. Phencyclidine (PCP), used to model schizophrenia (SCHZ), was combined with an established model of nicotine minipump infusions (NIC). The combined insults led to worse outcomes than each insult separately when considering the absolute number of deregulated proteins and that of exclusively deregulated ones. Partially shared Reactome pathways between sexes and between PCP, NIC and PCPNIC groups indicate functional overlaps. Distinctively, proteins differentially expressed exclusively in PCPNIC mice reveal unique effects associated with the comorbidity model. Interactome maps of these proteins identified sex-selective subnetworks, within which some proteins stood out: for females, peptidyl-prolyl cis-trans isomerase (Fkbp1a) and heat shock 70 kDa protein 1B (Hspa1b), both components of the oxidative stress subnetwork, and gamma-enolase (Eno2), a component of the energy metabolism subnetwork; and for males, amphiphysin (Amph), a component of the synaptic transmission subnetwork. These are proposed to be further investigated and validated as markers of the combined insult during adolescence.
Topics: Mice; Animals; Male; Female; Phencyclidine; Schizophrenia; Nicotine; Prefrontal Cortex; Synaptic Transmission; Disease Models, Animal
PubMed: 37834084
DOI: 10.3390/ijms241914634 -
BioRxiv : the Preprint Server For... Dec 2023Genetic analyses of Schizophrenia (SCZ) patients have identified thousands of risk factors. In silico protein-protein interaction (PPI) network analysis has provided...
Genetic analyses of Schizophrenia (SCZ) patients have identified thousands of risk factors. In silico protein-protein interaction (PPI) network analysis has provided strong evidence that disrupted PPI networks underlie SCZ pathogenesis. In this study, we performed PPI analysis of several SCZ risk factors in the rodent brain. Using endogenous antibody immunoprecipitations coupled to mass spectrometry (MS) analysis, we constructed a SCZ network comprising 1612 unique PPI with a 5% FDR. Over 90% of the PPI were novel, reflecting the lack of previous PPI MS studies in brain tissue. Our SCZ PPI network was enriched with known SCZ risk factors, which supports the hypothesis that an accumulation of disturbances in selected PPI networks underlies SCZ. We used Stable Isotope Labeling in Mammals (SILAM) to quantitate phencyclidine (PCP) perturbations in the SCZ network and found that PCP weakened most PPI but also led to some enhanced or new PPI. These findings demonstrate that quantitating PPI in perturbed biological states can reveal alterations to network biology.
PubMed: 38168169
DOI: 10.1101/2023.12.12.571320 -
Frontiers in Pharmacology 2023Ketamine acts primarily by blocking the N-methyl-D-aspartate (NMDA) receptor at the phencyclidine site. The rapid antidepressant properties of ketamine were demonstrated...
Ketamine acts primarily by blocking the N-methyl-D-aspartate (NMDA) receptor at the phencyclidine site. The rapid antidepressant properties of ketamine were demonstrated in the clinic and several behavioral models of depression in rodents. We hypothesized that the normalization of abnormal activity of monoamine neurons in Wistar Kyoto (WKY) rats contributes to the rapid antidepressant effects of ketamine. A single administration of ketamine (10 mg/kg, i. p) or saline was administered to anesthetized WKY rats before electrophysiological recordings of dorsal raphe nucleus (DRN) serotonin (5-HT), locus coeruleus (LC) norepinephrine (NE) and ventral tegmental area (VTA) dopamine (DA) neuronal activity. Pyramidal neurons from the medial prefrontal cortex (mPFC) were also recorded before and after a ketamine injection. In the VTA, ketamine elicited a significant increase in the population activity of DA neurons. This enhancement was consistent with findings in other depression-like models in which such a decreased population activity was observed. In the LC, ketamine normalized increased NE neuron burst activity found in WKY rats. In the DRN, ketamine did not significantly reverse 5-HT neuronal activity in WKY rats, which is dampened compared to Wistar rats. Ketamine did not significantly alter the neuronal activity of mPFC pyramidal neurons. These findings demonstrate that ketamine normalized NE neuronal activity and enhanced DA neuronal activity in WKY rats, which may contribute to its rapid antidepressant effect.
PubMed: 38026921
DOI: 10.3389/fphar.2023.1276309 -
CNS Neuroscience & Therapeutics Apr 2024We aimed to evaluate the potential of a novel selective α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) potentiator, LT-102, in treating...
Novel α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) potentiator LT-102: A promising therapeutic agent for treating cognitive impairment associated with schizophrenia.
AIMS
We aimed to evaluate the potential of a novel selective α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) potentiator, LT-102, in treating cognitive impairments associated with schizophrenia (CIAS) and elucidating its mechanism of action.
METHODS
The activity of LT-102 was examined by Ca influx assays and patch-clamp in rat primary hippocampal neurons. The structure of the complex was determined by X-ray crystallography. The selectivity of LT-102 was evaluated by hERG tail current recording and kinase-inhibition assays. The electrophysiological characterization of LT-102 was characterized by patch-clamp recording in mouse hippocampal slices. The expression and phosphorylation levels of proteins were examined by Western blotting. Cognitive function was assessed using the Morris water maze and novel object recognition tests.
RESULTS
LT-102 is a novel and selective AMPAR potentiator with little agonistic effect, which binds to the allosteric site formed by the intradimer interface of AMPAR's GluA2 subunit. Treatment with LT-102 facilitated long-term potentiation in mouse hippocampal slices and reversed cognitive deficits in a phencyclidine-induced mouse model. Additionally, LT-102 treatment increased the protein level of brain-derived neurotrophic factor and the phosphorylation of GluA1 in primary neurons and hippocampal tissues.
CONCLUSION
We conclude that LT-102 ameliorates cognitive impairments in a phencyclidine-induced model of schizophrenia by enhancing synaptic function, which could make it a potential therapeutic candidate for CIAS.
Topics: Animals; Mice; Rats; Phencyclidine; Schizophrenia; Cognitive Dysfunction; Isoxazoles; Propionates
PubMed: 38615362
DOI: 10.1111/cns.14713 -
Case Reports in Psychiatry 2023Venlafaxine is an antidepressant belonging to the class of serotonin-norepinephrine reuptake inhibitors that are US Food and Drug Administration-approved to treat and...
Venlafaxine is an antidepressant belonging to the class of serotonin-norepinephrine reuptake inhibitors that are US Food and Drug Administration-approved to treat and manage symptoms of depression, anxiety, and other mood disorders in adults. We describe an adolescent patient who likely had a false-positive phencyclidine result detected with an 11-panel urine drug screen in an outpatient setting of long-term use of therapeutic venlafaxine extended release for the treatment of recurrent major depressive disorder and generalized anxiety disorder. We believe that this may be the first published case report to characterize this phenomenon in a young patient in the absence of an acute overdose.
PubMed: 37404674
DOI: 10.1155/2023/6666197 -
Neuropsychopharmacology Reports Jun 2024The therapeutic potential of N-methyl-D-aspartate glutamate receptor (NMDAR) antagonists, particularly ketamine, in mood disorders, is linked to their modulation of...
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.
Topics: Dizocilpine Maleate; Prefrontal Cortex; Animals; Dopamine; Male; Excitatory Amino Acid Antagonists; Rats; Receptors, N-Methyl-D-Aspartate; Locomotion; Rats, Sprague-Dawley; Microdialysis
PubMed: 38376999
DOI: 10.1002/npr2.12420