-
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 -
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 -
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 -
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 -
Neuroscience Letters Mar 2024Cannabidiol (CBD), a non-psychoactive compound derived from the cannabis plant, has been confirmed to induce anxiolytic-like and antipsychotic-like effects. However, the...
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-HT receptor (5-HTR) in vitro (CHO cells expressing human 5-HTR) 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. Concurrently, we investigated whether WAY-100635, a typical 5-HTR antagonist, could attenuate these effects. Furthermore, the neurotransmitter changes through high-performance liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) were studied. Results revealed that CBD exhibits selective 5-HTR agonists-mediated effects in the rat lower lip retraction test, aligning with the robust agonistic (EC = 1.75 μM) profile observed in CHO cells. CBD at 3 mg/kg significantly reduced SIH (ΔT), a response that WAY-100635 abolished. Chronic administration of CBD at 100 mg/kg mitigated the increase in PCP-induced immobility time in the forced swim test (FST) and tail suspension test (TST). Moreover, it induced significant alterations in gamma-aminobutyric acid (GABA) and norepinephrine (NE) levels within the hippocampus (HPC). Thus, we concluded that the 5-HTR mediates CBD's anxiolytic-like effects. Additionally, CBD's effects on the negative symptoms of schizophrenia may be linked to changes in GABA and NE levels in the hippocampus. These findings offer novel insights for advancing the exploration of CBD's anxiolytic-like and antipsychotic-like effects.
Topics: Cricetinae; Mice; Rats; Humans; Animals; Antipsychotic Agents; Anti-Anxiety Agents; Cannabidiol; Serotonin; Cricetulus; Chromatography, Liquid; Tandem Mass Spectrometry; gamma-Aminobutyric Acid
PubMed: 38467272
DOI: 10.1016/j.neulet.2024.137723 -
American Journal of Perinatology May 2024The U.S. opioid epidemic has been characterized by increases in opioid misuse, overdose deaths, and neonatal opioid withdrawal syndrome. Research suggests that...
OBJECTIVE
The U.S. opioid epidemic has been characterized by increases in opioid misuse, overdose deaths, and neonatal opioid withdrawal syndrome. Research suggests that marijuana legalization has contributed to decreased use of opiates, although many studies had methodological weaknesses and failed to address the pregnant population. Implementation of medical cannabis laws has the potential to reduce maternal opioid use and, therefore, neonatal exposure to the drugs. This study aimed to examine the association between Oklahoma's implementation of state medical marijuana laws and the neonatal exposure to opioids.
STUDY DESIGN
Electronic medical records at two sites (Oklahoma City and Lawton) were searched for results of cord, urine, and meconium screens to detect amphetamines, barbiturates, benzodiazepines, cocaine, ethanol, opiates, phencyclidine, and tetrahydrocannabinol (THC). Two study periods were compared: 19 months before Oklahoma's medical marijuana law took effect and 19 months after legalization began.
RESULTS
A total of 16,804 babies were born alive at the two sites during the study period. The rate of positive THC tests per 1,000 liveborn infants significantly increased from 16.2 per 1,000 during the prelaw period to 22.2 per 1,000 during the postlaw period ( = 0.004). Neonatal opioid exposure incidence showed a nonsignificant decrease from 7.6 positive tests per 1,000 liveborn infants to 6.8 per 1,000 from prelaw to postlaw period ( = 0.542). The number of positive tests for THC and concomitant use of opioids doubled from the prelaw period ( = 4) to postlaw ( = 9), but there were too few cases for statistical significance. Infants at the more rural site had significantly higher rates for amphetamines, benzodiazepines, and THC, with a trend toward higher rates for opiates.
CONCLUSION
Marijuana legalization was related to significant increases in positive test rates for THC, but no significant change/association was noted for neonatal exposure to opioids.
KEY POINTS
· Prior studies have not examined neonatal exposure to opioids following marijuana legalization.. · Oklahoma's new law led to higher neonatal marijuana exposure.. · Legalization of medical marijuana did not change Oklahoma's neonatal opioid positivity rate..
Topics: Humans; Oklahoma; Infant, Newborn; Female; Pregnancy; Medical Marijuana; Adult; Analgesics, Opioid; Neonatal Abstinence Syndrome; Opioid-Related Disorders; Male; Dronabinol; Meconium; Substance Abuse Detection; Legislation, Drug; Young Adult
PubMed: 36452967
DOI: 10.1055/a-1990-8311 -
Archiv Der Pharmazie Jun 2024Cyclopenta[g]quinolones of type 4 were designed with the aim to bioisosterically replace the phenol of potent GluN2B ligands such as ifenprodil and Ro 25-6981 by the...
Cyclopenta[g]quinolones of type 4 were designed with the aim to bioisosterically replace the phenol of potent GluN2B ligands such as ifenprodil and Ro 25-6981 by the quinolone system and to restrict the conformational flexibility of the aminopropanol substructure in a cyclopentane system. The designed ligands were synthesized in an eight-step sequence starting with terephthalaldehyde (5). Key steps pf the synthesis were the intramolecular Friedel-Crafts acylation of propionic acids 10 to yield the cyclopenta[g]quinolinediones 11 and the Mannich reaction of diketone 11a followed by conjugate addition at the α,β-unsaturated ketone 12a. Although the quinolones 13a, 15a, and 16a contain an H-bond donor group (secondary lactam) as ifenprodil and Ro 25-6981, they show only moderate GluN2B affinity (K > 410 nM). However, the introduction of lipophilic substituents at the quinolone N-atom resulted in more than 10-fold increased GluN2B affinity of the benzyl and benzyloxymethyl derivatives cis-13c (K = 36 nM) and 13e (K = 27 nM). All compounds are selective over the phencyclidine (PCP) binding site of the N-methyl-D-aspartate (NMDA) receptor. The benzyl derivative 13c showed six- and threefold selectivity over σ and σ receptors, respectively.
PubMed: 38889396
DOI: 10.1002/ardp.202400279 -
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 -
Journal of Addiction MedicineLittle contemporary research has explored phencyclidine (PCP) use in people with alcohol use disorder. Therefore, we sought to determine the prevalence of PCP positivity...
OBJECTIVES
Little contemporary research has explored phencyclidine (PCP) use in people with alcohol use disorder. Therefore, we sought to determine the prevalence of PCP positivity on urine toxicology screening among patients admitted for alcohol withdrawal, identify correlates of PCP positivity, and investigate PCP positivity's relationship to length of stay (LOS) and risk of facility readmission.
METHODS
This was a retrospective study of patients admitted to a dual-diagnosis medically assisted withdrawal unit for alcohol withdrawal from 2014 to 2019. Univariate tests and logistic regression were used to investigate potential correlates of PCP positivity on admission toxicology screening (primary outcome). Multivariable linear regression models and survival analyses analyzing LOS and risk of readmission (secondary outcomes) were also developed.
RESULTS
Ninety of 3731 patients (2.4%) screened positive for PCP. There were significant associations on univariate testing between PCP positivity and age, race, homeless status, and urine toxicology positivity for amphetamines, benzodiazepines, barbiturates, cocaine, tetrahydrocannabinol, and oxycodone. On multivariate logistic regression, only tetrahydrocannabinol, barbiturates, and cocaine positivity were associated with PCP positivity. Multivariate logistic regression and survival analysis found no statistically significant associations between PCP positivity and LOS or risk of readmission.
CONCLUSIONS
This study provides rare analysis of contemporary data on PCP use among patients undergoing medically assisted alcohol withdrawal. Phencyclidine positivity was uncommon, but use appears considerably higher among this patient population than the general population. There was no significant association between PCP positivity and LOS or readmission risk.
Topics: Humans; Alcoholism; Substance Withdrawal Syndrome; Phencyclidine; Dronabinol; Drug Evaluation, Preclinical; Retrospective Studies; Substance-Related Disorders; Cocaine; Barbiturates
PubMed: 37934534
DOI: 10.1097/ADM.0000000000001217 -
Neuropsychopharmacology : Official... Aug 2023The ability to appropriately update the value of a given action is a critical component of flexible decision making. Several psychiatric disorders, including...
The ability to appropriately update the value of a given action is a critical component of flexible decision making. Several psychiatric disorders, including schizophrenia, are associated with impairments in flexible decision making that can be evaluated using the probabilistic reversal learning (PRL) task. The PRL task has been reverse-translated for use in rodents. Disrupting glutamate neurotransmission during early postnatal neurodevelopment in rodents has induced behavioral, cognitive, and neuropathophysiological abnormalities relevant to schizophrenia. Here, we tested the hypothesis that using the NMDA receptor antagonist phencyclidine (PCP) to disrupt postnatal glutamatergic transmission in rats would lead to impaired decision making in the PRL. Consistent with this hypothesis, compared to controls the postnatal PCP-treated rats completed fewer reversals and exhibited disruptions in reward and punishment sensitivity (i.e., win-stay and lose-shift responding, respectively). Moreover, computational analysis of behavior revealed that postnatal PCP-treatment resulted in a pronounced impairment in the learning rate throughout PRL testing. Finally, a deep neural network (DNN) trained on the rodent behavior could accurately predict the treatment group of subjects. These data demonstrate that disrupting early postnatal glutamatergic neurotransmission impairs flexible decision making and provides evidence that DNNs can be trained on behavioral datasets to accurately predict the treatment group of new subjects, highlighting the potential for DNNs to aid in the diagnosis of schizophrenia.
Topics: Animals; Rats; Phencyclidine; Schizophrenia; Reversal Learning; Synaptic Transmission; Reward
PubMed: 36509858
DOI: 10.1038/s41386-022-01514-y