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Neuropsychopharmacology : Official... Mar 2024One of the critical unmet medical needs in schizophrenia is the treatment for cognitive deficits. However, the neural circuit mechanisms of them remain unresolved.... (Comparative Study)
Comparative Study
Activation of prefrontal parvalbumin interneurons ameliorates working memory deficit even under clinically comparable antipsychotic treatment in a mouse model of schizophrenia.
One of the critical unmet medical needs in schizophrenia is the treatment for cognitive deficits. However, the neural circuit mechanisms of them remain unresolved. Previous studies utilizing animal models of schizophrenia did not consider the fact that patients with schizophrenia generally cannot discontinue antipsychotic medication due to the high risk of relapse. Here, we used multi-dimensional approaches, including histological analysis of the prelimbic cortex (PL), LC-MS/MS-based in vivo dopamine D2 receptor occupancy analysis for antipsychotics, in vivo calcium imaging, and behavioral analyses of mice using chemogenetics to investigate neural mechanisms and potential therapeutic strategies for working memory deficit in a chronic phencyclidine (PCP) mouse model of schizophrenia. Chronic PCP administration led to alterations in excitatory and inhibitory synapses, specifically in dendritic spines of pyramidal neurons, vesicular glutamate transporter 1 (VGLUT1) positive terminals, and parvalbumin (PV) positive GABAergic interneurons located in layer 2-3 of the PL. Continuous administration of olanzapine, which achieved a sustained therapeutic window of dopamine D2 receptor occupancy (60-80%) in the striatum, did not ameliorate these synaptic abnormalities and working memory deficit in the chronic PCP-treated mice. We demonstrated that chemogenetic activation of PV neurons in the PL, as confirmed by in vivo calcium imaging, ameliorated working memory deficit in this model even under clinically comparable olanzapine treatment which by itself inhibited only PCP-induced psychomotor hyperactivity. Our study suggests that targeting prefrontal PV neurons could be a promising therapeutic intervention for cognitive deficits in schizophrenia in combination with antipsychotic medication.
Topics: Animals; Humans; Mice; Antipsychotic Agents; Calcium; Chromatography, Liquid; Disease Models, Animal; Interneurons; Memory Disorders; Olanzapine; Parvalbumins; Phencyclidine; Prefrontal Cortex; Receptors, Dopamine D2; Schizophrenia; Tandem Mass Spectrometry
PubMed: 38049583
DOI: 10.1038/s41386-023-01769-z -
Radiology Case Reports Oct 2023Cerebellar, hippocampal, and basal nuclei transient edema with restricted diffusion (CHANTER) syndrome is a constellation of specific imaging findings characterized by...
Cerebellar, hippocampal, and basal nuclei transient edema with restricted diffusion (CHANTER) syndrome is a constellation of specific imaging findings characterized by cytotoxic edema in the bilateral hippocampi, cerebellar cortices, and basal ganglia in patients presenting with altered mental status in the setting of substance intoxication. Previous case reports have demonstrated a strong correlation between CHANTER syndrome and polysubstance abuse, particularly with opioid intoxication. The patient we present in this case was found unresponsive following opioid use and demonstrated a constellation of findings on initial and follow-up imaging, consistent with CHANTER syndrome. While cases of irreversible brain damage or death during hospitalization have been reported in the literature, our patient demonstrated near-full recovery a few days after admission to the hospital. We aim to highlight the presentation and progression of CHANTER syndrome and alert clinicians and radiologists to include this entity in their diagnostic checklist for patients with polysubstance abuse and altered mental status.
PubMed: 37554665
DOI: 10.1016/j.radcr.2023.07.015 -
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 -
Biological Psychiatry Global Open... Jan 2024The orbitofrontal cortex (OFC) is essential for decision making, and functional disruptions within the OFC are evident in schizophrenia. Postnatal phencyclidine (PCP)...
BACKGROUND
The orbitofrontal cortex (OFC) is essential for decision making, and functional disruptions within the OFC are evident in schizophrenia. Postnatal phencyclidine (PCP) administration in rats is a neurodevelopmental manipulation that induces schizophrenia-relevant cognitive impairments. We aimed to determine whether manipulating OFC glutamate cell activity could ameliorate postnatal PCP-induced deficits in decision making.
METHODS
Male and female Wistar rats ( = 110) were administered saline or PCP on postnatal days 7, 9, and 11. In adulthood, we expressed YFP (yellow fluorescent protein) (control), ChR2 (channelrhodopsin-2) (activation), or eNpHR 3.0 (enhanced halorhodopsin) (inhibition) in glutamate neurons within the ventromedial OFC (vmOFC). Rats were tested on the probabilistic reversal learning task once daily for 20 days while we manipulated the activity of vmOFC glutamate cells. Behavioral performance was analyzed using a Q-learning computational model of reinforcement learning.
RESULTS
Compared with saline-treated rats expressing YFP, PCP-treated rats expressing YFP completed fewer reversals, made fewer win-stay responses, and had lower learning rates. We induced similar performance impairments in saline-treated rats by activating vmOFC glutamate cells (ChR2). Strikingly, PCP-induced performance deficits were ameliorated when the activity of vmOFC glutamate cells was inhibited (halorhodopsin).
CONCLUSIONS
Postnatal PCP-induced deficits in decision making are associated with hyperactivity of vmOFC glutamate cells. Thus, normalizing vmOFC activity may represent a potential therapeutic target for decision-making deficits in patients with schizophrenia.
PubMed: 38298783
DOI: 10.1016/j.bpsgos.2023.08.002 -
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 -
Journal of Analytical Toxicology Jul 20233-Hydroxyphencyclidine (3-OH-PCP) is a hydroxy derivative of phencyclidine, synthesized in 1978 to investigate the structure-activity relationship of phencyclidine...
3-Hydroxyphencyclidine (3-OH-PCP) is a hydroxy derivative of phencyclidine, synthesized in 1978 to investigate the structure-activity relationship of phencyclidine derivates. In vitro studies have shown that 3-OH-PCP, like phencyclidine, acts on the N-methyl-D-aspartate receptor and has a higher affinity for this receptor than phencyclidine. The authors report the case of a 38-year-old man, known for drug addiction, found dead at home with two plastic bags of powders found near his body. Using liquid chromatography coupled to tandem mass spectrometry, peripheral blood toxicological analysis revealed consumption of 3-OH-PCP with a concentration of 3-OH-PCP being 524 ng/mL. Blood also tested positive for nordiazepam, methylphenidate, amisulpride, methadone and benzoylecgonine, all at concentrations near those observed after recreational abuse. The blood concentration of 3-OH-PCP is the highest ever reported in the literature. Hair testing also revealed 3-OH-PCP, at 174 pg/mg, which may correspond to a chronic consumption of this molecule. A nuclear magnetic resonance analysis of the two powders highlighted 3-OH-PCP and 5-methoxy-dimethyltryptamine, estimated to have a purity of 85.4 and 91.3%, respectively, using the Electronic Reference To access In vivo Concentrations method.
Topics: Male; Humans; Adult; Phencyclidine; Powders; Substance-Related Disorders; Hair
PubMed: 37279962
DOI: 10.1093/jat/bkad031 -
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 -
European Journal of Pharmacology Aug 2023Antipsychotic drugs of different chemical/pharmacological families show preferential dopamine (DA) D receptor (D-R) vs. D receptor (D-R) affinity, with the exception of...
Antipsychotic drugs of different chemical/pharmacological families show preferential dopamine (DA) D receptor (D-R) vs. D receptor (D-R) affinity, with the exception of clozapine, the gold standard of schizophrenia treatment, which shows a comparable affinity for both DA receptors. Here, we examined the ability of Lu AF35700 (preferential D-R>D-R antagonist), to reverse the alterations in thalamo-cortical activity induced by phencyclidine (PCP), used as a pharmacological model of schizophrenia. Lu AF35700 reversed the PCP-induced alteration of neuronal discharge and low frequency oscillation (LFO, 0.15-4 Hz) in thalamo-cortical networks. Likewise, Lu AF35700 prevented the increased c-fos mRNA expression induced by PCP in thalamo-cortical regions of awake rats. We next examined the contribution of D-R and D-R to the antipsychotic reversal of PCP effects. The D-R antagonist haloperidol reversed PCP effects on thalamic discharge rate and LFO. Remarkably, the combination of sub-effective doses of haloperidol and SCH-23390 (DA D-R antagonist) fully reversed the PCP-induced fall in thalamo-cortical LFO. However, unlike with haloperidol, SCH-23390 elicited different degrees of potentiation of the effects of low clozapine and Lu AF35700 doses. Overall, the present data support a synergistic interaction between both DA receptors to reverse the PCP-induced alterations of oscillatory activity in thalamo-cortical networks, possibly due to their simultaneous blockade in direct and indirect pathways of basal ganglia. The mild potentiation induced by SCH-23390 in the case of clozapine and Lu AF35700 suggests that, at effective doses, these agents reverse PCP effects through the simultaneous blockade of both DA receptors.
Topics: Rats; Animals; Phencyclidine; Clozapine; Haloperidol; Dopamine; Antipsychotic Agents; Dopamine Antagonists; Receptors, Dopamine D1
PubMed: 37295763
DOI: 10.1016/j.ejphar.2023.175802