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International Journal of Molecular... Jul 20211-cyclohexyl-x-methoxybenzene is a novel psychoactive substance (NPS), first discovered in Europe in 2012 as unknown racemic mixture of its three stereoisomers: ortho,... (Comparative Study)
Comparative Study
1-cyclohexyl-x-methoxybenzene is a novel psychoactive substance (NPS), first discovered in Europe in 2012 as unknown racemic mixture of its three stereoisomers: ortho, meta and para. Each of these has structural similarities with the analgesic tramadol and the dissociative anesthetic phencyclidine. In light of these structural analogies, and based on the fact that both tramadol and phencyclidine are substances that cause toxic effects in humans, the aim of this study was to investigate the in vitro and in vivo pharmacodynamic profile of these molecules, and to compare them with those caused by tramadol and phencyclidine. In vitro studies demonstrated that tramadol, ortho, meta and para were inactive at mu, kappa and delta opioid receptors. Systemic administration of the three stereoisomers impairs sensorimotor responses, modulates spontaneous motor activity, induces modest analgesia, and alters thermoregulation and cardiorespiratory responses in the mouse in some cases, with a similar profile to that of tramadol and phencyclidine. Naloxone partially prevents only the visual sensorimotor impairments caused by three stereoisomers, without preventing other effects. The present data show that 1-cyclohexyl-x-methoxybenzene derivatives cause pharmaco-toxicological effects by activating both opioid and non-opioid mechanisms and suggest that their use could potentially lead to abuse and bodily harm.
Topics: Analgesics, Opioid; Animals; Anisoles; Benzene Derivatives; Cells, Cultured; Cricetinae; Hallucinogens; In Vitro Techniques; Male; Mice; Mice, Inbred ICR; Models, Animal; Phencyclidine; Psychotropic Drugs; Receptors, Opioid; Tramadol
PubMed: 34299276
DOI: 10.3390/ijms22147659 -
Pharmacology, Biochemistry, and Behavior Dec 2018Chronic methamphetamine (meth) abuse often turns into a compulsive drug-taking disorder accompanied by persistent cognitive deficits and re-occurring psychosis. Possible... (Comparative Study)
Comparative Study
Chronic methamphetamine self-administration dysregulates 5-HT2A and mGlu2 receptor expression in the rat prefrontal and perirhinal cortex: Comparison to chronic phencyclidine and MK-801.
Chronic methamphetamine (meth) abuse often turns into a compulsive drug-taking disorder accompanied by persistent cognitive deficits and re-occurring psychosis. Possible common neurobiological substrates underlying meth-induced deficits and schizophrenia remain poorly understood. Serotonin 2A (5-HT2A) and metabotropic glutamate 2 (mGlu2) receptors co-regulate psychosis-like behaviors and cognitive function in animals. Therefore, in the present study we examined the effects of chronic exposure to three different drugs known to produce persistent deficits in sensorimotor gating and cognition [meth, phencyclidine (PCP) and MK-801] on the expression of 5-HT2A and mGlu2 within the rat medial prefrontal cortex (mPFC), dorsal hippocampus (dHPC) and perirhinal cortex (PRh). Adult male rats underwent 14 days of: (a) meth self-administration (6 h/day), (b) phencyclidine (PCP; 5 mg/kg, twice/day) administration, or (c) MK-801 (0.3 mg/kg, twice/day) administration. Seven days after the discontinuation of drug administration, tissues of interest were collected for protein expression analysis. We found that despite different pharmacological mechanism of action, chronic meth, PCP, and MK-801 similarly dysregulated 5-HT2A and mGlu2, as indicated by an increase in the 5-HT2A/mGlu2 expression ratio in the mPFC (all three tested drugs), PRh (meth and PCP), and dHPC (MK-801 only). Complementary changes in G-protein expression (increase in Gα and decrease in Gα) were also observed in the mPFC of meth animals. Finally, we found that 5-HT2A/mGlu2 cooperation can be mediated in part by the formation of the receptor heteromer in some, but not all cortical regions. In summary, these data suggest that a shift towards increased availability (and G-protein coupling) of cortical 5-HT2A vs. mGlu2 receptors may represent a common neurobiological mechanism underlying the emergence of psychosis and cognitive deficits observed in subjects with meth use disorder and schizophrenia.
Topics: Animals; Antibodies; Dizocilpine Maleate; Immunoprecipitation; Male; Methamphetamine; Perirhinal Cortex; Phencyclidine; Prefrontal Cortex; Rats; Rats, Long-Evans; Rats, Wistar; Receptor, Serotonin, 5-HT2A; Receptors, Metabotropic Glutamate; Reproducibility of Results
PubMed: 30240581
DOI: 10.1016/j.pbb.2018.09.007 -
Journal of Proteome Research Aug 2015Schizophrenia is a neuropsychiatric disorder affecting 1% of the world's population. Due to both a broad range of symptoms and disease heterogeneity, current therapeutic...
Schizophrenia is a neuropsychiatric disorder affecting 1% of the world's population. Due to both a broad range of symptoms and disease heterogeneity, current therapeutic approaches to treat schizophrenia fail to address all symptomatic manifestations of the disease. Therefore, disease models that reproduce core pathological features of schizophrenia are needed for the elucidation of pathological disease mechanisms. Here, we employ a comprehensive global label-free liquid chromatography-mass spectrometry proteomic (LC-MS(E)) and metabonomic (LC-MS) profiling analysis combined with the targeted proteomics (selected reaction monitoring and multiplex immunoassay) of serum and brain tissues to investigate a chronic phencyclidine (PCP) rat model in which glutamatergic hypofunction is induced through noncompetitive NMDAR-receptor antagonism. Using a multiplex immunoassay, we identified alterations in the levels of several cytokines (IL-5, IL-2, and IL-1β) and fibroblast growth factor-2. Extensive proteomic and metabonomic brain tissue profiling revealed a more prominent effect of chronic PCP treatment on both the hippocampal proteome and metabonome compared to the effect on the frontal cortex. Bioinformatic pathway analysis confirmed prominent abnormalities in NMDA-receptor-associated pathways in both brain regions, as well as alterations in other neurotransmitter systems such as kainate, AMPA, and GABAergic signaling in the hippocampus and in proteins associated with neurodegeneration. We further identified abundance changes in the level of the superoxide dismutase enzyme (SODC) in both the frontal cortex and hippocampus, which indicates alterations in oxidative stress and substantiates the apoptotic pathway alterations. The present study could lead to an increased understanding of how perturbed glutamate receptor signaling affects other relevant biological pathways in schizophrenia and, therefore, support drug discovery efforts for the improved treatment of patients suffering from this debilitating psychiatric disorder.
Topics: Animals; Apoptosis; Chromatography, Liquid; Cytokines; Disease Models, Animal; Frontal Lobe; Hallucinogens; Hippocampus; Humans; Male; Mass Spectrometry; Metabolome; Metabolomics; Oxidative Stress; Phencyclidine; Proteome; Proteomics; Rats, Sprague-Dawley; Schizophrenia; Signal Transduction; Superoxide Dismutase; Synaptic Transmission
PubMed: 26043028
DOI: 10.1021/acs.jproteome.5b00105 -
The International Journal of... Nov 2016Dysfunction of dopaminergic, GABAergic, and glutamatergic function underlies many core symptoms of schizophrenia. Combined neonatal injection of the N-methyl-D-aspartate...
Down-Regulation of Hippocampal Genes Regulating Dopaminergic, GABAergic, and Glutamatergic Function Following Combined Neonatal Phencyclidine and Post-Weaning Social Isolation of Rats as a Neurodevelopmental Model for Schizophrenia.
BACKGROUND
Dysfunction of dopaminergic, GABAergic, and glutamatergic function underlies many core symptoms of schizophrenia. Combined neonatal injection of the N-methyl-D-aspartate (NMDA) receptor antagonist, phencyclidine (PCP), and post-weaning social isolation of rats produces a behavioral syndrome with translational relevance to several core symptoms of schizophrenia. This study uses DNA microarray to characterize alterations in hippocampal neurotransmitter-related gene expression and examines the ability of the sodium channel blocker, lamotrigine, to reverse behavioral changes in this model.
METHODS
Fifty-four male Lister-hooded rat pups either received phencyclidine (PCP, 10mg/kg, s.c.) on post-natal days (PND) 7, 9, and 11 before being weaned on PND 23 into separate cages (isolation; PCP-SI; n = 31) or received vehicle injection and group-housing (2-4 per cage; V-GH; n = 23) from weaning. The effect of lamotrigine on locomotor activity, novel object recognition, and prepulse inhibition of acoustic startle was examined (PND 60-75) and drug-free hippocampal gene expression on PND 70.
RESULTS
Acute lamotrigine (10-15mg/kg i.p.) reversed the hyperactivity and novel object recognition impairment induced by PCP-SI but had no effect on the prepulse inhibition deficit. Microarray revealed small but significant down-regulation of hippocampal genes involved in glutamate metabolism, dopamine neurotransmission, and GABA receptor signaling and in specific schizophrenia-linked genes, including parvalbumin (PVALB) and GAD67, in PCP-SI rats, which resemble changes reported in schizophrenia.
CONCLUSIONS
Findings indicate that alterations in dopamine neurotransmission, glutamate metabolism, and GABA signaling may contribute to some of the behavioral deficits observed following PCP-SI, and that lamotrigine may have some utility as an adjunctive therapy to improve certain cognitive deficits symptoms in schizophrenia.
Topics: Animals; Animals, Newborn; Behavior, Animal; Disease Models, Animal; Dopaminergic Neurons; GABAergic Neurons; Gene Expression Profiling; Gene Expression Regulation; Genetic Predisposition to Disease; Glutamic Acid; Hippocampus; Lamotrigine; Locomotion; Male; Oligonucleotide Array Sequence Analysis; Phencyclidine; Phenotype; Prepulse Inhibition; Rats, Inbred Strains; Recognition, Psychology; Reflex, Startle; Schizophrenia; Schizophrenic Psychology; Social Isolation; Sodium Channel Blockers; Synaptic Transmission; Time Factors; Triazines; Weaning
PubMed: 27382048
DOI: 10.1093/ijnp/pyw062 -
The Journal of Neuroscience : the... Mar 1995Phencyclidine (PCP), dizocilpine maleate (MK801), and other NMDA antagonists are toxic to neurons in the posterior cingulate and retrosplenial cortex. To determine if... (Comparative Study)
Comparative Study
Phencyclidine (PCP), dizocilpine maleate (MK801), and other NMDA antagonists are toxic to neurons in the posterior cingulate and retrosplenial cortex. To determine if additional neurons are damaged, the distribution of microglial activation and 70 kDa heat shock protein (HSP70) induction was studied following the administration of PCP and MK801 to rats. PCP (10-50 mg/kg) induced microglial activation and neuronal HSP70 mRNA and protein expression in the posterior cingulate and retrosplenial cortex. In addition, coronal sections of the cerebellar vermis of PCP (50 mg/kg) treated rats contained vertical stripes of activated microglial in the molecular layer. In the sagittal plane, the microglial activation occurred in irregularly shaped patches, suggesting damage to Purkinje cells. In accord with this finding, PCP induced HSP70 protein and mRNA expression in Purkinje cells. Although there were relatively few foci of microglial activation and cells with HSP70 protein induction, HSP70 mRNA was detected in many Purkinje cells located throughout the cerebellar hemispheres as well as the vermis. MK801, at doses of 5-10 mg/kg, induced microglial activation and neuronal HSP70 mRNA and protein expression in the cingulate and retrosplenial cortex but not in the cerebellum. At the dose of 1 mg/kg MK801 induced HSP70 but did not consistently activate microglia. These data suggest that microglia are activated by MK801 doses that kill or severely damage neurons, whereas HSP70 is induced in "stressed" neurons at MK801 doses well below those that produce severe neurotoxicity. These observations suggest that PCP, but not MK801, is toxic to Purkinje cells and raise the question of whether NMDA antagonists or sigma ligands other than PCP are toxic to the cerebellum. Moreover, this study illustrates the usefulness of microglial activation and HSP70 induction as markers of neurotoxicity.
Topics: Animals; Base Sequence; Cerebellum; Dizocilpine Maleate; Gene Expression Regulation; Gyrus Cinguli; HSP70 Heat-Shock Proteins; Male; Microglia; Molecular Sequence Data; Nerve Tissue Proteins; Parietal Lobe; Phencyclidine; Purkinje Cells; Pyramidal Cells; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Receptors, sigma
PubMed: 7891155
DOI: 10.1523/JNEUROSCI.15-03-02097.1995 -
International Journal of Molecular... Jun 2020The dissociative anesthetic phencyclidine (PCP) and PCP derivatives, including 4'-F-PCP, are illegally sold and abused worldwide for recreational and non-medical uses....
The dissociative anesthetic phencyclidine (PCP) and PCP derivatives, including 4'-F-PCP, are illegally sold and abused worldwide for recreational and non-medical uses. The psychopharmacological properties and abuse potential of 4'-F-PCP have not been fully characterized. In this study, we evaluated the psychomotor, rewarding, and reinforcing properties of 4'-F-PCP using the open-field test, conditioned place preference (CPP), and self-administration paradigms in rodents. Using Western immunoblotting, we also investigated the expression of dopamine (DA)-related proteins and DA-receptor-mediated downstream signaling cascades in the nucleus accumbens (NAc) of 4'-F-PCP-self-administering rats. Intraperitoneal administration of 10 mg/kg 4'-F-PCP significantly increased locomotor and rearing activities and increased CPP in mice. Intravenous administration of 1.0 mg/kg/infusion of 4'-F-PCP significantly enhanced self-administration during a 2 h session under fixed ratio schedules, showed a higher breakpoint during a 6 h session under progressive ratio schedules of reinforcement, and significantly altered the expression of DA transporter and DA D1 receptor in the NAc of rats self-administering 1.0 mg/kg 4'-F-PCP. Additionally, the expression of phosphorylated (p) ERK, pCREB, c-Fos, and FosB/ΔFosB in the NAc was significantly enhanced by 1.0 mg/kg 4'-F-PCP self-administration. Taken together, these findings suggest that 4'-F-PCP has a high potential for abuse, given its robust psychomotor, rewarding, and reinforcing properties via activation of DAergic neurotransmission and the downstream signaling pathways in the NAc.
Topics: Animals; Behavior, Addictive; Dopamine; Dopamine Plasma Membrane Transport Proteins; Male; Mice; Mice, Inbred C57BL; Nucleus Accumbens; Phencyclidine; Phencyclidine Abuse; Proto-Oncogene Proteins c-fos; Psychomotor Performance; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1; Reinforcement, Psychology; Reward; Self Administration
PubMed: 32610694
DOI: 10.3390/ijms21134631 -
Journal of Medical Toxicology :... Sep 2015Phencyclidine (PCP) is a synthetic compound derived from piperidine and used as an anesthetic and hallucinogenic. Little has been recently published regarding the...
BACKGROUND
Phencyclidine (PCP) is a synthetic compound derived from piperidine and used as an anesthetic and hallucinogenic. Little has been recently published regarding the clinical presentation of PCP intoxication. PCP use as a recreational drug is resurging.
OBJECTIVE
Our objective was to describe clinical findings in patients presenting to the emergency department (ED) under the influence of PCP.
METHODS
This was a case series study conducted at a tertiary care center with an annual census of 100,000 patients/year. Emergency physicians, residents, physician assistants, and research assistants identified patients with possible PCP intoxication. Self-reported PCP use, report by bystanders or Emergency Medical Services (EMS) staff, was used in this process. A structured data collection form was completed, documenting both clinical and behavioral events observed by the treating team during the ED visit.
RESULTS
We collected data on 219 patients; 184 were analyzed; two patients were excluded secondary to incomplete data. The mean age of patients was 32.5 years (±7 years) with 65.2 % being males. PCP use was self-reported by 60.3 % of patients. Of the 184 patients, 153 (83.1 %) received a urine drug screen (UDS); 152 (98.7 %) were positive for PCP. On arrival, 78.3 % of patients were awake and alert, and 51.6 % were oriented to self, time/date, and place. Mean physiological parameters were the following: heart rate 101.1 bpm (±24.3), RR 18.9 bpm (±3.4), BP 146.3 (±19.4)/86.3 (±14.0) mmHg, 36.9° C (±0.5), and pulse oximetry 98.2 % (±1.9). Clinical findings were the following: retrograde amnesia in 46 (25 %), horizontal nystagmus in 118 (64.1 %), vertical nystagmus in 90 (48.9 %), hypertension in 87 (47.3 %), and agitation in 71 (38.6 %). Concomitant use of at least one other substance was reported by 99 (53.8 %) patients. The mean length of stay in the ED for all subjects was 261.1 (±172.8) minutes. Final disposition for 152 (82.6 %) patients was to home. Of the 184 patients, 14 (7.6 %) required admission; 12 were referred to Crisis Response Center.
CONCLUSION
Patients with PCP intoxication tended to be young males. The prevalent clinical signs and symptoms were the following: retrograde amnesia, nystagmus, hypertension, and psychomotor agitation. Co-use of other substances was the norm. Most patients presenting to the ED with PCP intoxication do well and can be discharged home after a period of observation.
Topics: Adult; Emergency Service, Hospital; Female; Hallucinogens; Humans; Length of Stay; Male; Middle Aged; Phencyclidine; Phencyclidine Abuse; Philadelphia; Prevalence; Risk Factors; Substance Abuse Detection; Tertiary Care Centers; Time Factors; Treatment Outcome; Young Adult
PubMed: 25502414
DOI: 10.1007/s13181-014-0453-9 -
Japanese Journal of Pharmacology Jun 2000Catecholaminergic and/or cyclic AMP (cAMP) systems have been demonstrated to be involved in the development of drug dependence. We investigated the involvement of both... (Review)
Review
Catecholaminergic and/or cyclic AMP (cAMP) systems have been demonstrated to be involved in the development of drug dependence. We investigated the involvement of both systems in psychological dependence on phencyclidine (PCP) by using tyrosine hydroxylase (TH) heterozygous (TH+/-) and cAMP response element binding protein (CREB) binding protein (CBP) heterozygous (CBP+/-) mice. PCP (8 mg/kg) induced place preference in wild-type mice pretreated with PCP (10 mg/kg once a day for 28 days). In these mice, the level of cAMP in the striatum, but not in the thalamus, was increased one day after the last injection of PCP (10 mg/kg). In TH+/- and CBP+/- mice pretreated with PCP (10 mg/kg per day for 28 days), however, no PCP (8 mg/kg)-induced place preference was observed. The level of cAMP in the striatum was increased in CBP+/- mice, but not TH+/- mice. Furthermore, we have demonstrated that the place preference induced by PCP is attenuated by 6-hydroxydopamine, a dopaminergic neurotoxin, and (+) SCH-23390, a dopamine-D1 receptor antagonist, but not by DSP-4, a noradrenergic neurotoxin, and (-) sulpiride, a dopamine-D2 receptor antagonist. These findings suggest that catecholamines and CBP are involved in the development of psychological dependence on PCP and that changes in dopaminergic and/or cAMP systems induced by repeated PCP treatment play an important role in the addiction to PCP.
Topics: Animals; Catecholamines; Cyclic AMP; Mice; Mice, Mutant Strains; Phencyclidine; Receptors, Dopamine; Substance-Related Disorders
PubMed: 10928319
DOI: 10.1254/jjp.83.89 -
The Western Journal of Medicine Jan 1980
Topics: Adolescent; Adult; Child; Humans; Phencyclidine; Substance-Related Disorders
PubMed: 7376649
DOI: No ID Found -
Journal of Pharmacological Sciences 2013Schizophrenia is a multifactorial psychiatric disorder in which both genetic and environmental factors play a role. Genetic [e.g., Disrupted-in-schizophrenia 1 (DISC1),... (Review)
Review
Schizophrenia is a multifactorial psychiatric disorder in which both genetic and environmental factors play a role. Genetic [e.g., Disrupted-in-schizophrenia 1 (DISC1), Neuregulin-1 (NRG1)] and environmental factors (e.g., maternal viral infection, obstetric complications, social stress) may act during the developmental period to increase the incidence of schizophrenia. In animal models, interactions between susceptibility genes and the environment can be controlled in ways not possible in humans; therefore, such models are useful for investigating interactions between or within factors in the pathogenesis and pathophysiology of schizophrenia. We provide an overview of schizophrenic animal models investigating interactions between or within factors. First, we reviewed gene-environment interaction animal models, in which schizophrenic candidate gene mutant mice were subjected to perinatal immune activation or adolescent stress. Next, environment-environment interaction animal models, in which mice were subjected to a combination of perinatal immune activation and adolescent administration of drugs, were described. These animal models showed interaction between or within factors; behavioral changes, which were obscured by each factor, were marked by interaction of factors and vice versa. Appropriate behavioral approaches with such models will be invaluable for translational research on novel compounds, and also for providing insight into the pathogenesis and pathophysiology of schizophrenia.
Topics: Adenylyl Cyclases; Animals; Behavior, Animal; Disease Models, Animal; Gene-Environment Interaction; Humans; Mice; Nerve Tissue Proteins; Neuregulin-1; Nuclear Receptor Subfamily 4, Group A, Member 2; Peptides; Phencyclidine; Phenotype; Point Mutation; Schizophrenia; Schizophrenic Psychology
PubMed: 23449491
DOI: 10.1254/jphs.12r15cp