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Journal of Anaesthesiology, Clinical... 2021Ketamine, a phencyclidine derivative and -methyl-D-aspartate (NMDA) receptor antagonist, is widely used as an anesthetic, analgesic, and sedative agent in daily... (Review)
Review
Ketamine, a phencyclidine derivative and -methyl-D-aspartate (NMDA) receptor antagonist, is widely used as an anesthetic, analgesic, and sedative agent in daily pediatric practice. Experimental studies have suggested that early prenatal or postnatal exposure to ketamine can induce neuroapoptosis, and establish neurobehavioral deficits that are evident in adulthood. However, most of the currently available clinical evidence is derived from retrospective and observational clinical studies. We, herein, attempt a brief review of the cellular and molecular mechanisms suggested to mediate ketamine-induced developmental neurotoxicity, utilizing a selected number of recent experimental evidence.
PubMed: 34103820
DOI: 10.4103/joacp.JOACP_415_19 -
Frontiers in Pharmacology 2018Pridopidine is in clinical trials for Huntington's disease treatment. Originally developed as a dopamine D receptor (DR) ligand, pridopidine displays about 100-fold...
Pridopidine is in clinical trials for Huntington's disease treatment. Originally developed as a dopamine D receptor (DR) ligand, pridopidine displays about 100-fold higher affinity for the sigma-1 receptor (sigma-1R). Interestingly, pridopidine slows disease progression and improves motor function in Huntington's disease model mice and, in preliminarily reports, Huntington's disease patients. The present study examined the anti-amnesic potential of pridopidine. Thus, memory impairment was produced in mice by administration of phencyclidine (PCP, 10 mg/kg/day) for 10 days, followed by 14 days' treatment with pridopidine (6 mg/kg/day), or saline. Finally, novel object recognition performance was assessed in the animals. Mice receiving PCP and saline exhibited deficits in novel object recognition, as expected, while pridopidine treatment counteracted PCP-induced memory impairment. The effect of pridopidine was attenuated by co-administration of the sigma receptor antagonist, NE-100 (10 mg/kg). Our results suggest that pridopidine exerts anti-amnesic and potentially neuroprotective actions. These data provide new insights into the therapeutic potential of pridopidine as a pro-cognitive drug.
PubMed: 29692729
DOI: 10.3389/fphar.2018.00338 -
The International Journal of... May 2021Anhedonia, the loss of pleasure in previously rewarding activities, is a prominent feature of major depressive disorder and often resistant to first-line antidepressant...
BACKGROUND
Anhedonia, the loss of pleasure in previously rewarding activities, is a prominent feature of major depressive disorder and often resistant to first-line antidepressant treatment. A paucity of translatable cross-species tasks to assess subdomains of anhedonia, including reward learning, presents a major obstacle to the development of effective therapeutics. One assay of reward learning characterized by orderly behavioral and pharmacological findings in both humans and rats is the probabilistic reward task. In this computerized task, subjects make discriminations across numerous trials in which correct responses to one alternative are rewarded more often (rich) than correct responses to the other (lean). Healthy control subjects reliably develop a response bias to the rich alternative. However, participants with major depressive disorder as well as rats exposed to chronic stress typically exhibit a blunted response bias.
METHODS
The present studies validated a touchscreen-based probabilistic reward task for the marmoset, a small nonhuman primate with considerable translational value. First, probabilistic reinforcement contingencies were parametrically examined. Next, the effects of ketamine (1.0-10.0 mg/kg), a US Food and Drug Administration-approved rapid-acting antidepressant, and phencyclidine (0.01-0.1 mg/kg), a pharmacologically similar N-methyl-D-aspartate receptor antagonist with no known antidepressant efficacy, were evaluated.
RESULTS
Increases in the asymmetry of rich:lean probabilistic contingencies produced orderly increases in response bias. Consistent with their respective clinical profiles, ketamine but not phencyclidine produced dose-related increases in response bias at doses that did not reduce task discriminability.
CONCLUSIONS
Collectively, these findings confirm task and pharmacological sensitivity in the marmoset, which may be useful in developing medications to counter anhedonia across neuropsychiatric disorders.
Topics: Anhedonia; Animals; Antidepressive Agents; Behavior, Animal; Callithrix; Excitatory Amino Acid Antagonists; Ketamine; Male; Neuropsychological Tests; Phencyclidine; Probability Learning; Reward; Translational Research, Biomedical
PubMed: 33280005
DOI: 10.1093/ijnp/pyaa090 -
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 -
Journal of Analytical Toxicology Apr 2018In this study, a quantitative polarity switching liquid chromatography coupled with a tandem mass spectrometer (LC-MS/MS) method was developed to detect and quantify...
In this study, a quantitative polarity switching liquid chromatography coupled with a tandem mass spectrometer (LC-MS/MS) method was developed to detect and quantify cocaine and metabolites (cocaethylene, benzoylecgonine and meta-hydroxybenzoylecgonine), phencyclidine (PCP) and barbiturates (phenobarbital and butalbital) in meconium. Accuracy and precision samples at 0.0125% and 75% of the upper limit of quantitation (ULOQ) were analyzed in triplicate over 5 days with accuracy above 84% and average %CV values below 11%. Within-run (n = 15) and between-run (n = 15) %CV values were ≤5%. Analytical measurement ranges were reproducible and linear (R ≥ 0.995) for cocaine and metabolites (20-2,000 ng/g), PCP (10-1,000 ng/g) and barbiturates (50-5,000 ng/g). Accuracy of 100 ± 20% was observed at (the limits of detection) 10 ng/g for cocaine and metabolites, 2.5 ng/g for PCP and 25 ng/g for barbiturates. No carryover was observed at 2X ULOQ and no interfering substances were identified. Sample preparation recoveries were 53-83%. Fifty-one authentic patient samples previously characterized correlated with the newly developed test having R2 values ≥0.996. This combined method allows accurate quantitation of the targeted drugs in a complex matrix while decreasing sample preparation and analysis time with reduced sample volume. Clinical data and positivity rates were similar to previously published positivity rates. Validation data and positivity rate agreement signifies a reliable and robust assay.
Topics: Barbiturates; Biotransformation; Chromatography, Liquid; Cocaine; Cocaine-Related Disorders; Female; Humans; Limit of Detection; Meconium; Pentobarbital; Phencyclidine; Phencyclidine Abuse; Predictive Value of Tests; Pregnancy; Reproducibility of Results; Substance Abuse Detection; Tandem Mass Spectrometry; Workflow
PubMed: 29244082
DOI: 10.1093/jat/bkx097 -
The American Journal of Emergency... Mar 2023
Topics: Humans; Phencyclidine; Lamotrigine; Anticonvulsants; Substance Abuse Detection; False Positive Reactions; Phencyclidine Abuse
PubMed: 36604235
DOI: 10.1016/j.ajem.2022.12.016 -
Journal of Analytical Toxicology Oct 2022Presented are phencyclidine (PCP)-positive cases received by the Toxicology Laboratory at the Southwestern Institute of Forensic Sciences from local law enforcement...
Presented are phencyclidine (PCP)-positive cases received by the Toxicology Laboratory at the Southwestern Institute of Forensic Sciences from local law enforcement agencies and the Office of the Medical Examiner (OME) between 1 January 2015 and 31 December 2020. Of the 43,940 requests for testing received during that time, 898 (2.04%) were positive for PCP. These cases were evaluated for PCP concentration, additional/concurrently reported drug concentrations and demographics. For ME cases, the cause and manner of death were also evaluated. Although the number of requests received by the Toxicology Laboratory increased each year, the percentage positive for PCP remained consistent. Subjects ranged from 18 to 71 years old (median 48 years) and were predominantly black (94.19%) and male (78.49%). PCP concentrations for all case types ranged from 0.02 to 2.33 mg/L (median 0.05 mg/L); driving while intoxicated (DWI) cases ranged from 0.02 to 0.14 mg/L (median 0.04 mg/L) and ME cases ranged from 0.02 to 2.33 mg/L (median 0.13 mg/L). In addition to PCP, one or more drug(s) or metabolite(s) was identified concurrently in 69.49% of cases. Cannabinoids were the most frequently detected (39.8%), followed by cocaine and its metabolites (22.0%) and ethanol (18.5%). Results were similar when comparing the additional drugs reported in ME and DWI cases. PCP concentrations in ME samples were generally higher, especially for stimulant drugs. Of the 264 ME cases positive for PCP, the manner of death was determined to be an accident for the majority of cases (62.54%), and the most common cause of death was drug toxicity (35.61%). The results from this study facilitate comparison of laboratory- or region-specific data sets, help determine whether laboratory scopes meet testing needs, contribute to reference ranges and provide the foundation for well-informed policy decisions.
Topics: Adolescent; Adult; Aged; Cannabinoids; Cocaine; Ethanol; Humans; Male; Middle Aged; Phencyclidine; Retrospective Studies; Young Adult
PubMed: 35689545
DOI: 10.1093/jat/bkac035 -
Psychopharmacology Feb 2021There is a need to develop animal models of schizophrenia-like behaviors that have both construct and predictive validity. Recently, a neonatal phencyclidine (PCP) and...
Neonatal phencyclidine and social isolation in the rat: effects of clozapine on locomotor activity, social recognition, prepulse inhibition, and executive functions deficits.
RATIONALE
There is a need to develop animal models of schizophrenia-like behaviors that have both construct and predictive validity. Recently, a neonatal phencyclidine (PCP) and post-weaning social isolation dual-hit model was developed; however, its face and predictive validities need to be further investigated.
OBJECTIVE
The aims of this study were to extend the characterization of the behavioral changes occurring in the neonatal PCP and post-weaning social isolation dual-hit rat model and to evaluate the effects of chronic treatment with clozapine on signs related to schizophrenia.
METHODS
Male Wistar rat pups were treated with PCP (10 mg/kg s.c.) on postnatal days (PND) 7, 9, and 11. Starting from weaning, neonatal PCP-treated rat pups were socially isolated, while control saline-treated rats were group housed. At adulthood, rats were assessed using behavioral tasks evaluating locomotor activity, social recognition, prepulse inhibition, and reversal learning. Clozapine (3 mg/kg i.p.) was administered daily starting from a week before behavioral tests and until the end of the study.
RESULTS
Neonatal PCP-treated and post-weaning social isolated (PCP-SI) rats displayed persistent and robust locomotor hyperactivity as well as social recognition impairment. The latter could not be explained by variations in the motivation to interact with a juvenile rat. Weak-to-moderate deficits in prepulse inhibition and reversal learning were also observed. Chronic treatment with clozapine attenuated the observed locomotor hyperactivity and social recognition deficits.
CONCLUSION
The PCP-SI model presents enduring and robust deficits (hyperactivity and social recognition impairment) associated with positive symptoms and cognitive/social deficits of schizophrenia, respectively. These deficits are normalized by chronic treatment with clozapine, thereby confirming the predictive validity of this animal model.
Topics: Animals; Animals, Newborn; Antipsychotic Agents; Behavior, Animal; Clozapine; Disease Models, Animal; Executive Function; Locomotion; Male; Phencyclidine; Prepulse Inhibition; Rats; Rats, Wistar; Recognition, Psychology; Reversal Learning; Schizophrenia; Schizophrenic Psychology; Social Isolation
PubMed: 33169202
DOI: 10.1007/s00213-020-05700-y -
Adolescent Medicine: State of the Art... Dec 2015NMDA receptor antagonists include the prescription medication ketamine, the illicit xenobiotics PCP, MXE, and other novel PCP analogs, and the OTC medication DXM. The... (Review)
Review
NMDA receptor antagonists include the prescription medication ketamine, the illicit xenobiotics PCP, MXE, and other novel PCP analogs, and the OTC medication DXM. The NMDA receptor antagonist most commonly abused by adolescents in the United States is DXM. These xenobiotics cause dissociative effects by non-competitively inhibiting the action of glutamate at the NMDA receptor. Additionally, these agents modulate the actions of monoamine neurotransmitters, agonize opioid receptors, and inhibit nitric oxide synthase. Patients typically present with sympathomimetic and neuropsychiatric clinical manifestations after abuse of NMDA receptor antagonists. Treatment is generally symptomatic and supportive. Interventions include benzodiazepines, propofol, fluids, antiemetics, aggressive cooling, and respiratory support.
Topics: Adolescent; Amphetamine-Related Disorders; Cannabinoids; Central Nervous System Stimulants; Designer Drugs; Dextroamphetamine; Dextromethorphan; Excitatory Amino Acid Antagonists; Hallucinogens; Humans; Inhalant Abuse; Ketamine; Methylphenidate; N-Methyl-3,4-methylenedioxyamphetamine; Phencyclidine Abuse; Receptors, N-Methyl-D-Aspartate; Substance-Related Disorders; Xenobiotics
PubMed: 27282013
DOI: No ID Found -
Neuroscience Bulletin Apr 2015The prefrontal cortex is implicated in cognitive functioning and schizophrenia. Prefrontal dysfunction is closely associated with the symptoms of schizophrenia. In... (Review)
Review
The prefrontal cortex is implicated in cognitive functioning and schizophrenia. Prefrontal dysfunction is closely associated with the symptoms of schizophrenia. In addition to the features typical of schizophrenia, patients also present with aspects of cognitive disorders. Based on these relationships, a monkey model mimicking the cognitive symptoms of schizophrenia has been made using treatment with the non-specific competitive N-methyl-D-aspartate receptor antagonist, phencyclidine. The symptoms are ameliorated by atypical antipsychotic drugs such as clozapine. The beneficial effects of clozapine on behavioral impairment might be a specific indicator of schizophrenia-related cognitive impairment.
Topics: Animals; Antipsychotic Agents; Cognition Disorders; Disease Models, Animal; Excitatory Amino Acid Antagonists; Haplorhini; Phencyclidine; Prefrontal Cortex; Psychomotor Performance; Schizophrenia
PubMed: 25822218
DOI: 10.1007/s12264-014-1506-4