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International Journal of Molecular... Mar 2023Cognitive impairment represents one of the core features of schizophrenia. Prolyl Oligopeptidase (POP) inhibition is an emerging strategy for compensating cognitive...
Cognitive impairment represents one of the core features of schizophrenia. Prolyl Oligopeptidase (POP) inhibition is an emerging strategy for compensating cognitive deficits in hypoglutamatergic states such as schizophrenia, although little is known about how POP inhibitors exert their pharmacological activity. The mitochondrial and nuclear protein Prohibitin 2 (PHB2) could be dysregulated in schizophrenia. However, altered PHB2 levels in schizophrenia linked to N-methyl-D-aspartate receptor (NMDAR) activity and cognitive deficits are still unknown. To shed light on this, we measured the PHB2 levels by immunoblot in a postmortem dorsolateral prefrontal cortex (DLPFC) of schizophrenia subjects, in the frontal pole of mice treated with the NMDAR antagonists phencyclidine and dizocilpine, and in rat cortical astrocytes and neurons treated with dizocilpine. Mice and cells were treated in combination with the POP inhibitor IPR19. The PHB2 levels were also analyzed by immunocytochemistry in rat neurons. The PHB2 levels increased in DLPFC in cases of chronic schizophrenia and were associated with cognitive impairments. NMDAR antagonists increased PHB2 levels in the frontal pole of mice and in rat astrocytes and neurons. High levels of PHB2 were found in the nucleus and cytoplasm of neurons upon NMDAR inhibition. IPR19 restored PHB2 levels in the acute NMDAR inhibition. These results show that IPR19 restores the upregulation of PHB2 in an acute NMDAR hypoactivity stage suggesting that the modulation of PHB2 could compensate NMDAR-dependent cognitive impairments in schizophrenia.
Topics: Animals; Rats; Cognition; Cognitive Dysfunction; Dizocilpine Maleate; Prohibitins; Prolyl Oligopeptidases; Psychotic Disorders; Receptors, N-Methyl-D-Aspartate; Schizophrenia
PubMed: 37046989
DOI: 10.3390/ijms24076016 -
Cells Mar 2023The cognitive deficits of schizophrenia are linked to imbalanced excitatory and inhibitory signalling in the prefrontal cortex (PFC), disrupting gamma oscillations. We...
The cognitive deficits of schizophrenia are linked to imbalanced excitatory and inhibitory signalling in the prefrontal cortex (PFC), disrupting gamma oscillations. We previously demonstrated that two mGlu5 receptor-positive allosteric modulators (PAMs), VU0409551 and VU0360172, restore cognitive deficits in the sub-chronic PCP (scPCP) rodent model for schizophrenia via distinct changes in PFC intracellular signalling molecules. Here, we have assessed ex vivo gamma oscillatory activity in PFC slices from scPCP rats and investigated the effects of VU0409551 and VU0360172 upon oscillatory power. mGlu5 receptor, protein kinase C (PKC), and phospholipase C (PLC) inhibition were also used to examine 'modulation bias' in PAM activity. The amplitude and area power of gamma oscillations were significantly diminished in the scPCP model. Slice incubation with either VU0409551 or VU0360172 rescued scPCP-induced oscillatory deficits in a concentration-dependent manner. MTEP blocked the PAM-induced restoration of oscillatory power, confirming the requirement of mGlu5 receptor modulation. Whilst PLC inhibition prevented the power increase mediated by both PAMs, PKC inhibition diminished the effects of VU0360172 but not VU0409551. This aligns with previous reports that VU0409551 exhibits preferential activation of the phosphatidylinositol-3-kinase (PI3K) signalling pathway over the PKC cascade. Restoration of the excitatory/inhibitory signalling balance and gamma oscillations may therefore underlie the mGluR5 PAM-mediated correction of scPCP-induced cognitive deficits.
Topics: Rats; Animals; Schizophrenia; Signal Transduction; Niacinamide; Prefrontal Cortex
PubMed: 36980260
DOI: 10.3390/cells12060919 -
Neurology International Mar 2023While driving under the influence of drugs, drivers are more likely to be involved in and cause more accidents than drivers who do not drive under the influence.... (Review)
Review
While driving under the influence of drugs, drivers are more likely to be involved in and cause more accidents than drivers who do not drive under the influence. Ketamine is derived from phencyclidine and acts as a noncompetitive antagonist and allosteric modulator of N-methyl-D-aspartate receptors. Ketamine has been used to treat a variety of psychiatric disorders, with the most notable being treatment-resistant depression. With the rise of at-home ketamine treatment companies, the safety of unsupervised administration remains under evaluation. A study with ketamine and a ketamine-like medication, rapasitnel, showed that those who were given ketamine experienced more sleepiness and had decreased self-reported motivation and confidence in their driving abilities. Moreover, there seem to be significant differences in the acute versus persistent effects of ketamine, as well as the anesthetic versus subanesthetic doses, both in terms of effects and outcomes. These divergent effects complicate the clinical uses of ketamine, specifically involving driving, drowsiness, and cognitive abilities. This review aims to describe not only the various clinical uses of ketamine but also the potentially detrimental effects of driving under the influence, which should be understood to help with counseling the patients who use these substances, both for their well-being and to protect public safety.
PubMed: 36976666
DOI: 10.3390/neurolint15010023 -
Molecular Imaging and Biology Aug 2023NMDA receptors (NMDARs) dysfunction plays a central role in the physiopathology of psychiatric and neurodegenerative disorders whose mechanisms are still poorly...
PURPOSE
NMDA receptors (NMDARs) dysfunction plays a central role in the physiopathology of psychiatric and neurodegenerative disorders whose mechanisms are still poorly understood. The development of a PET (positron emission tomography) tracer able to selectively bind to the NMDARs intra-channel PCP site may make it possible to visualize NMDARs in an open and active state. We describe the in vitro pharmacological characterization of [F]-fluoroethylnormemantine ([F]-FNM) and evaluate its ability to localize activated NMDA receptors in a rat preclinical model of excitotoxicity.
PROCEDURES
The affinity of the non-radioactive analog for the intra-channel PCP site was determined in a radioligand competition assay using [H]TCP ([H]N-(1-[thienyl]cyclohexyl)piperidine) on rat brain homogenates. Selectivity was also investigated by the displacement of specific radioligands targeting various cerebral receptors. In vivo brain lesions were performed using stereotaxic quinolinic acid (QA) injections in the left motor area (M1) of seven Sprague Dawley rats. Each rat was imaged with a microPET/CT camera, 40 min after receiving a dose of 30 MBq + / - 20 of [F]-FNM, 24 and 72 h after injury. Nine non-injured rats were also imaged using the same protocol.
RESULTS
FNM displayed IC value of 13.0 ± 8.9 µM in rat forebrain homogenates but also showed significant bindings on opioid receptors. In the frontal and left somatosensory areas, [F]FNM PET detected a mean of 37% and 41% increase in [F]FNM uptake (p < 0,0001) 24 and 72 h after QA stereotaxic injection, respectively, compared to the control group.
CONCLUSIONS
In spite of FNM's poor affinity for NMDAR PCP site, this study supports the ability of this tracer to track massive activation of NMDARs in neurological diseases.
Topics: Rats; Animals; Receptors, N-Methyl-D-Aspartate; Rats, Sprague-Dawley; Phencyclidine; Brain Injuries; Positron-Emission Tomography; Brain
PubMed: 36944798
DOI: 10.1007/s11307-023-01811-y -
Biology Feb 2023In January 2020, the World Health Organization (WHO) issued a Public Health Emergency of International Concern, declaring the COVID-19 outbreak a pandemic in March 2020.... (Review)
Review
In January 2020, the World Health Organization (WHO) issued a Public Health Emergency of International Concern, declaring the COVID-19 outbreak a pandemic in March 2020. Stringent measures decreased consumption of some drugs, moving the illicit market to alternative substances, such as New Psychoactive Substances (NPS). A systematic literature search was performed, using scientific databases such as PubMed, Scopus, Web of Science and institutional and government websites, to identify reported intoxications and fatalities from NPS during the COVID-19 pandemic. The search terms were: COVID-19, SARS-CoV-2, severe acute respiratory syndrome coronavirus 2, coronavirus disease 2019, intox*, fatal*, new psychoactive substance, novel psychoactive substance, smart drugs, new psychoactive substance, novel synthetic opioid, synthetic opioid, synthetic cathinone, bath salts, legal highs, nitazene, bath salt, legal high, synthetic cannabinoid, phenethylamine, phencyclidine, piperazine, novel benzodiazepine, benzodiazepine analogue, designer benzodiazepines, tryptamine and psychostimulant. From January 2020 to March 2022, 215 NPS exposures were reported in Europe, UK, Japan and USA. Single NPS class intoxications accounted for 25, while mixed NPS class intoxications represented only 3 cases. A total of 130 NPS single class fatalities and 56 fatalities involving mixed NPS classes were published during the pandemic. Synthetic opioids were the NPS class most abused, followed by synthetic cathinones and synthetic cannabinoids. Notably, designer benzodiazepines were frequently found in combination with fentalogues. Considering the stress to communities and healthcare systems generated by the pandemic, NPS-related information may be underestimated. However, we could not define the exact impacts of COVID-19 on processing of toxicological data, autopsy and death investigations.
PubMed: 36829550
DOI: 10.3390/biology12020273 -
Pharmacology, Biochemistry, and Behavior Feb 2023Aberrant cortical oscillations in the beta and gamma range are associated with symptoms of schizophrenia and other psychiatric conditions. We have thus investigated the...
Modulation of circuit oscillations in the rat anterior cingulate cortex (ACC) in vitro by mGlu2 metabotropic glutamate receptors and alleviation of the effects of phencyclidine-induced NMDA-receptor hypofunction.
Aberrant cortical oscillations in the beta and gamma range are associated with symptoms of schizophrenia and other psychiatric conditions. We have thus investigated the ability of anterior cingulate cortex (ACC) in vitro to generate beta and gamma oscillations, and how these are affected by Group II metabotropic glutamate (mGlu) receptor activation and blockade of N-methyl-d-aspartate (NMDA) receptors. Activation of Group II mGlu receptors, and mGlu2 specifically, with orthosteric agonists reduced the power of both beta and gamma oscillations in ACC without a significant effect on oscillation peak frequencies. The NMDA receptor blocker phencyclidine (PCP), known to evoke certain schizophrenia-like symptoms in humans, elevated the power of beta oscillations in ACC and caused a shift in oscillation frequency from the gamma range to the beta range. These enhanced beta oscillations were reduced by the Group II mGlu receptor agonists. These results show that Group II mGlu receptors, and specifically mGlu2, modulate network oscillations. Furthermore, attenuation of the effect of PCP suggests that mGlu2 receptors may stabilise aberrant network activity. These results underline the importance of Group II mGlu receptors, and particularly mGlu2, as targets for the treatment of neuropsychiatric and neurodegenerative diseases.
Topics: Humans; Rats; Animals; Receptors, Metabotropic Glutamate; Phencyclidine; Gyrus Cinguli; N-Methylaspartate
PubMed: 36822254
DOI: 10.1016/j.pbb.2023.173532 -
Cadernos de Saude Publica 2023This study aimed to estimate the prevalence of psychoactive substance use by adolescents from public schools. This is a cross-sectional study that used a random sample...
This study aimed to estimate the prevalence of psychoactive substance use by adolescents from public schools. This is a cross-sectional study that used a random sample of adolescents from five public schools located in a municipality in the central-west region of the São Paulo Metropolitan Area, Brazil. Information on demographic, socioeconomic, and drug use was collected using self-report questionnaires. The sample consisted of 1,460 students, 716 (49%) males, aged 10-19 years (13.19±2.04 years). The prevalence of psychoactive substance use in the last month was 51% for analgesics; 48.8% for alcohol; 37.3% for tobacco; 30.8% for tranquilizers; 23.1% for marijuana; 22.6% for anabolic steroids; 21.6% for ecstasy; 15.3% for amphetamines/stimulants; 13.4% for phencyclidine; 12.9% for cocaine/crack; 12.6% for inhalants/solvents; 11.5% for opiates; 11.4% for hallucinogens; and 16.2% for other unclassified drugs. Elementary and middle school students were more likely to consume tobacco (OR = 2.306; 95%CI: 1.733-3.068; p < 0.001), and male students were more likely to consume any type of substance. We identified a high use of psychoactive substances among this study participants, with a higher prevalence among male students.
Topics: Humans; Male; Adolescent; Female; Prevalence; Brazil; Cross-Sectional Studies; Substance-Related Disorders; Surveys and Questionnaires; Ethanol
PubMed: 36820725
DOI: 10.1590/0102-311XEN169722 -
Veterinary and Animal Science Mar 2023Pets can have accidental, intentional, or malicious exposure to illicit drugs. It is a growing concern over the last decade because there is an increase in usage of... (Review)
Review
Pets can have accidental, intentional, or malicious exposure to illicit drugs. It is a growing concern over the last decade because there is an increase in usage of illicit drugs in humans and diagnosis is difficult. Owners are often not aware of exposure, or they are reluctant to admit possession of recreational drugs in the household due to potential legal consequences. In addition, illicit drugs sold on the black market are often adulterated with other substances resulting in non-specific clinical presentation and aggravation of symptoms. There are affordable onsite diagnostic tests on the market which could facilitate diagnosis of intoxication with illicit drugs, but they give a lot of false positive results due to low specificity of the tests. In this paper we gathered information about the most common recreational drugs such as amphetamines, methamphetamine, 3,4-methylenedioxy-methamphetamine (MDMA), phencyclidine (PCP), lysergic acid diethylamide (LSD), psilocybin mushrooms and cocaine in terms of toxicokinetic properties, mechanism of toxic action, clinical presentation and treatment in dogs and cats.
PubMed: 36798946
DOI: 10.1016/j.vas.2023.100288 -
European Archives of Psychiatry and... Oct 2023Cognitive impairment has been observed in patients with various psychiatric disorders, including schizophrenia, major depressive disorder (MDD), and bipolar disorder... (Review)
Review
Cognitive impairment has been observed in patients with various psychiatric disorders, including schizophrenia, major depressive disorder (MDD), and bipolar disorder (BD). Although modern therapeutic drugs can improve certain symptoms (i.e., psychosis, depression) in these patients, these drugs have not been found to improve cognitive impairment. The N-methyl-D-aspartate receptor antagonist (R,S)-ketamine has attracted attention as a rapidly acting antidepressant. In addition to its robust antidepressant effects, (R,S)-ketamine has been suggested to improve cognitive impairment in patients with MDD and BD, despite causing cognitive impairment in healthy control subjects. (R,S)-ketamine is a racemic mixture of equal amounts of (R)-ketamine (or arketamine) and (S)-ketamine (or esketamine). Arketamine has been found to have more potent antidepressant-like actions than esketamine in rodents. Interestingly, arketamine, but not esketamine, has been suggested to improve phencyclidine-induced cognitive deficits in mice. Furthermore, arketamine has been suggested to ameliorate cognitive deficits in rodent offspring after maternal immune activation. In the current article, it is proposed that arketamine has therapeutic potential for treating cognitive impairment in patients with psychiatric disorders. Additionally, the potential role of the gut-microbiome-brain axis in cognitive impairment in psychiatric disorders is discussed.
Topics: Animals; Mice; Ketamine; Depressive Disorder, Major; Cognitive Dysfunction; Antidepressive Agents
PubMed: 36786865
DOI: 10.1007/s00406-023-01570-5 -
Physiology & Behavior May 2023Treatments for schizophrenia are not effective in ameliorating cognitive deficits. Therefore, novel therapies are needed to treat cognitive impairments associated with...
Treatments for schizophrenia are not effective in ameliorating cognitive deficits. Therefore, novel therapies are needed to treat cognitive impairments associated with schizophrenia (CIAS), which are modelled in rats through administration of sub-chronic phencyclidine (scPCP). We have previously shown that enrichment via voluntary exercise prevents and reverses impairments in novel object recognition (NOR) in this model. The present study aimed to investigate if handling could prevent delay-induced NOR deficits and prevent and reverse scPCP-induced NOR deficits. Two cohorts of adult female Lister Hooded rats were used. In experiment one, handling (five minutes/day, five days/week for two weeks), took place before scPCP administration (2 mg/kg, i.p. twice-daily for seven days). NOR tests were conducted at two, four, and seven weeks post-handling with a one-minute inter-trial interval (ITI) and at five weeks post-dosing with a six-hour ITI. In experiment two, rats were handled after scPCP administration and tested immediately in the one-minute ITI NOR task and again at two weeks post-handling. In both handling regimens, the scPCP control groups failed to discriminate novelty, conversely the scPCP handled groups significantly discriminated in this task. In the 6 h ITI test, vehicle control and scPCP control failed to discriminate novelty; however, the vehicle handled and scPCP handled groups did significantly discriminate. Handling rats prevented and reversed scPCP-induced deficits and prevented delay-induced NOR deficits. These findings add to evidence that environmental enrichment is a viable treatment for cognitive deficits in rodent tests and models of relevance to schizophrenia, with potential to translate into effective treatments for CIAS.
Topics: Rats; Female; Animals; Phencyclidine; Schizophrenia; Cognitive Dysfunction; Cognition Disorders; Cognition; Disease Models, Animal
PubMed: 36781093
DOI: 10.1016/j.physbeh.2023.114117