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Biomolecules Jun 2020N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP), dizocilpine (MK-801) and ketamine have long been considered a model of schizophrenia, both... (Review)
Review
N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP), dizocilpine (MK-801) and ketamine have long been considered a model of schizophrenia, both in animals and humans. However, ketamine has been recently approved for treatment-resistant depression, although with severe restrictions. Interestingly, the dosage in both conditions is similar, and positive symptoms of schizophrenia appear before antidepressant effects emerge. Here, we describe the temporal mechanisms implicated in schizophrenia-like and antidepressant-like effects of NMDA blockade in rats, and postulate that such effects may indicate that NMDA receptor antagonists induce similar mechanistic effects, and only the basal pre-drug state of the organism delimitates the overall outcome. Hence, blockade of NMDA receptors in depressive-like status can lead to amelioration or remission of symptoms, whereas healthy individuals develop psychotic symptoms and schizophrenia patients show an exacerbation of these symptoms after the administration of NMDA receptor antagonists.
Topics: Animals; Brain; Depression; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Humans; Ketamine; Phencyclidine; Receptors, N-Methyl-D-Aspartate; Schizophrenia
PubMed: 32585886
DOI: 10.3390/biom10060947 -
British Journal of Pharmacology Sep 2015The history of ketamine and phencyclidine from their development as potential clinical anaesthetics through drugs of abuse and animal models of schizophrenia to... (Review)
Review
The history of ketamine and phencyclidine from their development as potential clinical anaesthetics through drugs of abuse and animal models of schizophrenia to potential rapidly acting antidepressants is reviewed. The discovery in 1983 of the NMDA receptor antagonist property of ketamine and phencyclidine was a key step to understanding their pharmacology, including their psychotomimetic effects in man. This review describes the historical context and the course of that discovery and its expansion into other hallucinatory drugs. The relevance of these findings to modern hypotheses of schizophrenia and the implications for drug discovery are reviewed. The findings of the rapidly acting antidepressant effects of ketamine in man are discussed in relation to other glutamatergic mechanisms.
Topics: Animals; Antidepressive Agents; Excitatory Amino Acid Antagonists; Humans; Ketamine; Phencyclidine; Receptors, N-Methyl-D-Aspartate; Schizophrenia
PubMed: 26075331
DOI: 10.1111/bph.13222 -
International Journal of Molecular... Dec 2022Since the 2000s, an increasing number of new psychoactive substances (NPS) have appeared on the drug market. Arylcyclohexylamine (ACH) compounds such as ketamine,... (Review)
Review
Since the 2000s, an increasing number of new psychoactive substances (NPS) have appeared on the drug market. Arylcyclohexylamine (ACH) compounds such as ketamine, phencyclidine and eticyclidine derivatives are of particular concern, given their rapidly increasing use and the absence of detailed toxicity data. First used mainly for their pharmacological properties in anesthesia, their recreational use is increasing. ACH derivatives have an antagonistic activity against the N-methyl-D-aspartate receptor, which leads to dissociative effects (dissociation of body and mind). Synthetic ketamine derivatives produced in Asia are now arriving in Europe, where most are not listed as narcotics and are, thus, legal. These structural derivatives have pharmacokinetic and pharmacodynamic properties that are sometimes very different from ketamine. Here, we describe the pharmacology, epidemiology, chemistry and metabolism of ACH derivatives, and we review the case reports on intoxication.
Topics: Ketamine; Phencyclidine; Receptors, N-Methyl-D-Aspartate; Asia; Europe
PubMed: 36555217
DOI: 10.3390/ijms232415574 -
Tidsskrift For Den Norske Laegeforening... Oct 2005For the first time in ten years, phencyclidine (PCP) has been confiscated in Norway. Physicians should be aware of this substance when treating intoxications. (Review)
Review
BACKGROUND
For the first time in ten years, phencyclidine (PCP) has been confiscated in Norway. Physicians should be aware of this substance when treating intoxications.
METHODS
Relevant literature was identified by search in Medline. This review presents the pharmacological properties and effects of phencyclidine as well as symptoms and treatment of phencyclidine intoxication.
RESULTS AND INTERPRETATION
Phencyclidine exhibits hallucinogenic, depressant and stimulant properties. Phencyclidine interacts as an antagonist to the N-methyl-D-aspartate (NMDA) receptor in the central nervous system. Severe NMDA receptor hypofunction can elicit clinical symptoms similar to a schizophrenic episode.
Topics: Diagnosis, Differential; Hallucinogens; Humans; Phencyclidine; Phencyclidine Abuse; Psychotic Disorders; Receptors, N-Methyl-D-Aspartate; Schizophrenia
PubMed: 16244678
DOI: No ID Found -
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 -
Pharmacology, Biochemistry, and Behavior Apr 2021Adolescence is a period of profound developmental changes, which run the gamut from behavioral and neural to physiological and hormonal. It is also a time at which there... (Review)
Review
Adolescence is a period of profound developmental changes, which run the gamut from behavioral and neural to physiological and hormonal. It is also a time at which there is an increased propensity to engage in risk-taking and impulsive behaviors like drug use. This review examines the human and preclinical literature on adolescent drug use and its consequences, with a focus on dissociatives (PCP, ketamine, DXM), classic psychedelics (LSD, psilocybin), and MDMA. It is the case for all the substances reviewed here that very little is known about their effects in adolescent populations. An emerging aspect of the literature is that dissociatives and MDMA produce mixed reinforcing and aversive effects and that the balance between reinforcement and aversion may differ between adolescents and adults, with consequences for drug use and addiction. However, many studies have failed to directly compare adults and adolescents, which precludes definitive conclusions about these consequences. Other important areas that are largely unexplored are sex differences during adolescence and the long-term consequences of adolescent use of these substances. We provide suggestions for future work to address the gaps we identified in the literature. Given the widespread use of these drugs among adolescent users, and the potential for therapeutic use, this work will be crucial to understanding abuse potential and consequences of use in this developmental stage.
Topics: Adolescent; Adult; Age Factors; Animals; Dextromethorphan; Female; Hallucinogens; Humans; Ketamine; Lysergic Acid Diethylamide; Male; N-Methyl-3,4-methylenedioxyamphetamine; Phencyclidine; Psilocybin; Risk-Taking; Substance-Related Disorders
PubMed: 33515586
DOI: 10.1016/j.pbb.2021.173129 -
The Israel Journal of Psychiatry and... 2010Schizophrenia is a serious mental disorder that affects up to 1% of the population worldwide. Traditional models of schizophrenia have emphasized dopaminergic... (Review)
Review
Schizophrenia is a serious mental disorder that affects up to 1% of the population worldwide. Traditional models of schizophrenia have emphasized dopaminergic dysfunction. Over the last 20 years, however, limitations of the dopamine model have become increasingly apparent, necessitating development of alternative models. Glutamatergic models are based upon the observation that the psychotomimetic agents such as phencyclidine (PCP) and ketamine induce psychotic symptoms and neurocognitive disturbances similar to those of schizophrenia by blocking neurotransmission at N-methyl-D-aspartate (NMDA)-type glutamate receptors. Because glutamate/NMDA receptors are located throughout the brain, glutamatergic models predict widespread cortical dysfunction with particular involvement of NMDA receptors throughout the brain. Further, NMDA receptors are located on brain circuits that regulate dopamine release, suggesting that dopaminergic deficits in schizophrenia may also be secondary to underlying glutamatergic dysfunction. Agents that stimulate NMDA receptor-mediated neurotransmission, including glycine-site agonists and glycine transport inhibitors, have shown encouraging results in preclinical studies and are currently undergoing clinical development. Encouraging results have been observed as well with agents such as metabotropic 2/3 agonists that decrease resting glutamate levels, reversing potential disruption in firing patterns within prefrontal cortex and possibly other brain regions. Overall, these findings suggest that glutamatergic theories may lead to new conceptualizations and treatment approaches that would not be possible based upon dopaminergic models alone.
Topics: Animals; Brain; Dopamine; Excitatory Amino Acid Antagonists; Glutamic Acid; Humans; Ketamine; Nerve Net; Phencyclidine; Prefrontal Cortex; Psychological Theory; Receptors, Dopamine D2; Receptors, Glutamate; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Schizophrenic Psychology; Synaptic Transmission
PubMed: 20686195
DOI: No ID Found -
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 -
Journal of Psychopharmacology (Oxford,... Apr 2014The observation that antagonists of the N-methyl-D-aspartate receptor (NMDAR), such as phencyclidine (PCP) and ketamine, transiently induce symptoms of acute... (Review)
Review
The observation that antagonists of the N-methyl-D-aspartate receptor (NMDAR), such as phencyclidine (PCP) and ketamine, transiently induce symptoms of acute schizophrenia had led to a paradigm shift from dopaminergic to glutamatergic dysfunction in pharmacological models of schizophrenia. The glutamate hypothesis can explain negative and cognitive symptoms of schizophrenia better than the dopamine hypothesis, and has the potential to explain dopamine dysfunction itself. The pharmacological and psychomimetic effects of ketamine, which is safer for human subjects than phencyclidine, are herein reviewed. Ketamine binds to a variety of receptors, but principally acts at the NMDAR, and convergent genetic and molecular evidence point to NMDAR hypofunction in schizophrenia. Furthermore, NMDAR hypofunction can explain connectional and oscillatory abnormalities in schizophrenia in terms of both weakened excitation of inhibitory γ-aminobutyric acidergic (GABAergic) interneurons that synchronize cortical networks and disinhibition of principal cells. Individuals with prenatal NMDAR aberrations might experience the onset of schizophrenia towards the completion of synaptic pruning in adolescence, when network connectivity drops below a critical value. We conclude that ketamine challenge is useful for studying the positive, negative, and cognitive symptoms, dopaminergic and GABAergic dysfunction, age of onset, functional dysconnectivity, and abnormal cortical oscillations observed in acute schizophrenia.
Topics: Age of Onset; Animals; Dopamine; Humans; Ketamine; Phencyclidine; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Schizophrenic Psychology; gamma-Aminobutyric Acid
PubMed: 24257811
DOI: 10.1177/0269881113512909 -
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