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Chemistry (Weinheim An Der Bergstrasse,... Feb 2021We report investigations of the use of cucurbit[8]uril (CB[8]) macrocycles as an antidote to counteract the in vivo biological effects of phencyclidine. We investigate...
We report investigations of the use of cucurbit[8]uril (CB[8]) macrocycles as an antidote to counteract the in vivo biological effects of phencyclidine. We investigate the binding of CB[8] and its derivative Me CB[8] toward ten drugs of abuse (3-9, 12-14) by a combination of H NMR spectroscopy and isothermal titration calorimetry in phosphate buffered water. We find that the cavity of CB[8] and Me CB[8] are able to encapsulate the 1-amino-1-aryl-cyclohexane ring system of phencyclidine (PCP) and ketamine as well as the morphinan skeleton of morphine and hydromorphone with K values ≤50 nm. In vitro cytotoxicity (MTS metabolic and adenylate kinase cell death assays in HEK293 and HEPG2 cells) and in vivo maximum tolerated dose studies (Swiss Webster mice) which were performed for Me CB[8] indicated good tolerability. The tightest host⋅guest pair (Me CB[8]⋅PCP; K =2 nm) was advanced to in vivo efficacy studies. The results of open field tests demonstrate that pretreatment of mice with Me CB[8] prevents subsequent hyperlocomotion induction by PCP and also that treatment of animals previously dosed with PCP with Me CB[8] significantly reduces the locomotion levels.
Topics: Animals; Bridged-Ring Compounds; HEK293 Cells; Hep G2 Cells; Humans; Imidazoles; Locomotion; Mice; Phencyclidine
PubMed: 33206421
DOI: 10.1002/chem.202004380 -
Psychopharmacology Oct 2023Sex-biased differences in schizophrenia are evident in several features of the disease, including symptomatology and response to pharmacological treatments. As a...
Sex-biased differences in schizophrenia are evident in several features of the disease, including symptomatology and response to pharmacological treatments. As a neurodevelopmental disorder, these differences might originate early in life and emerge later during adolescence. Considering that the disruption of the glutamatergic system during development is known to contribute to schizophrenia, we hypothesized that the neonatal phencyclidine model could induce sex-dependent behavioral and neurochemical changes associated with this disorder during adolescence. C57BL/6 mice received either saline or phencyclidine (5, 10, or 20 mg/kg) on postnatal days (PN) 7, 9, and 11. Behavioral assessment occurred in late adolescence (PN48-50), when mice were submitted to the open field, social interaction, and prepulse inhibition tests. Either olanzapine or saline was administered before each test. The NMDAR obligatory GluN1 subunit and the postsynaptic density protein 95 (PSD-95) were evaluated in the frontal cortex and hippocampus at early (PN30) and late (PN50) adolescence. Neonatal phencyclidine evoked dose-dependent deficits in all analyzed behaviors and males were more susceptible. Males also had reduced GluN1 expression in the frontal cortex at PN30. There were late-emergent effects at PN50. Cortical GluN1 was increased in both sexes, while phencyclidine increased cortical and decreased hippocampal PSD-95 in females. Olanzapine failed to mitigate most phencyclidine-evoked alterations. In some instances, this antipsychotic aggravated the deficits or potentiated subthreshold effects. These results lend support to the use of neonatal phencyclidine as a sex-biased neurodevelopmental preclinical model of schizophrenia. Olanzapine null effects and deleterious outcomes suggest that its use during adolescence should be further evaluated.
Topics: Male; Female; Animals; Mice; Phencyclidine; Schizophrenia; Olanzapine; Mice, Inbred C57BL; Antipsychotic Agents; Disease Models, Animal
PubMed: 37530885
DOI: 10.1007/s00213-023-06434-3 -
Journal of Integrative Neuroscience Jan 2022Locomotor hyperactivity induced by psychotomimetic drugs, such as amphetamine and phencyclidine, is widely used as an animal model of psychosis-like behaviour and is...
Locomotor hyperactivity induced by psychotomimetic drugs, such as amphetamine and phencyclidine, is widely used as an animal model of psychosis-like behaviour and is commonly attributed to an interaction with dopamine release and N-methyl-D-aspartate (NMDA) receptors, respectively. However, what is often not sufficiently taken into account is that the pharmacological profile of these drugs is complex and may involve other neurotransmitter/receptor systems. Therefore, this study aimed to assess the effect of three antagonists targeting different monoamine pathways on amphetamine- and phencyclidine-induced locomotor hyperactivity. A total of 32 rats were pre-treated with antagonists affecting dopaminergic, noradrenergic and serotonergic transmission: haloperidol (0.05 mg/kg), prazosin (2 mg/kg) and ritanserin (1 mg/kg), respectively. After 30 min of spontaneous activity, rats were injected with amphetamine (0.5 mg/kg) or phencyclidine (2.5 mg/kg) and distance travelled, stereotypy and rearing recorded in photocell cages over 90 min. Pre-treatment with haloperidol or prazosin both reduced amphetamine-induced hyperactivity although pre-treatment with ritanserin had only a partial effect. None of the pre-treatments significantly altered the hyperlocomotion effects of phencyclidine. These findings suggest that noradrenergic as well as dopaminergic neurotransmission is critical for amphetamine-induced locomotor hyperactivity. Hyperlocomotion effects of phencyclidine are dependent on other factors, most likely NMDA receptor antagonism. These results help to interpret psychotomimetic drug-induced locomotor hyperactivity as an experimental model of psychosis.
Topics: Adrenergic alpha-1 Receptor Antagonists; Akathisia, Drug-Induced; Amphetamine; Animals; Behavior, Animal; Central Nervous System Stimulants; Disease Models, Animal; Dopamine Antagonists; Excitatory Amino Acid Antagonists; Male; Phencyclidine; Psychoses, Substance-Induced; Rats; Rats, Sprague-Dawley; Serotonin Antagonists
PubMed: 35164453
DOI: 10.31083/j.jin2101017 -
Journal of Psychopharmacology (Oxford,... Nov 2016Here, Reynolds and Neill describe the studies that preceded and followed publication of this paper, which reported a deficit in parvalbumin (PV), a calcium-binding... (Review)
Review
Here, Reynolds and Neill describe the studies that preceded and followed publication of this paper, which reported a deficit in parvalbumin (PV), a calcium-binding protein found in GABA interneurons known to be reduced in schizophrenia patients, in conjunction with a deficit in reversal learning in an animal model for schizophrenia. This publication resulted from common research interests: Reynolds in the neurotransmitter pathology of schizophrenia, and Neill in developing animal models for schizophrenia symptomatology. The animal model, using a sub-chronic dosing regimen (sc) with the non-competitive NMDA receptor antagonist PCP (phencyclidine), evolved from previous work in rats (for PCP) and primates (for cognition). The hypothesis of a PV deficit came from emerging evidence for a GABAergic dysfunction in schizophrenia, in particular a deficit in PV-containing GABA interneurons. Since this original publication, a PV deficit has been identified in other animal models for schizophrenia, and the PV field has expanded considerably. This includes mechanistic work attempting to identify the link between oxidative stress and GABAergic dysfunction using this scPCP model, and assessment of the potential of the PV neuron as a target for new antipsychotic drugs. The latter has included development of a molecule targeting KV3.1 channels located on PV-containing GABA interneurons which can restore both PV expression and cognitive deficits in the scPCP model.
Topics: Animals; Antipsychotic Agents; Cognition; Humans; Interneurons; Parvalbumins; Phencyclidine; Receptors, N-Methyl-D-Aspartate; Schizophrenia; gamma-Aminobutyric Acid
PubMed: 27624147
DOI: 10.1177/0269881116667668 -
Pediatric Clinics of North America Dec 2019Club drugs and "other" abusable substances are briefly overviewed as a reminder about the wide variety of known and unknown substances used by adolescents, the high... (Review)
Review
Club drugs and "other" abusable substances are briefly overviewed as a reminder about the wide variety of known and unknown substances used by adolescents, the high potential for direct and interactive substance use effects to manifest acutely and chronically, and the vigilance needed to anticipate and recognize the new effects and drug-drug interactions arising as novel substances continue to be custom "designed," manufactured, and marketed to meet substance use trends. This article discusses dextromethorphan, flunitrazepam (Rohypnol), gamma-hydroxybutyrate, inhalants, ketamine, lysergic acid diethylamide, methylenedioxymethamphetamine, phencyclidine, Salvia divinorum (salvia), synthetic cannabinoids, and synthetic cathinones (bath salts).
Topics: Adolescent; Adolescent Behavior; Humans; Illicit Drugs; Substance-Related Disorders; United States
PubMed: 31679602
DOI: 10.1016/j.pcl.2019.08.013 -
Neuropharmacology Oct 2018Novel psychoactive substances are intoxicating compounds developed to mimic the effects of well-established drugs of abuse. They are not controlled by the United Nations...
Novel psychoactive substances are intoxicating compounds developed to mimic the effects of well-established drugs of abuse. They are not controlled by the United Nations drug convention and pose serious health concerns worldwide. Among them, the dissociative drug methoxetamine (MXE) is structurally similar to ketamine (KET) and phencyclidine (PCP) and was created to purposely mimic the psychotropic effects of its "parent" compounds. Recent animal studies show that MXE is able to stimulate the mesolimbic dopaminergic transmission and to induce KET-like discriminative and rewarding effects. In light of the renewed interest in KET and PCP analogs, we decided to deepen the investigation of MXE-induced effects by a battery of behavioral tests widely used in studies of "safety-pharmacology" for the preclinical characterization of new molecules. To this purpose, the acute effects of MXE on neurological and sensorimotor functions in mice, including visual, acoustic and tactile responses, thermal and mechanical pain, motor activity and acoustic startle reactivity were evaluated in comparisons with KET and PCP to better appreciate its specificity of action. Cardiorespiratory parameters and blood pressure were also monitored in awake and freely moving animals. Acute systemic administrations of MXE, KET and PCP (0.01-30 mg/kg i.p.) differentially alter neurological and sensorimotor functions in mice depending in a dose-dependent manner specific for each parameter examined. MXE and KET (1 and 30 mg/kg i.p.) and PCP (1 and 10 mg/kg i.p.) also affect significantly cardiorespiratory parameters, systolic and diastolic blood pressure in mice.
Topics: Animals; Behavior, Animal; Blood Pressure; Cyclohexanones; Cyclohexylamines; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Heart Rate; Ketamine; Male; Mice; Motor Activity; Oxygen; Pain Measurement; Phencyclidine; Reflex, Startle; Respiration
PubMed: 30165078
DOI: 10.1016/j.neuropharm.2018.08.017 -
Neuropsychopharmacology : Official... Jan 2019The pituitary neuropeptide oxytocin promotes social behavior, and is a potential adjunct therapy for social deficits in schizophrenia and autism. Oxytocin may mediate...
The pituitary neuropeptide oxytocin promotes social behavior, and is a potential adjunct therapy for social deficits in schizophrenia and autism. Oxytocin may mediate pro-social effects by modulating monoamine release in limbic and cortical areas, which was investigated herein using in vivo microdialysis, after establishing a dose that did not produce accompanying sedative or thermoregulatory effects that could concomitantly influence behavior. The effects of oxytocin (0.03-0.3 mg/kg subcutaneous) on locomotor activity, core body temperature, and social behavior (social interaction and ultrasonic vocalizations) were examined in adult male Lister-hooded rats, using selective antagonists to determine the role of oxytocin and vasopressin V receptors. Dopamine and serotonin efflux in the prefrontal cortex and nucleus accumbens of conscious rats were assessed using microdialysis. 0.3 mg/kg oxytocin modestly reduced activity and caused hypothermia but only the latter was attenuated by the V receptor antagonist, SR49059 (1 mg/kg intraperitoneal). Oxytocin at 0.1 mg/kg, which did not alter activity and had little effect on temperature, significantly attenuated phencyclidine-induced hyperactivity and increased social interaction between unfamiliar rats without altering the number or pattern of ultrasonic vocalizations. In the same rats, oxytocin (0.1 mg/kg) selectively elevated dopamine overflow in the nucleus accumbens, but not prefrontal cortex, without influencing serotonin efflux. Systemic oxytocin administration attenuated phencyclidine-induced hyperactivity and increased pro-social behavior without decreasing core body temperature and selectively enhanced nucleus accumbens dopamine release, consistent with activation of mesocorticolimbic circuits regulating associative/reward behavior being involved. This highlights the therapeutic potential of oxytocin to treat social behavioral deficits seen in psychiatric disorders such as schizophrenia.
Topics: Animals; Behavior, Animal; Body Temperature; Dopamine; Excitatory Amino Acid Antagonists; Male; Motor Activity; Nucleus Accumbens; Oxytocin; Phencyclidine; Prefrontal Cortex; Rats; Serotonin; Social Behavior
PubMed: 30120410
DOI: 10.1038/s41386-018-0171-0 -
Pharmacotherapy Jul 2022Ketamine, an anesthetic available since 1970, and esketamine, its newer S-enantiomer, provide a novel approach for the treatment of depression and other psychiatric... (Review)
Review
Ketamine, an anesthetic available since 1970, and esketamine, its newer S-enantiomer, provide a novel approach for the treatment of depression and other psychiatric disorders. At subanesthetic doses, the two drugs, along with their older congener, phencyclidine (PCP), induce a transient, altered mental state by blocking the N-methyl-D-aspartate (NMDA) receptor for glutamate, the primary excitatory neurotransmitter in the mammalian central nervous system. This multidisciplinary review examines the pharmacology/direct effects on consciousness, effectiveness in depression and acute suicidality, and safety of these fast-acting NMDA antagonists. To capture the essence of 60 years of peer-reviewed literature, we used a semi-structured approach to the subtopics, each of which required a different search strategy. We review the evidence for the three primary reported benefits of the two clinical drugs when used for depression: success in difficult-to-treat patients, rapid onset of action within a day, and immediate effects on suicidality. Key safety issues include the evidence-and lack thereof-for the effects of repeatedly inducing this altered mental state, and whether an adequate safety margin exists to rule out the neurotoxic effects seen in animal studies. This review includes evidence from multiple sources that raise substantial questions about both safety and effectiveness of ketamine and esketamine for psychiatric disorders.
Topics: Animals; Depression; Humans; Ketamine; Mammals; N-Methylaspartate; Phencyclidine; Receptors, N-Methyl-D-Aspartate
PubMed: 35665948
DOI: 10.1002/phar.2707 -
Military Medicine Oct 2014Recent years have seen the emergence and proliferation of "legal highs" or "designer drugs," compounds purposefully designed as legal alternatives to controlled... (Review)
Review
Recent years have seen the emergence and proliferation of "legal highs" or "designer drugs," compounds purposefully designed as legal alternatives to controlled substances of abuse. This article describes methoxetamine, a dissociative drug belonging to the arylcyclohexylamine class including phencyclidine and ketamine. Methoxetamine acts principally on the glutamatergic N-methyl-D-aspartate receptor and the serotonin receptor. It is sold as a white or off-white powder. Marketed as a "bladder friendly" alternative to ketamine, preliminary research suggests renal and cystic toxicity similar to ketamine. Methoxetamine is primarily ingested nasally, though also orally, intramuscularly, intravenously, and rectally. Users report dissociative features and, at higher doses, an "m-hole" experience akin to ketamine's "k-hole" described as extreme depersonalization and derealization. The 13 cases of acute methoxetamine toxicity described in the literature are summarized. The toxidrome consists of dissociation/delirium, sympathetic activation, and cerebellar symptoms. Methoxetamine is not detected in standard urine drug tests and there are no reliable laboratory findings. Management of acute methoxetamine toxicity is supportive, consisting of benzodiazepines, antiemetics, intravenous fluids, and respiratory support as indicated. Should methoxetamine conform to the observed 2-year lag of designer drugs migrating from Europe to the United States usage may increase in early 2014.
Topics: Cyclohexanones; Cyclohexylamines; Designer Drugs; Humans; Illicit Drugs; Military Personnel; Substance-Related Disorders; United States
PubMed: 25269134
DOI: 10.7205/MILMED-D-13-00470 -
Neurochemistry International May 2019Phencyclidine (PCP) is a dissociative anesthetic that induces psychotic symptoms and neurocognitive deficits in rodents similar to those observed in schizophrenia... (Review)
Review
Phencyclidine (PCP) is a dissociative anesthetic that induces psychotic symptoms and neurocognitive deficits in rodents similar to those observed in schizophrenia patients. PCP administration in healthy human subjects induces schizophrenia-like symptoms such as positive and negative symptoms, and a range of cognitive deficits. It has been reported that PCP, ketamine, and related drugs such as N-methyl-D-aspartate-type (NMDA) glutamate receptor antagonists, induce behavioral effects by blocking neurotransmission at NMDA receptors. Further, NMDA receptor antagonists reproduce specific aspects of the symptoms of schizophrenia. Neurochemical models based on the actions of PCP are well established, with increased focus on glutamatergic dysfunction as a basis for both symptoms and cognitive dysfunction in schizophrenia. On the other hand, the endogenous NMDA receptor antagonist, kynurenic acid (KYNA), which is a product of tryptophan-kynurenine pathway (KP) metabolism, is involved in schizophrenia pathogenesis. KYNA concentrations are elevated in the prefrontal cortex and cerebrospinal fluid of patients with schizophrenia. KYNA elevation affects neurotransmitter release in a similar manner to that of psychotomimetic agents such as PCP, underscoring a molecular basis of its involvement in schizophrenia pathophysiology. This review will highlight the relationship between PCP and KP metabolites based on evidence that both exogenous and endogenous NMDA receptor antagonists are involved in the pathogenesis of schizophrenia, and discuss our current understanding of the mechanisms underlying dysfunctional glutamatergic signaling as potential therapeutic targets for schizophrenia.
Topics: Animals; Brain; Humans; Kynurenine; Phencyclidine; Schizophrenia; Signal Transduction; Tryptophan
PubMed: 30731185
DOI: 10.1016/j.neuint.2019.02.001