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Cells Mar 2022Dysfunction in the hippocampus-prefrontal cortex (H-PFC) circuit is a critical determinant of schizophrenia. Screening of pyridazinone-risperidone hybrids on this...
Dysfunction in the hippocampus-prefrontal cortex (H-PFC) circuit is a critical determinant of schizophrenia. Screening of pyridazinone-risperidone hybrids on this circuit revealed EGIS 11150 (S 36549). EGIS 11150 induced theta rhythm in hippocampal slice preparations in the stratum lacunosum molecular area of CA1, which was resistant to atropine and prazosin. EGIS 11150 enhanced H-PFC coherence, and increased the 8−9 Hz theta band of the EEG power spectrum (from 0.002 mg/kg i.p, at >30× lower doses than clozapine, and >100× for olanzapine, risperidone, or haloperidol). EGIS 11150 fully blocked the effects of phencyclidine (PCP) or ketamine on EEG. Inhibition of long-term potentiation (LTP) in H-PFC was blocked by platform stress, but was fully restored by EGIS 11150 (0.01 mg/kg i.p.), whereas clozapine (0.3 mg/kg ip) only partially restored LTP. EGIS 11150 has a unique electrophysiological profile, so phenotypical screening on H-PFC connectivity can reveal novel antipsychotics.
Topics: Animals; Antipsychotic Agents; Clozapine; Hippocampus; Neuronal Plasticity; Prefrontal Cortex; Rats; Rats, Wistar; Risperidone
PubMed: 35406745
DOI: 10.3390/cells11071181 -
Brain and Neuroscience Advances 2021Encoding information into memory is sensitive to distraction while retrieving that memory may be compromised by proactive interference from pre-existing memories. These...
Encoding information into memory is sensitive to distraction while retrieving that memory may be compromised by proactive interference from pre-existing memories. These two debilitating effects are common in neuropsychiatric conditions, but modelling them preclinically to date is slow as it requires prolonged operant training. A step change would be the validation of functionally equivalent but fast, simple, high-throughput tasks based on spontaneous behaviour. Here, we show that spontaneous object preference testing meets these requirements in the subchronic phencyclidine rat model for cognitive impairments associated with schizophrenia. Subchronic phencyclidine rats show clear memory sensitivity to distraction in the standard novel object recognition task. However, due to this, standard novel object recognition task cannot assess proactive interference. Therefore, we compared subchronic phencyclidine performance in standard novel object recognition task to that using the continuous novel object recognition task, which offers minimal distraction, allowing disease-relevant memory deficits to be assessed directly. We first determined that subchronic phencyclidine treatment did not affect whisker movements during object exploration. Subchronic phencyclidine rats exhibited the expected distraction standard novel object recognition task effect but had intact performance on the first continuous novel object recognition task trial, effectively dissociating distraction using two novel object recognition task variants. In remaining continuous novel object recognition task trials, the cumulative discrimination index for subchronic phencyclidine rats was above chance throughout, but, importantly, their detection of object novelty was increasingly impaired relative to controls. We attribute this effect to the accumulation of proactive interference. This is the first demonstration that increased sensitivity to distraction and proactive interference, both key cognitive impairments in schizophrenia, can be dissociated in the subchronic phencyclidine rat using two variants of the same fast, simple, spontaneous object memory paradigm.
PubMed: 35392130
DOI: 10.1177/23982128211003199 -
Journal of Integrative Neuroscience Jan 2022Locomotor hyperactivity induced by psychotomimetic drugs, such as amphetamine and phencyclidine, is widely used as an animal model of psychosis-like behaviour and is...
Locomotor hyperactivity induced by psychotomimetic drugs, such as amphetamine and phencyclidine, is widely used as an animal model of psychosis-like behaviour and is commonly attributed to an interaction with dopamine release and N-methyl-D-aspartate (NMDA) receptors, respectively. However, what is often not sufficiently taken into account is that the pharmacological profile of these drugs is complex and may involve other neurotransmitter/receptor systems. Therefore, this study aimed to assess the effect of three antagonists targeting different monoamine pathways on amphetamine- and phencyclidine-induced locomotor hyperactivity. A total of 32 rats were pre-treated with antagonists affecting dopaminergic, noradrenergic and serotonergic transmission: haloperidol (0.05 mg/kg), prazosin (2 mg/kg) and ritanserin (1 mg/kg), respectively. After 30 min of spontaneous activity, rats were injected with amphetamine (0.5 mg/kg) or phencyclidine (2.5 mg/kg) and distance travelled, stereotypy and rearing recorded in photocell cages over 90 min. Pre-treatment with haloperidol or prazosin both reduced amphetamine-induced hyperactivity although pre-treatment with ritanserin had only a partial effect. None of the pre-treatments significantly altered the hyperlocomotion effects of phencyclidine. These findings suggest that noradrenergic as well as dopaminergic neurotransmission is critical for amphetamine-induced locomotor hyperactivity. Hyperlocomotion effects of phencyclidine are dependent on other factors, most likely NMDA receptor antagonism. These results help to interpret psychotomimetic drug-induced locomotor hyperactivity as an experimental model of psychosis.
Topics: Adrenergic alpha-1 Receptor Antagonists; Akathisia, Drug-Induced; Amphetamine; Animals; Behavior, Animal; Central Nervous System Stimulants; Disease Models, Animal; Dopamine Antagonists; Excitatory Amino Acid Antagonists; Male; Phencyclidine; Psychoses, Substance-Induced; Rats; Rats, Sprague-Dawley; Serotonin Antagonists
PubMed: 35164453
DOI: 10.31083/j.jin2101017 -
Genes, Brain, and Behavior Apr 2022Genetic studies implicate disruption to the DLG2 gene in copy number variants as increasing risk for schizophrenia, autism spectrum disorders and intellectual...
Genetic studies implicate disruption to the DLG2 gene in copy number variants as increasing risk for schizophrenia, autism spectrum disorders and intellectual disability. To investigate psychiatric endophenotypes associated with DLG2 haploinsufficiency (and concomitant PSD-93 protein reduction) a novel clinically relevant Dlg2 rat was assessed for abnormalities in anxiety, sensorimotor gating, hedonic reactions, social behaviour, and locomotor response to the N-Methyl-D-aspartic acid receptor antagonist phencyclidine. Dlg gene and protein expression were also investigated to assess model validity. Reductions in PSD-93 messenger RNA and protein were observed in the absence of compensation by other related genes or proteins. Behaviourally Dlg2 rats show a potentiated locomotor response to phencyclidine, as is typical of psychotic disorder models, in the absence of deficits in the other behavioural phenotypes assessed here. This shows that the behavioural effects of Dlg2 haploinsufficiency may specifically relate to psychosis vulnerability but are subtle, and partially dissimilar to behavioural deficits previously reported in Dlg2 mouse models demonstrating issues surrounding the comparison of models with different aetiology and species. Intact performance on many of the behavioural domains assessed here, such as anxiety and reward processing, will remove these as confounds when continuing investigation into this model using more complex cognitive tasks.
Topics: Animals; Disease Models, Animal; Guanylate Kinases; Haploinsufficiency; Humans; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Mice; Phencyclidine; Rats; Schizophrenia; Social Behavior; Tumor Suppressor Proteins
PubMed: 35075790
DOI: 10.1111/gbb.12797 -
The International Journal of... May 2022Schizophrenia is a severe mental disorder featuring psychotic, depressive, and cognitive alterations. Current antipsychotic drugs preferentially target dopamine D2-R...
Schizophrenia is a severe mental disorder featuring psychotic, depressive, and cognitive alterations. Current antipsychotic drugs preferentially target dopamine D2-R and/or serotonergic 5-HT2A/1A-R. They partly alleviate psychotic symptoms but fail to treat negative symptoms and cognitive deficits. Here we report on the putative antipsychotic activity of (1-[(3-fluorophenyl)sulfonyl]-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline dihydrochloride) (FPPQ), a dual serotonin 5-HT3-R/5-HT6-R antagonist endowed with pro-cognitive properties. FPPQ fully reversed phencyclidine-induced decrease of low-frequency oscillations in the medial prefrontal cortex of anaesthetized rats, a fingerprint of antipsychotic activity. This effect was mimicked by the combined administration of the 5-HT3-R and 5-HT6-R antagonists ondansetron and SB-399 885, respectively, but not by either drug alone. In freely moving rats, FPPQ countered phencyclidine-induced hyperlocomotion and augmentation of gamma and high-frequency oscillations in medial prefrontal cortex, dorsal hippocampus, and nucleus accumbens. Overall, this supports that simultaneous blockade of 5-HT3R and 5-HT6-R-like that induced by FPPQ-can be a new target in antipsychotic drug development.
Topics: Animals; Antipsychotic Agents; Brain; Hippocampus; Nucleus Accumbens; Phencyclidine; Prefrontal Cortex; Quinolines; Rats; Receptors, Serotonin; Serotonin Antagonists
PubMed: 35022720
DOI: 10.1093/ijnp/pyac003 -
Arhiv Za Higijenu Rada I Toksikologiju Dec 2021Lysergic acid diethylamide (LSD) is a classic hallucinogen, widely abused for decades, while phencyclidine (PCP) has increased in popularity in recent years, especially...
Lysergic acid diethylamide (LSD) is a classic hallucinogen, widely abused for decades, while phencyclidine (PCP) has increased in popularity in recent years, especially among the adolescents. Very little is known about the general toxicity of these compounds, especially about their possible neurotoxic effects at the cell level. The aim of this study was to address these gaps by assessing the toxic effects of 24-hour exposure to LSD and PCP in the concentration range of 0.39-100 μmol/L in the human neuroblastoma SH-SY5Y cell line. After cell viability was established, cells treated with concentrations that reduced their viability up to 30 % were further subjected to the alkaline comet assay and biochemical assays that enable estimation of oxidative stress-related effects. Treatment with LSD at 6.25 μmol/L and with PCP at 3.13 μmol/L resulted with 88.06±2.05 and 84.17±3.19 % of viable cells, respectively, and led to a significant increase in primary DNA damage compared to negative control. LSD also caused a significant increase in malondialdehyde level, reactive oxygen species (ROS) production, and glutathione (GSH) level, PCP significantly increased ROS but lowered GSH compared to control. Treatment with LSD significantly increased the activities of all antioxidant enzymes, while PCP treatment significantly increased superoxide dismutase (SOD) and glutathione peroxidase (GPx) but decreased catalase (CAT) activity compared to control. Our findings suggest that LSD has a greater DNA damaging potential and stronger oxidative activity than PCP in SH-SY5Y cells.
Topics: Adolescent; Cell Line; Cell Line, Tumor; DNA Damage; Humans; Lysergic Acid Diethylamide; Neuroblastoma; Oxidative Stress; Phencyclidine; Reactive Oxygen Species; Superoxide Dismutase
PubMed: 34985843
DOI: 10.2478/aiht-2021-72-3604 -
World Journal of Clinical Cases Nov 2021Capillary leak syndrome (CLS) is characterized by the leakage of large amounts of fluid and plasma proteins into the interstitial space, resulting in hypoalbuminemia,...
BACKGROUND
Capillary leak syndrome (CLS) is characterized by the leakage of large amounts of fluid and plasma proteins into the interstitial space, resulting in hypoalbuminemia, hypovolemic shock, elevated blood concentration, systemic progressive edema, and multiple serosal cavity effusion. Clinical syndromes such as cavity effusion pose a grave threat to the life and health of the patient.
CASE SUMMARY
A 58-year-old female patient was admitted to the hospital after being in a coma for 6 h following accidental ingestion of a pesticide. She was treated with phencyclidine hydrochloride and pralidoxime iodide for detoxification, mechanical ventilation to maintain oxygen supply, continuous renal replacement therapy to maintain the internal environment, and hemoperfusion to promote the excretion of toxins. She also received a transfusion of red blood cells and massive fluid resuscitation. However, her blood pressure was not maintained. The patient was diagnosed with CLS due to pesticide poisoning. Oxygenation was difficult to maintain under full ventilator support; therefore, veno-venous-extracorporeal membrane oxygenation (VV-ECMO) treatment was given 13 h after admission. Her oxygenation level improved, but a large amount of ascites and pleural effusion soon became apparent. We continued drainage with an indwelling drainage tube, and the ECMO flow stabilized. The leakage gradually decreased, and ECMO was discontinued 3 d later. On the 6 day, the patient recovered from unconsciousness, but on gastroscopic evaluation, severe erosions were found in her entire stomach. With the family's consent, treatment was stopped, and the patient was discharged from the hospital on the 7 day.
CONCLUSION
ECMO, liquid resuscitation and management, and improvement in plasma colloidal osmotic pressure, circulation, and tissue oxygen supply are crucial in treating CLS.
PubMed: 34904099
DOI: 10.12998/wjcc.v9.i33.10273 -
Forensic Sciences Research 20213-Methoxyphencyclidine (3-MeO-PCP) is a new psychoactive substance that belongs to the phencyclidines family, first identified in Europe in 2012. This drug presents a...
3-Methoxyphencyclidine (3-MeO-PCP) is a new psychoactive substance that belongs to the phencyclidines family, first identified in Europe in 2012. This drug presents a stronger binding to -methyl-D-aspartate (NMDA) receptors when compared to phencyclidine, which results in more potent effects, even at low concentrations. Very few articles have been published regarding 3-MeO-PCP in forensic toxicology. In this paper, the authors present a fatal 3-MeO-PCP intoxication case. In addition to the detection of the parent drug, metabolites were investigated in urine and, for the first time in the scientific literature, in blood. 3-MeO-PCP and its metabolites were quantitated by liquid chromatography-tandem mass spectrometry system (LC-MS/MS). Identification was confirmed by liquid chromatography-high resolution mass spectrometry (LC-HRMS). 3-MeO-PCP tested positive in femoral blood (3 525 ng/mL) and urine (7 384 ng/mL). The femoral blood concentration was higher than the fatal concentrations range already reported in the literature (from 50 to 3 200 ng/mL). 3-MeO-PCP metabolites, including -demethyl-3-MeO-PCP, piperidine-OH-3-MeO-PCP, -demethyl-piperidine-di-OH-3-MeO-PCP and piperidine-di-OH-3-MeO-PCP, were detected in blood. In addition, two new metabolites, -demethyl-piperidine-OH-3-MeO-PCP and -demethyl-cyclohexyl-OH, were identified in both blood and urine. Unfortunately, due to the lack of reference material on the market, it was not possible to measure the concentration of these metabolites. However, the ratios between the metabolites and the parent drug were useful to estimate their analytical response and prevalence. At this time, considering the low ratios (<1) between metabolites and parent drug, metabolites testing does not seem useful to increase the detection window of the drug.
PubMed: 34868712
DOI: 10.1080/20961790.2021.1928821 -
Schizophrenia Bulletin Mar 2022Allosteric modulation represents an important approach in drug discovery because of its advantages in safety and selectivity. SOMCL-668 is the first selective and potent...
Allosteric modulation represents an important approach in drug discovery because of its advantages in safety and selectivity. SOMCL-668 is the first selective and potent sigma-1 receptor allosteric modulator, discovered in our laboratory. The present work investigates the potential therapeutic effects of SOMCL-668 on phencyclidine (PCP)-induced schizophrenia-related behavior in mice and further elucidates underlying mechanisms for its antipsychotic-like effects. SOMCL-668 not only attenuated acute PCP-induced hyperactivity and PPI disruption, but also ameliorated social deficits and cognitive impairment induced by chronic PCP treatment. Pretreatment with the selective sigma-1 receptor antagonist BD1047 blocked the effects of SOMCL-668, indicating sigma-1 receptor-mediated responses. This was confirmed using sigma-1 receptor knockout mice, in which SOMCL-668 failed to ameliorate PPI disruption and hyperactivity induced by acute PCP and social deficits and cognitive impairment induced by chronic PCP treatment. Additionally, in vitro SOMCL-668 exerted positive modulation of sigma-1 receptor agonist-induced intrinsic plasticity in brain slices recorded by patch-clamp. Furthermore, in vivo lower dose of SOMCL-668 exerted positive modulation of improvement in social deficits and cognitive impairment induced by the selective sigma-1 agonist PRE084. Also, SOMCL-668 reversed chronic PCP-induced down-regulation in expression of frontal cortical p-AKT/AKT, p-CREB/CREB and BDNF in wide-type but not sigma-1 knockout mice. Moreover, administration of the PI3K/AKT inhibitor LY294002 abolished amelioration by SOMCL-668 of chronic PCP-induced schizophrenia-related behaviors by inhibition of BDNF expression. The present data provide initial, proof-of-concept evidence that allosteric modulation of the sigma-1 receptor may be a novel approach for the treatment of psychotic illness.
Topics: Allosteric Regulation; Animals; Antipsychotic Agents; Disease Models, Animal; Mice; Receptors, sigma; Sigma-1 Receptor
PubMed: 34865170
DOI: 10.1093/schbul/sbab137 -
Fa Yi Xue Za Zhi Aug 2021Objective To establish an ion chromatography method for the salt form determination of new psychoactive substances (NPS). Methods The method of conducting...
Objective To establish an ion chromatography method for the salt form determination of new psychoactive substances (NPS). Methods The method of conducting qualitative and quantitative analysis of six types of organic acid ions (acetate ion, tartrate ion, maleate ion, oxalate ion, fumarate ion, citrate ion) and five types of inorganic anions (fluoride ion, chloride ion, nitrate ion, sulfate ion, phosphate ion) in NPS sample by ion chromatography was developed. The salt forms of 222 seized NPS samples (103 samples with synthetic cannabinoids, 81 samples with cathinones, 44 samples with phenylethylamines, 12 samples with tryptamines, 7 samples with phencyclidines, 6 samples with piperazines, 2 samples with aminoindenes, 26 samples with fentanyls and 43 samples with other types of NPS) were analyzed by this method. Results Each anion had good linearity in the corresponding linear range, the correlation coefficients () were greater than 0.999, the limits of detection were 0.01-0.05 mg/L, and the limits of quantitative were 0.1-0.5 mg/L. Except that 5F-BEPIRAPIM was hydrochloride, the salt forms of the other 102 synthetic cannabinoids were all base. The salt form of 81 cathinone samples, 44 phenylethylamine samples, 7 phencyclidine samples and 2 aminoindene samples were all hydrochloride. The salt forms of tryptamine samples included base, hydrochloride, fumarate and oxalate. The salt forms of piperazine samples included base and hydrochloride. The salt forms of fentanyl samples and samples of other types included base, hydrochloride and citrate. Conclusion Ion chromatography is a simple, accurate and efficient method for determining the salt form of NPS samples, which makes the qualitative and quantitative conclusions of NPS more scientific and rigorous.
Topics: Chromatography, Liquid; Gas Chromatography-Mass Spectrometry; Ions; Psychotropic Drugs
PubMed: 34726002
DOI: 10.12116/j.issn.1004-5619.2021.310402