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Pharmaceuticals (Basel, Switzerland) Mar 2024New Psychoactive Substances (NPS) are modifying the drug scenario worldwide and have become a public health concern because of their toxicological profiles and their... (Review)
Review
New Psychoactive Substances (NPS) are modifying the drug scenario worldwide and have become a public health concern because of their toxicological profiles and their harmful physical/psychological effects. 3-Methoxy-Phencyclidine (3-MeO-PCP), a non-competitive antagonist of glutamate N-methyl-D-aspartate (NMDA) receptors, belongs to the phencyclidine-like subfamily of arylcyclohexylamines and has gained attention for its toxic, sometimes fatal, effects. Despite several cases of intoxication and death reported in the literature, little is known about substance-induced psychotic disorders (SIP) and potential cognitive impairment following 3-MeO-PCP intake. This literature review aimed to summarize available evidence about 3-MeO-PCP mechanisms of action and physical and psychotropic effects and to spread preliminary findings about persistent psychotic symptoms and impaired cognitive functioning. Additionally, the case of an SIP is reported in a 29-year-old man with small oral intakes of 3-MeO-PCP over two weeks until a high dose ingestion. Psychometric and neuropsychological assessment and brain [F]-fluorodeoxyglucose positron emission tomography integrated with computed tomography were used to support clinical description. Identifying and addressing the characteristic clinical features and neural substrates of NPS-induced psychoses might help clinicians with a more precise differentiation from other psychotic disorders. Although further studies are required, phenotyping the cognitive profile of NPS users might provide targets for tailored therapeutic approaches.
PubMed: 38675413
DOI: 10.3390/ph17040452 -
Research Square Dec 2023Cognitive deficits are a long-lasting consequence of drug use, yet the convergent mechanism by which classes of drugs with different pharmacological properties cause...
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. Stimulation of dopaminergic neurons in the ventral tegmental area is necessary and sufficient to produce this gain of GABA. Drug-induced prefrontal hyperactivity drives this change in transmitter identity. Returning prefrontal activity to baseline, chemogenetically or with clozapine, reverses the change in transmitter phenotype and rescues the associated memory deficits. The results reveal a shared and reversible mechanism that regulates the appearance of cognitive deficits upon exposure to different drugs.
PubMed: 38168375
DOI: 10.21203/rs.3.rs-3689243/v1 -
JAMA Network Open Mar 2024Young 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...
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. The setting was Rady Children's Hospital San Diego, a free-standing pediatric hospital in California. Participants included all emergency department and inpatient medical encounters involving children aged 12 years or younger with a positive urine drug test between 2016 and 2021. Statistical analysis was performed from February 2023 to January 2024.
EXPOSURE
Drug type, including amphetamines, barbiturates, benzodiazepines, cannabis, cocaine, fentanyl, opiates, and phencyclidine.
MAIN MEASURES AND OUTCOMES
CPS responses associated with the medical encounter including reports, substantiations, case openings, and out-of-home placements.
RESULTS
A total of 511 emergency department and inpatient medical encounters involving children had a positive drug test (262 [51.3%] were female; 309 [60.5%] were age 6 years or younger; fewer than 10 [<3.0%] were American Indian or Alaska Native; 252 [49.3%] were Hispanic [any race], 20 [3.9%] were non-Hispanic Asian, 56 [11.0%] were non-Hispanic Black, 143 [28.0%] were non-Hispanic White, 36 [7.0%] had other or unknown race and ethnicity; 233 [43.6%] had a CPS report prior to the medical encounter). Following the positive screen, 244 (47.7%) were reported to child protection, and 61 (11.9%) were placed out-of-home within 30 days. Mean (SD) quarterly counts of encounters with positive drug tests doubled after the COVID-19 pandemic onset (32.9 [9.8]) compared with prior to the pandemic onset (16.5 [4.7]); for encounters positive for cannabis, mean (SD) quarterly counts were 3 times as high after the pandemic onset than prior (16.6 [4.7] vs 5.7 [2.9]). Encounters for children under age 1 were significantly more likely to have associated child protection reports (relative risk [RR], 2.91 [95% CI, 2.21-3.83]) and child protection case openings (RR, 1.71 [95% CI, 1.07-2.72]) than encounters involving older children.
CONCLUSIONS AND RELEVANCE
In this cross-sectional study of emergency department and inpatient medical encounters, less than half of children with positive urine drug screens were reported to CPS; out-of-home placements were uncommon. With increased encounters for positive drug tests, it is unclear what services these children and families are receiving.
Topics: Child; Humans; Female; Adolescent; Child, Preschool; Male; Cross-Sectional Studies; Pandemics; Retrospective Studies; Urine; Urinalysis; Cannabinoid Receptor Agonists; Cannabis; Hallucinogens
PubMed: 38512254
DOI: 10.1001/jamanetworkopen.2024.3133 -
Biological Psychiatry Global Open... Jan 2024Phencyclidine (PCP) causes psychosis, is abused with increasing frequency, and was extensively used in antipsychotic drug discovery. PCP discoordinates hippocampal...
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. Mechanistic causality was assessed by comparing the PCP effects with the effects of inhibitors of protein synthesis, group I metabotropic glutamate receptors (mGluR1/5), and subunit-selective NMDARs.
RESULTS
Consistent with ionotropic actions, PCP discoordinated CA1 ensemble action potential discharge. PCP caused hyperactivity and impaired active place avoidance, despite the rodents having learned the task before PCP administration. Consistent with metabotropic actions, PCP exaggerated protein synthesis-dependent DHPG-induced mGluR1/5-stimulated long-term synaptic depression. Pretreatment with anisomycin or the mGluR1/5 antagonist MPEP, both of which repress translation, prevented PCP-induced discoordination and the cognitive and sensorimotor impairments. PCP as well as the NR2A-containing NMDAR antagonist NVP-AAM077 unbalanced translation that engages the Akt, mTOR (mechanistic target of rapamycin), and 4EBP1 translation machinery and increased protein synthesis, whereas the NR2B-containing antagonist Ro25-6981 did not.
CONCLUSIONS
PCP dysregulates translation, acting through NR2A-containing NMDAR subtypes, recruiting mGluR1/5 signaling pathways, and leading to neural discoordination that is central to the cognitive and sensorimotor impairments.
PubMed: 38298788
DOI: 10.1016/j.bpsgos.2023.04.009 -
Journal of Neuroscience Research Jan 2024Noncompetitive NMDA receptor (NMDAR) antagonists like phencyclidine (PCP) and ketamine cause psychosis-like symptoms in healthy humans, exacerbate schizophrenia symptoms...
Noncompetitive NMDA receptor (NMDAR) antagonists like phencyclidine (PCP) and ketamine cause psychosis-like symptoms in healthy humans, exacerbate schizophrenia symptoms in people with the disorder, and disrupt a range of schizophrenia-relevant behaviors in rodents, including hyperlocomotion. This is negated in mice lacking the GluN2D subunit of the NMDAR, suggesting the GluN2D subunit mediates the hyperlocomotor effects of these drugs. However, the role of GluN2D in mediating other schizophrenia-relevant NMDAR antagonist-induced behavioral disturbances, and in both sexes, is unclear. This study aimed to investigate the role of the GluN2D subunit in mediating schizophrenia-relevant behaviors induced by a range of NMDA receptor antagonists. Using both male and female GluN2D knockout (KO) mice, we examined the effects of the NMDAR antagonist's PCP, the S-ketamine enantiomer (S-ket), and the ketamine metabolite R-norketamine (R-norket) on locomotor activity, anxiety-related behavior, and recognition and short-term spatial memory. GluN2D-KO mice showed a blunted locomotor response to R-norket, S-ket, and PCP, a phenotype present in both sexes. GluN2D-KO mice of both sexes showed an anxious phenotype and S-ket, R-norket, and PCP showed anxiolytic effects that were dependent on sex and genotype. S-ket disrupted spatial recognition memory in females and novel object recognition memory in both sexes, independent of genotype. This datum identifies a role for the GluN2D subunit in sex-specific effects of NMDAR antagonists and on the differential effects of the R- and S-ket enantiomers.
Topics: Animals; Female; Humans; Male; Mice; Ketamine; Phencyclidine; Receptors, N-Methyl-D-Aspartate; Recognition, Psychology
PubMed: 37814998
DOI: 10.1002/jnr.25257 -
Analytical Chemistry Dec 2023The 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...
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. Here, we present NPS-MS, a deep learning method capable of accurately predicting the MS/MS spectra of known and hypothesized NPS from their chemical structures alone. NPS-MS is trained by transfer learning from a generic MS/MS prediction model on a large data set of MS/MS spectra. We show that this approach enables a more accurate identification of NPS from experimentally acquired MS/MS spectra than any existing method. We demonstrate the application of NPS-MS to identify a novel derivative of phencyclidine (PCP) within an unknown powder seized in Denmark without the use of any reference standards. We anticipate that NPS-MS will allow forensic laboratories to identify more rapidly both known and newly emerging NPS. NPS-MS is available as a web server at https://nps-ms.ca/, which provides MS/MS spectra prediction capabilities for given NPS compounds. Additionally, it offers MS/MS spectra identification against a vast database comprising approximately 8.7 million predicted NPS compounds from DarkNPS and 24.5 million predicted ESI-QToF-MS/MS spectra for these compounds.
Topics: Tandem Mass Spectrometry; Deep Learning; Psychotropic Drugs; Illicit Drugs; Spectrometry, Mass, Electrospray Ionization
PubMed: 38048435
DOI: 10.1021/acs.analchem.3c02413 -
Science Advances Jan 2024Metabotropic glutamate receptor 2 (mGlu) attracts particular attention as a possible target for a new class of antipsychotics. However, the signaling pathways...
Metabotropic glutamate receptor 2 (mGlu) attracts particular attention as a possible target for a new class of antipsychotics. However, the signaling pathways transducing the effects of mGlu in the brain remain poorly characterized. Here, we addressed this issue by identifying native mGlu interactome in mouse prefrontal cortex. Nanobody-based affinity purification and mass spectrometry identified 149 candidate mGlu partners, including the neurotrophin receptor TrkB. The later interaction was confirmed both in cultured cells and prefrontal cortex. mGlu activation triggers phosphorylation of TrkB on Tyr in primary cortical neurons and prefrontal cortex. Reciprocally, TrkB stimulation enhances mGlu-operated G protein activation. Furthermore, TrkB inhibition prevents the rescue of behavioral deficits by glutamatergic antipsychotics in phencyclidine-treated mice. Collectively, these results reveal a cross-talk between TrkB and mGlu, which is key to the behavioral response to glutamatergic antipsychotics.
Topics: Mice; Animals; Antipsychotic Agents; Receptor, trkB; Prefrontal Cortex; Cells, Cultured; Neurons
PubMed: 38277461
DOI: 10.1126/sciadv.adg1679 -
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 -
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 -
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