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CNS Neuroscience & Therapeutics Apr 2024As a phencyclidine (PCP) analog, ketamine can generate rapid-onset and substantial anesthetic effects. Contrary to traditional anesthetics, ketamine is a dissociative... (Review)
Review
BACKGROUND
As a phencyclidine (PCP) analog, ketamine can generate rapid-onset and substantial anesthetic effects. Contrary to traditional anesthetics, ketamine is a dissociative anesthetic and can induce loss of consciousness in patients. Recently, the subanaesthetic dose of ketamine was found to produce rapid-onset and lasting antidepressant effects.
AIM
However, how different concentrations of ketamine can induce diverse actions remains unclear. Furthermore, the molecular mechanisms underlying the NMDAR-mediated anesthetic and antidepressant effects of ketamine are not fully understood.
METHOD
In this review, we have introduced ketamine and its metabolism, summarized recent advances in the molecular mechanisms underlying NMDAR inhibition in the anesthetic and antidepressant effects of ketamine, explored the possible functions of NMDAR subunits in the effects of ketamine, and discussed the future directions of ketamine-based anesthetic and antidepressant drugs.
RESULT
Both the anesthetic and antidepressant effects of ketamine were thought to be mediated by N-methyl-D-aspartate receptor (NMDAR) inhibition.
CONCLUSION
The roles of NMDARs have been extensively studied in the anaesthetic effects of ketamine. However, the roles of NMDARs in antidepressant effects of ketamine are complicated and controversial.
Topics: Humans; Ketamine; Receptors, N-Methyl-D-Aspartate; Antidepressive Agents; Anesthetics
PubMed: 37680076
DOI: 10.1111/cns.14464 -
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 -
Behavioural Brain Research Oct 2023The serotonin (5-HT) receptor(R) is a widely distributed G-protein-coupled receptor, expressed abundantly in the central nervous system. Alstonine is a natural product...
NU-1223, a simplified analog of alstonine, with 5-HTR agonist-like activity, rescues memory deficit and positive and negative symptoms in subchronic phencyclidine mouse model of schizophrenia.
The serotonin (5-HT) receptor(R) is a widely distributed G-protein-coupled receptor, expressed abundantly in the central nervous system. Alstonine is a natural product that has significant properties of atypical antipsychotic drugs (AAPDs), in part attributed to 5-HTR agonism. Based on alstonine, we developed NU-1223, a simplified β carboline analog of alstonine, which shows efficacies comparable to alstonine and to other 5-HTR agonists, Ro-60-0175 and lorcaserin. The 5-HTR antagonism of some APDs, including olanzapine, contributes to weight gain, a major side effect which limits its tolerability, while the 5-HTR agonists and/or modulators, may minimize weight gain. We used the well-established rodent subchronic phencyclidine (PCP) model to test the efficacy of NU-1223 on episodic memory, using novel object recognition (NOR) task, positive (locomotor activity), and negative symptoms (social interaction) of schizophrenia (SCH). We found that NU-1223 produced both transient and prolonged rescue of the subchronic PCP-induced deficits in NOR and SI. Further, NU-1223, but not Ro-60-0175, blocked PCP and amphetamine (AMPH)-induced increase in LMA in subchronic PCP mice. These transient efficacies in LMA were blocked by the 5-HTR antagonist, SB242084. Sub-chronic NU-1223 treatment rescued NOR and SI deficits in subchronic PCP mice for at least 39 days after 3 days injection. Chronic treatment with NU-1223, ip, twice a day for 21 days, did not increase average body weight vs olanzapine. These findings clearly indicate NU-1223 as a class of small molecules with a possible 5-HTR-agonist-like mechanism of action, attributing to its efficacy. Additional in-depth receptor mechanistic studies are warranted, as this small molecule, both transiently and chronically rescued PCP-induced deficits. Furthermore, NU-1223 did not induce weight gain post long-term administrations vs AAPDs such as olanzapine, making NU-1223 a putative therapeutic compound for SCH.
Topics: Animals; Mice; Antipsychotic Agents; Memory Disorders; Olanzapine; Phencyclidine; Schizophrenia; Serotonin; Secologanin Tryptamine Alkaloids
PubMed: 37572758
DOI: 10.1016/j.bbr.2023.114614 -
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 -
Psychopharmacology Oct 2023Sex-biased differences in schizophrenia are evident in several features of the disease, including symptomatology and response to pharmacological treatments. As a...
Sex-biased differences in schizophrenia are evident in several features of the disease, including symptomatology and response to pharmacological treatments. As a neurodevelopmental disorder, these differences might originate early in life and emerge later during adolescence. Considering that the disruption of the glutamatergic system during development is known to contribute to schizophrenia, we hypothesized that the neonatal phencyclidine model could induce sex-dependent behavioral and neurochemical changes associated with this disorder during adolescence. C57BL/6 mice received either saline or phencyclidine (5, 10, or 20 mg/kg) on postnatal days (PN) 7, 9, and 11. Behavioral assessment occurred in late adolescence (PN48-50), when mice were submitted to the open field, social interaction, and prepulse inhibition tests. Either olanzapine or saline was administered before each test. The NMDAR obligatory GluN1 subunit and the postsynaptic density protein 95 (PSD-95) were evaluated in the frontal cortex and hippocampus at early (PN30) and late (PN50) adolescence. Neonatal phencyclidine evoked dose-dependent deficits in all analyzed behaviors and males were more susceptible. Males also had reduced GluN1 expression in the frontal cortex at PN30. There were late-emergent effects at PN50. Cortical GluN1 was increased in both sexes, while phencyclidine increased cortical and decreased hippocampal PSD-95 in females. Olanzapine failed to mitigate most phencyclidine-evoked alterations. In some instances, this antipsychotic aggravated the deficits or potentiated subthreshold effects. These results lend support to the use of neonatal phencyclidine as a sex-biased neurodevelopmental preclinical model of schizophrenia. Olanzapine null effects and deleterious outcomes suggest that its use during adolescence should be further evaluated.
Topics: Male; Female; Animals; Mice; Phencyclidine; Schizophrenia; Olanzapine; Mice, Inbred C57BL; Antipsychotic Agents; Disease Models, Animal
PubMed: 37530885
DOI: 10.1007/s00213-023-06434-3 -
Journal of Pharmaceutical and... Sep 2023Phencyclidine (PCP) is a frequently abused dissociative agent. It causes confusion, increased tendencies toward violence, and concentration-dependent cytotoxicity after...
Phencyclidine (PCP) is a frequently abused dissociative agent. It causes confusion, increased tendencies toward violence, and concentration-dependent cytotoxicity after entry into the body. The parent nucleus of phencyclidine-type substances is arylcyclohexylamine, which is easy to modify; therefore, abusers and dealers can readily synthesize substitutes beyond the drug control catalog. An urgent need exists to establish screening methods for phencyclidine-type substances to provide technical support for abuse monitoring. In this study, 20 mg of hair was pulverized in 500 mL of methanol containing 0.5 ng/mL PCP-d. After ultrasonication, centrifugation, and filtration, the supernatant was analyzed by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) operating in the multiple reaction monitoring mode. Phencyclidine-type substances were separated in 13 min on a biphenyl column using a mobile phase gradient composed of A (water, formic acid 0.1%, acetonitrile 5%, 20 mmol/L ammonium acetate) and B (acetonitrile). The developed and validated method showed good selectivity, sensitivity (limit of detection: 0.25-2 pg/mg and lower limit of quantitation: 0.5-4 pg/mg), linearity (R > 0.994), accuracy, and precision (< 20%), and a dilution effect. The method also showed good recovery and acceptable matrix effects for most of the targeted compounds. This analytical approach was successfully applied for the identification and quantification of phencyclidine-type substances in hair from 87 authentic forensic cases. Nine analytes were detected: ketamine (10.3-26211.3 pg/mg), 2-F-2-oxo-PCE (11.5-4034.9 pg/mg), 2-FDCK (14.0-43290.2 pg/mg), 2-BrDCK (10.6-21170.0 pg/mg), nor2-FDCK (10.1-16767.4 pg/mg), tiletamine (10.1-3250.8 pg/mg), O-PCE (43.3-166.1 pg/mg), DCK (10.2-90.4 pg/mg), and norDCK (24.9-103.0 pg/mg).
Topics: Phencyclidine; Chromatography, High Pressure Liquid; Chromatography, Liquid; Tandem Mass Spectrometry; Hair; Acetonitriles
PubMed: 37480824
DOI: 10.1016/j.jpba.2023.115577 -
Current Neuropharmacology 2024The development of new antipsychotics with pro-cognitive properties and less side effects represents a priority in schizophrenia drug research. In this study, we present...
The development of new antipsychotics with pro-cognitive properties and less side effects represents a priority in schizophrenia drug research. In this study, we present for the first time a preclinical exploration of the effects of the promising natural atypical antipsychotic Methyl-2-Amino-3- Methoxybenzoate (MAM), a brain-penetrable protoalkaloid from the seed of the plant Nigella damascena. Using animal models related to hyperdopaminergic activity, namely the pharmacogenetic apomorphine (D2/D1 receptor agonist)-susceptible (APO-SUS) rat model and pharmacologically induced mouse and rat models of schizophrenia, we found that MAM reduced gnawing stereotypy and climbing behaviours induced by dopaminergic agents. This predicts antipsychotic activity. In line, MAM antagonized apomorphine-induced c-Fos and NPAS4 mRNA levels in post-mortem brain nucleus accumbens and dorsolateral striatum of APO-SUS rats. Furthermore, phencyclidine (PCP, an NMDA receptor antagonist) and 2,5-Dimethoxy-4-iodoamphetamine (DOI, a 5HT2A/2C receptor agonist) induced prepulse inhibition deficits, reflecting the positive symptoms of schizophrenia, which were rescued by treatment with MAM and atypical antipsychotics alike. Post-mortem brain immunostaining revealed that MAM blocked the strong activation of both PCP- and DOI-induced c-Fos immunoreactivity in a number of cortical areas. Finally, during a 28-day subchronic treatment regime, MAM did not induce weight gain, hyperglycemia, hyperlipidemia or hepato- and nephrotoxic effects, side effects known to be induced by atypical antipsychotics. MAM also did not show any cataleptic effects. In conclusion, its brain penetrability, the apparent absence of preclinical side effects, and its ability to antagonize positive and cognitive symptoms associated with schizophrenia make MAM an exciting new antipsychotic drug that deserves clinical testing.
Topics: Rats; Mice; Animals; Antipsychotic Agents; Schizophrenia; Apomorphine; Hydroxybenzoate Ethers; Disease Models, Animal; Cognition
PubMed: 37475559
DOI: 10.2174/1570159X21666230720122354 -
The American Journal of Drug and... Jul 2023Illicit drug use has become a global epidemic, yet it is unclear if drug smoking increases the risk of tobacco-related cancers. We aimed to evaluate hypothesized...
Opium, phencyclidine, and crack cocaine smoking associations with lung and upper aerodigestive tract cancers: exploratory findings from a case-control study in Los Angeles County.
Illicit drug use has become a global epidemic, yet it is unclear if drug smoking increases the risk of tobacco-related cancers. We aimed to evaluate hypothesized associations between smoking three drugs - opium, phencyclidine (PCP) and crack cocaine and lung and upper aerodigestive tract (UADT) cancers. A population-based case-control study with 611 lung cancer cases (50% male), 601 UADT cancers cases (76% male), and 1,040 controls (60% male) was conducted in Los Angeles County (1999-2004). Epidemiologic data including drug smoking histories were collected in face-to-face interviews. Associations were estimated with logistic regressions. Adjusting for potential confounders, ever vs. never crack smoking was positively associated with UADT cancers (aOR = 1.56, 95% CI: 1.05, 2.33), and a dose-response relationship was observed for lifetime smoking frequency (p for trend = .024). Heavy (> median) vs. never crack smoking was associated with UADT cancers (aOR = 1.81, 95% CI: 1.07, 3.08) and lung cancer (aOR = 1.58, 95% CI: 0.88, 2.83). A positive association was also observed between heavy PCP smoking and UADT cancers (aOR = 2.29, 95% CI: 0.91, 5.79). Little or no associations were found between opium smoking and lung cancer or UADT cancers. The positive associations between illicit drug use and lung and/or UADT cancers suggest that smoking these drugs may increase the risk of tobacco-related cancers. Despite the low frequency of drug smoking and possible residual confounding, our findings may provide additional insights on the development of lung and UADT cancers.
Topics: Humans; Male; Female; Head and Neck Neoplasms; Opium; Phencyclidine; Cocaine Smoking; Los Angeles; Case-Control Studies; Lung Neoplasms; Lung; Illicit Drugs; Risk Factors
PubMed: 37433108
DOI: 10.1080/00952990.2023.2220875