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Heliyon May 2024Infectious diseases can contribute to substance abuse. Here, a fatal case of borreliosis and substance abuse is reported. This patient had a history of multiple tick...
BACKGROUND
Infectious diseases can contribute to substance abuse. Here, a fatal case of borreliosis and substance abuse is reported. This patient had a history of multiple tick bites and increasing multisystem symptoms, yet diagnosis and treatment were delayed. He experimented with multiple substances including phencyclidine (PCP), an N-methyl-d-aspartate (NMDA) receptor antagonist that opposes NMDA agonism caused by infection. During PCP withdrawal, he committed one homicide, two assaults, and suicide.
METHODS
Brain tissue was obtained from autopsy and stained for microglial activation and quinolinic acid (QA). Immunoflouresence (IFA) and fluorescence hybridization (FISH) were used to identify the presence of pathogens in autopsy tissue.
RESULTS
Autopsy tissue evaluation demonstrated in the pancreas by IFA and heart by IFA and FISH. Activated microglia and QA were found in the brain, indicating neuroinflammation. It is postulated that PCP withdrawal may exacerbate symptoms produced by -induced biochemical imbalances in the brain. This combination may have greatly increased his acute homicidal and suicidal risk. Patient databases also demonstrated the risk of homicide or suicide in patients diagnosed with borreliosis and confirmed multiple symptoms in these patients, including chronic pain, anxiety, and anhedonia.
CONCLUSIONS
Late-stage borreliosis is associated with multiple symptoms that may contribute to an increased risk of substance abuse and addictive disorders. More effective diagnosis and treatment of borreliosis, and attention to substance abuse potential may help reduce associated morbidity and mortality in patients with borreliosis, particularly in endemic areas.
PubMed: 38779029
DOI: 10.1016/j.heliyon.2024.e31159 -
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 -
CNS Neuroscience & Therapeutics Apr 2024We 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...
Novel α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) potentiator LT-102: A promising therapeutic agent for treating cognitive impairment associated with schizophrenia.
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 Ca 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. The electrophysiological characterization of LT-102 was characterized by patch-clamp recording in mouse hippocampal slices. The expression and phosphorylation levels of proteins were examined by Western blotting. Cognitive function was assessed using the Morris water maze and novel object recognition tests.
RESULTS
LT-102 is a novel and selective AMPAR potentiator with little agonistic effect, which binds to the allosteric site formed by the intradimer interface of AMPAR's GluA2 subunit. Treatment with LT-102 facilitated long-term potentiation in mouse hippocampal slices and reversed cognitive deficits in a phencyclidine-induced mouse model. Additionally, LT-102 treatment increased the protein level of brain-derived neurotrophic factor and the phosphorylation of GluA1 in primary neurons and hippocampal tissues.
CONCLUSION
We conclude that LT-102 ameliorates cognitive impairments in a phencyclidine-induced model of schizophrenia by enhancing synaptic function, which could make it a potential therapeutic candidate for CIAS.
Topics: Animals; Mice; Rats; Phencyclidine; Schizophrenia; Cognitive Dysfunction; Isoxazoles; Propionates
PubMed: 38615362
DOI: 10.1111/cns.14713 -
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 -
Neuropsychopharmacology Reports Jun 2024The therapeutic potential of N-methyl-D-aspartate glutamate receptor (NMDAR) antagonists, particularly ketamine, in mood disorders, is linked to their modulation of...
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.
METHODS
In vivo microdialysis and high-performance liquid chromatography assessed extracellular dopamine levels in the mPFC following subchronic MK-801 treatment. Locomotor activity was measured using a computed video tracking system.
RESULTS
Intermittent subchronic MK-801 administration, followed by a 24-h withdrawal, preserved both dopamine synthesis capacity and responsiveness to MK-801 challenge in the mPFC. However, altered locomotor activity was observed, deviating from previous findings indicating impaired dopamine synthesis and responsiveness in the mPFC with twice-daily subchronic NMDAR antagonist treatment.
CONCLUSION
These findings offer crucial biochemical insights into the diverse impacts of NMDAR antagonists on dopamine dynamics and the distinct therapeutic mechanisms associated with ketamine in depression treatment. However, further investigation is imperative to pinpoint potential inconsistencies stemming from variances in drug type, dosage, or administration frequency.
Topics: Dizocilpine Maleate; Prefrontal Cortex; Animals; Dopamine; Male; Excitatory Amino Acid Antagonists; Rats; Receptors, N-Methyl-D-Aspartate; Locomotion; Rats, Sprague-Dawley; Microdialysis
PubMed: 38376999
DOI: 10.1002/npr2.12420 -
Scientific Reports Feb 2024KPNA1 is a mediator of nucleocytoplasmic transport that is abundantly expressed in the mammalian brain and regulates neuronal differentiation and synaptic function. De...
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. Microarray assessment revealed that the expression levels of dopamine d1/d2 receptors, an RNA editing enzyme, and a cytoplasmic dynein component were significantly altered in the nucleus accumbens brain region in a gene-environment (G × E) interaction-dependent manner. Our findings demonstrate that Kpna1-deficient mice may be useful as a G × E interaction mouse model for psychiatric disorders and for further investigation into the pathogenesis of such diseases and disorders.
Topics: Humans; Mice; Animals; Schizophrenia; Gene-Environment Interaction; Genome-Wide Association Study; Psychotropic Drugs; Phencyclidine; Nucleus Accumbens; Mammals; alpha Karyopherins
PubMed: 38336912
DOI: 10.1038/s41598-024-53237-3 -
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 -
Biological Psychiatry Global Open... Jan 2024The orbitofrontal cortex (OFC) is essential for decision making, and functional disruptions within the OFC are evident in schizophrenia. Postnatal phencyclidine (PCP)...
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 ( = 110) were administered saline or PCP on postnatal days 7, 9, and 11. In adulthood, we expressed YFP (yellow fluorescent protein) (control), ChR2 (channelrhodopsin-2) (activation), or eNpHR 3.0 (enhanced halorhodopsin) (inhibition) in glutamate neurons within the ventromedial OFC (vmOFC). Rats were tested on the probabilistic reversal learning task once daily for 20 days while we manipulated the activity of vmOFC glutamate cells. Behavioral performance was analyzed using a Q-learning computational model of reinforcement learning.
RESULTS
Compared with saline-treated rats expressing YFP, PCP-treated rats expressing YFP completed fewer reversals, made fewer win-stay responses, and had lower learning rates. We induced similar performance impairments in saline-treated rats by activating vmOFC glutamate cells (ChR2). Strikingly, PCP-induced performance deficits were ameliorated when the activity of vmOFC glutamate cells was inhibited (halorhodopsin).
CONCLUSIONS
Postnatal PCP-induced deficits in decision making are associated with hyperactivity of vmOFC glutamate cells. Thus, normalizing vmOFC activity may represent a potential therapeutic target for decision-making deficits in patients with schizophrenia.
PubMed: 38298783
DOI: 10.1016/j.bpsgos.2023.08.002 -
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 -
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