Phencyclidin

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 Ca2+ 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...

IMPORTANCE: Young children are ingesting illicit drugs at increased rates, but it is unknown what the associated child protection system (CPS) responses are when a child tests positive. OBJECTIVE: To document the child protection system involvement and the characteristics of children who test positive for illicit substances. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cross-sectional study linked medical discharge and child protection system administrative data...

Hypofunctioning of NMDA receptors, and the resulting shift in the balance between excitation and inhibition, is considered a key process in the pathophysiology of schizophrenia. One important manifestation of this phenomenon is changes in neural oscillations, those above 30 Hz (i.e., gamma-band oscillations), in particular. Although both preclinical and clinical studies observed increased gamma activity following acute administration of NMDA receptor antagonists, the relevance of this phenomenon has been recently questioned given the reduced gamma oscillations typically observed during sensory and cognitive tasks in schizophrenia...

Cannabidiol (CBD), a non-psychoactive compound derived from the cannabis plant, has been confirmed to induce anxiolytic-like and antipsychotic-like effects. However, the exact mechanisms remain unclear. This study substantiated CBD's interaction with the 5-HT1A receptor (5-HT1A R) in vitro (CHO cells expressing human 5-HT1A R) and in vivo (rat lower lip retraction test, LLR test). We then assessed the impact of CBD in mice using the stress-induced hyperthermia (SIH) model and the phencyclidine (PCP)-induced negative symptoms of schizophrenia model, respectively...

Due to the increase in the use of novel psychoactive substances (NPS) and their overall prevalence, it is important to have effective and reliable screening technologies to detect NPS in biological matrices. Enzyme-linked immunosorbent assays (ELISA) are among the most popular screening methods. To evaluate the effectiveness of ELISA for NPS detection, five subclasses of NPS (novel synthetic opioids, fentanyl analogs, stimulants, benzodiazepines and hallucinogens) were evaluated in whole blood for their cross-reactivity on commercially available ELISA kits...

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...

The pathogenesis of schizophrenia begins in early neurodevelopment and leads to excitatory-inhibitory imbalance. It is therefore essential that preclinical models used to understand disease, select drug targets and evaluate novel therapeutics encompass similar neurochemical deficits. One approach to improved preclinical modelling incorporates dual-hit neurodevelopmental insults, like neonatal administration of phencyclidine (PCP, to disrupt development of glutamatergic circuitry) then post-weaning isolation (Iso, to mimic adolescent social stress)...

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...

BACKGROUND: Phencyclidine (PCP) causes psychosis, is abused with increasing frequency, and was extensively used in antipsychotic drug discovery. PCP discoordinates hippocampal ensemble action potential discharge and impairs cognitive control in rats, but how this uncompetitive NMDA receptor (NMDAR) antagonist impairs cognition remains unknown. METHODS: The effects of PCP were investigated on hippocampal CA1 ensemble action potential discharge in vivo in urethane-anesthetized rats and during awake behavior in mice, on synaptic responses in ex vivo mouse hippocampus slices, in mice on a hippocampus-dependent active place avoidance task that requires cognitive control, and on activating the molecular machinery of translation in acute hippocampus slices...

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 ( n  = 110) were administered saline or PCP on postnatal days 7, 9, and 11...

A safe and productive workplace requires a sober workforce, free from substances that impair judgment and concentration. Although drug monitoring programs already exist, the scope and loopholes of standard workplace testing panels are well-known, allowing other substances to remain a source of risk. Therefore, a high-throughput urine screening method for psilocin, mitragynine, phencyclidine, ketamine, norketamine, and dehydronorketamine was developed and validated in conjunction with a urine and blood confirmation method...

Metabotropic glutamate receptor 2 (mGlu2 ) attracts particular attention as a possible target for a new class of antipsychotics. However, the signaling pathways transducing the effects of mGlu2 in the brain remain poorly characterized. Here, we addressed this issue by identifying native mGlu2 interactome in mouse prefrontal cortex. Nanobody-based affinity purification and mass spectrometry identified 149 candidate mGlu2 partners, including the neurotrophin receptor TrkB. The later interaction was confirmed both in cultured cells and prefrontal cortex...

Abuse of novel arylcyclohexylamines (ACX) poses risks for toxicities including adverse neurocognitive effects. In vivo effects of ring-substituted analogs of phencyclidine (PCP), eticyclidine (PCE), and ketamine are understudied. Adult male NIH Swiss mice were used to assess locomotor effects of PCP and its 3-OH, 3-MeO, 3-Cl and 4-MeO analogs; PCE and its 3-OH and 3-MeO analogs; and ketamine and its deschloro and 2F-deschloro analogs, in comparison to those of methamphetamine (METH), 3,4-methylenedioxymethamphetamine (MDMA), and two benzofuran analogs of MDMA...

Cognitive deficits are a long-lasting consequence of drug use, yet the convergent mechanism by which classes of drugs with different pharmacological properties cause similar deficits is unclear. We find that both phencyclidine and methamphetamine, despite differing in their targets in the brain, cause the same glutamatergic neurons in the medial prefrontal cortex to gain a GABAergic phenotype and decrease their expression of the vesicular glutamate transporter. Suppressing the drug-induced gain of GABA with RNA-interference prevents the appearance of memory deficits...

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 in vivo 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...

BACKGROUND: Polymorphisms in the gene encoding for metabotropic glutamate receptor 3 (mGlu3 receptor) are associated with an increased likelihood of schizophrenia diagnosis and can predict improvements in negative symptoms following treatment with antipsychotics. However, the mechanisms by which mGlu3 receptors can regulate brain circuits involved in schizophrenia pathophysiology are not clear. METHODS: We employed selective pharmacological tools and a variety of approaches including whole-cell patch-clamp electrophysiology, slice optogenetics, and fiber photometry to investigate the effects of mGlu3 receptor activation on phencyclidine (PCP)-induced impairments in thalamo-accumbal transmission and sociability deficits...

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...

The market for illicit drugs has been reshaped by the emergence of more than 1100 new psychoactive substances (NPS) over the past decade, posing a major challenge to the forensic and toxicological laboratories tasked with detecting and identifying them. Tandem mass spectrometry (MS/MS) is the primary method used to screen for NPS within seized materials or biological samples. The most contemporary workflows necessitate labor-intensive and expensive MS/MS reference standards, which may not be available for recently emerged NPS on the illicit market...

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...

Phencyclidine (PCP), a dissociative anesthetic, is a commonly abused recreational drug. In the 1950s, initially tested as an intravenous anesthetic, PCP was discontinued for clinical use due to its severe adverse effects. Since then, it has gained popularity as a recreational drug due to its ability to induce hallucinations and alter perception. PCP can be detected in urine, serum, or plasma by immunoassays and quantified and its presence confirmed by gas or liquid chromatography-mass spectrometry. In the method described here, a deuterated internal standard is added to the sample and the drug is extracted under alkaline conditions...