RESUMEN
Environmental perturbations during the first years of life are a major factor in psychiatric diseases. Phencyclidine (PCP), a drug of abuse, has psychomimetic effects, and neonatal subchronic administration of PCP in rodents leads to long-term behavioral changes relevant for schizophrenia. The cerebellum is increasingly recognized for its role in diverse cognitive functions. However, little is known about potential cerebellar changes in models of schizophrenia. Here, we analyzed the characteristics of the cerebellum in the neonatal subchronic PCP model. We found that, while the global cerebellar cytoarchitecture and Purkinje cell spontaneous spiking properties are unchanged, climbing fiber/Purkinje cell synaptic connectivity is increased in juvenile mice. Neonatal subchronic administration of PCP is accompanied by increased cFos expression, a marker of neuronal activity, and transient modification of the neuronal surfaceome in the cerebellum. The largest change observed is the overexpression of Ctgf, a gene previously suggested as a biomarker for schizophrenia. This neonatal increase in Ctgf can be reproduced by increasing neuronal activity in the cerebellum during the second postnatal week using chemogenetics. However, it does not lead to increased climbing fiber/Purkinje cell connectivity in juvenile mice, showing the complexity of PCP action. Overall, our study shows that administration of the drug of abuse PCP during the developmental period of intense cerebellar synaptogenesis and circuit remodeling has long-term and specific effects on Purkinje cell connectivity and warrants the search for this type of synaptic changes in psychiatric diseases.
Asunto(s)
Alucinógenos , Fenciclidina , Células de Purkinje , Esquizofrenia , Animales , Factor de Crecimiento del Tejido Conjuntivo/genética , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Modelos Animales de Enfermedad , Alucinógenos/administración & dosificación , Alucinógenos/efectos adversos , Ratones , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fenciclidina/administración & dosificación , Fenciclidina/efectos adversos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Células de Purkinje/efectos de los fármacos , Células de Purkinje/fisiología , Células de Purkinje/ultraestructura , Receptores de Fenciclidina/agonistas , Esquizofrenia/inducido químicamente , Esquizofrenia/patología , Sinapsis/efectos de los fármacos , Sinapsis/ultraestructuraRESUMEN
Cyclin-dependent kinase 5 (CDK5) is a serine/threonine kinase that has emerged as a key regulator of neurotransmission in complex cognitive processes. Its expression is altered in treated schizophrenia patients, and cannabinoids modulate CDK5 levels in the brain of rodents. However, the role of this kinase, and its interaction with cannabis use in first-episode psychosis (FEP) patients is still not known. Hence, we studied the expression changes of CDK5 and its signaling partner, postsynaptic density protein 95 (PSD95) in olfactory neuroepithelial (ON) cells of FEP patients with (FEP/c) and without (FEP/nc) prior cannabis use, and in a dual-hit mouse model of psychosis. In this model, adolescent mice were exposed to the cannabinoid receptor 1 agonist (CB1R) WIN-55,212-2 (WIN: 1 mg/kg) during 21 days, and to the N-methyl-d-aspartate receptor (NMDAR) blocker phencyclidine (PCP: 10 mg/kg) during 10 days. FEP/c showed less social functioning deficits, lower CDK5 and higher PSD95 levels than FEP/nc. These changes correlated with social skills, but not cognitive deficits. Consistently, exposure of ON cells from FEP/nc patients to WIN in vitro reduced CDK5 levels. Convergent results were obtained in mice, where PCP by itself induced more sociability deficits, and PSD95/CDK5 alterations in the prefrontal cortex and hippocampus than exposure to PCP-WIN. In addition, central blockade of CDK5 activity with roscovitine in PCP-treated mice restored both sociability impairments and PSD95 levels. We provide translational evidence that increased CDK5 could be an early indicator of psychosis associated with social deficits, and that this biomarker is modulated by prior cannabis use.
Asunto(s)
Cannabinoides , Trastornos Psicóticos , Esquizofrenia , Ratones , Animales , Quinasa 5 Dependiente de la Ciclina/metabolismo , Trastornos Psicóticos/tratamiento farmacológico , Fenciclidina/farmacología , Agonistas de Receptores de Cannabinoides , Homólogo 4 de la Proteína Discs LargeRESUMEN
Background: Although the misuse of ketamine constitutes a worldwide issue, ketamine is quickly taking its place as a therapeutic option in the management of several mental disorders. However, the use of ketamine and/or its analogues, as well as combinations with other drugs, can be fatal.Objective: To outline the cases of overdoses and deaths related to the use of ketamine and/or its analogues, as reported in the scientific literature. To investigate if ketamine is safe in a therapeutic context, particularly in its use as an antidepressant.Methods: Electronic searches were performed on three medical databases. Articles describing cases of overdose and/or death associated with ketamine and/or its analogues were included. After the removal of duplicates, title analysis and full-text analysis, 34 articles were included in this review.Results: Eighteen articles described fatal cases and sixteen described overdoses. Poly-substance use was mentioned in 53% of the selected articles. Most cases were males and the ages varied from two to 65 years old. A total of 312 overdose cases and 138 deaths were reported. In both death reports and overdose cases, ketamine was preponderant: 89.1% and 79%, respectively. No cases of overdose or death related to the use of ketamine as an antidepressant in a therapeutic setting were found; most of the deaths occurred in the circumstances of polydrug use and overdoses left no sequelae.Conclusion: There is legitimate concern about the risks involving the use of ketamine and its analogues, especially in recreational settings. On the other hand, ketamine as medicine is considered safe and it is listed as an essential medicine by the World Health Organization. Although clinicians must remain vigilant, this should not deter appropriate prescription.
Asunto(s)
Sobredosis de Droga , Ketamina , Trastornos Relacionados con Sustancias , Masculino , Humanos , Preescolar , Niño , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Femenino , Ketamina/efectos adversos , Sobredosis de Droga/epidemiología , Trastornos Relacionados con Sustancias/epidemiología , Analgésicos OpioidesRESUMEN
Background: Illicit drug use has become a global epidemic, yet it is unclear if drug smoking increases the risk of tobacco-related cancers.Objectives: We aimed to evaluate hypothesized associations between smoking three drugs - opium, phencyclidine (PCP) and crack cocaine and lung and upper aerodigestive tract (UADT) cancers.Methods: A population-based case-control study with 611 lung cancer cases (50% male), 601 UADT cancers cases (76% male), and 1,040 controls (60% male) was conducted in Los Angeles County (1999-2004). Epidemiologic data including drug smoking histories were collected in face-to-face interviews. Associations were estimated with logistic regressions.Results: Adjusting for potential confounders, ever vs. never crack smoking was positively associated with UADT cancers (aOR = 1.56, 95% CI: 1.05, 2.33), and a dose-response relationship was observed for lifetime smoking frequency (p for trend = .024). Heavy (> median) vs. never crack smoking was associated with UADT cancers (aOR = 1.81, 95% CI: 1.07, 3.08) and lung cancer (aOR = 1.58, 95% CI: 0.88, 2.83). A positive association was also observed between heavy PCP smoking and UADT cancers (aOR = 2.29, 95% CI: 0.91, 5.79). Little or no associations were found between opium smoking and lung cancer or UADT cancers.Conclusion: The positive associations between illicit drug use and lung and/or UADT cancers suggest that smoking these drugs may increase the risk of tobacco-related cancers. Despite the low frequency of drug smoking and possible residual confounding, our findings may provide additional insights on the development of lung and UADT cancers.
Asunto(s)
Neoplasias de Cabeza y Cuello , Drogas Ilícitas , Neoplasias Pulmonares , Humanos , Masculino , Femenino , Opio , Fenciclidina , Fumar Cocaína , Los Angeles , Estudios de Casos y Controles , Neoplasias Pulmonares/epidemiología , Pulmón , Factores de RiesgoRESUMEN
Phencyclidine (PCP) causes mental symptoms that closely resemble schizophrenia through the inhibition of the glutamatergic system. The kynurenine (KYN) pathway (KP) generates metabolites that modulate glutamatergic systems such as kynurenic acid (KA), quinolinic acid (QA), and xanthurenic acid (XA). Kynurenine 3-monooxygenase (KMO) metabolizes KYN to 3-hydroxykynurenine (3-HK), an upstream metabolite of QA and XA. Clinical studies have reported lower KMO mRNA and higher KA levels in the postmortem brains of patients with schizophrenia and exacerbation of symptoms in schizophrenia by PCP. However, the association between KMO deficiency and PCP remains elusive. Here, we demonstrated that a non-effective dose of PCP induced impairment of prepulse inhibition (PPI) in KMO KO mice. KA levels were increased in the prefrontal cortex (PFC) and hippocampus (HIP) of KMO KO mice, but 3-HK levels were decreased. In wild-type C57BL/6 N mice, the PPI impairment induced by PCP is exacerbated by KA, while attenuated by 3-HK, QA and XA. Taken together, KMO KO mice were vulnerable to the PPI impairment induced by PCP through an increase in KA and a decrease in 3-HK, suggesting that an increase in the ratio of KA to 3-HK (QA and XA) may play an important role in the pathophysiology of schizophrenia.
Asunto(s)
Quinurenina 3-Monooxigenasa , Quinurenina , Animales , Ácido Quinurénico/metabolismo , Quinurenina/metabolismo , Quinurenina 3-Monooxigenasa/genética , Quinurenina 3-Monooxigenasa/metabolismo , Ratones , Ratones Endogámicos C57BL , Fenciclidina , Inhibición Prepulso , Ácido Quinolínico/metabolismo , ARN MensajeroRESUMEN
BACKGROUND: Urine toxicology screens are useful in diagnosing patients who present with acute psychosis with a history of substance abuse. Being aware of potential false positive reactants is paramount in diagnostic accuracy. Currently, lamotrigine is not listed among common cross-reactants with phencyclidine (PCP). CASE REPORT: A 49 year old male (98 kg) was brought to the ED by a family member for worsening confusion and agitation. He had a history of Bipolar I, PTSD, schizoaffective disorder, hypertension, and cannabis/opioid abuse. His home medications included paliperidone, duloxetine, lamotrigine, tizanidine, hydroxyzine, and lisinopril. Upon examination, he denied intentional overdose or illicit substances, but largely mumbled incoherently. Blood pressure was 140/90 mmHg, pulse 113. A urine toxicology screen was positive for PCP and cannabinoids. Other labs were unremarkable, co-ingestants negative. By day three, his mental status vacillated but he largely gave unintelligible responses. Given the short half-life of PCP, false positives were investigated. A confirmatory blood test (collected upon admission) for PCP was found to be negative, and a serum lamotrigine level was confirmed to be positive (1.5µg/ml). Once more lucid, the patient admitted to taking large quantities of mirtazapine and tizanidine, making serotonin syndrome the more likely diagnosis. DISCUSSION: There is little in the medical literature describing cross-reactivity of lamotrigine and PCP on urine drug screens. This can be especially difficult to deduce in a known drug abuser who presents psychotic and non-contributory in their work up.
Asunto(s)
Cannabinoides , Fenciclidina , Humanos , Masculino , Persona de Mediana Edad , Lamotrigina , Mirtazapina , Clorhidrato de Duloxetina , Palmitato de Paliperidona , Lisinopril , HidroxizinaRESUMEN
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.
Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 1/farmacología , Acatisia Inducida por Medicamentos/prevención & control , Anfetamina/farmacología , Conducta Animal/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/farmacología , Antagonistas de Dopamina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Fenciclidina/farmacología , Psicosis Inducidas por Sustancias/prevención & control , Antagonistas de la Serotonina/farmacología , Antagonistas de Receptores Adrenérgicos alfa 1/administración & dosificación , Acatisia Inducida por Medicamentos/etiología , Anfetamina/administración & dosificación , Animales , Estimulantes del Sistema Nervioso Central/administración & dosificación , Modelos Animales de Enfermedad , Antagonistas de Dopamina/administración & dosificación , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Masculino , Fenciclidina/administración & dosificación , Psicosis Inducidas por Sustancias/etiología , Ratas , Ratas Sprague-Dawley , Antagonistas de la Serotonina/administración & dosificaciónRESUMEN
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.
Asunto(s)
Ketamina , Ketamina/farmacología , Fenciclidina , Receptores de N-Metil-D-Aspartato , Asia , Europa (Continente)RESUMEN
Mental illness modeling is still a major challenge for scientists. Animal models of schizophrenia are essential to gain a better understanding of the disease etiopathology and mechanism of action of currently used antipsychotic drugs and help in the search for new and more effective therapies. We can distinguish among pharmacological, genetic, and neurodevelopmental models offering various neuroanatomical disorders and a different spectrum of symptoms of schizophrenia. Modeling schizophrenia is based on inducing damage or changes in the activity of relevant regions in the rodent brain (mainly the prefrontal cortex and hippocampus). Such artificially induced dysfunctions approximately correspond to the lesions found in patients with schizophrenia. However, notably, animal models of mental illness have numerous limitations and never fully reflect the disease state observed in humans.
Asunto(s)
Antipsicóticos , Esquizofrenia , Animales , Antipsicóticos/efectos adversos , Conducta Animal , Modelos Animales de Enfermedad , Hipocampo , Humanos , Corteza Prefrontal , Esquizofrenia/tratamiento farmacológicoRESUMEN
Schizophrenia is probably ascribed to perinatal neurodevelopmental deficits, and its onset might be affected by environmental factors. Hypofrontality with glutamatergic and dopaminergic neuronal dysfunction are known factors, but a way to mitigate abnormalities remains unfound. An early enriched environment such as a wheel running in rodents may contribute to the prevention, but its clinical applicability is very limited. From our studies, low-intensity exercise training (LET) based on physiological indices, such as lactate threshold, easily translates to humans and positively affects the brains. Hence, LET during adolescence may ameliorate abnormalities in neurodevelopment and prevent the development of schizophrenia. In the current study, LET prevented sensitization to phencyclidine (PCP) treatment, impairment of cognition, and affective behavioral abnormalities in an animal model of schizophrenia induced by prenatal PCP treatment. Further, LET increased dopamine turnover and attenuated the impairment of phosphorylation of ERK1/2 after exposure to a novel object in the prenatal PCP-treated mice. These results suggest that LET during adolescence completely improves schizophrenia-like abnormal behaviors associated with improved glutamate uptake and the dopamine-induced ERK1/2 signaling pathway in the PFC.
Asunto(s)
Condicionamiento Físico Animal/métodos , Esquizofrenia/prevención & control , Ácido 3,4-Dihidroxifenilacético/metabolismo , Factores de Edad , Animales , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Dopamina/metabolismo , Antagonistas de Aminoácidos Excitadores/toxicidad , Femenino , Ácido Homovanílico/metabolismo , Sistema de Señalización de MAP Quinasas , Masculino , Ratones , Ratones Endogámicos ICR , Fenciclidina/toxicidad , Fosforilación , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Efectos Tardíos de la Exposición Prenatal/psicología , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/inducido químicamente , Esquizofrenia/fisiopatología , Psicología del EsquizofrénicoRESUMEN
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.
Asunto(s)
Antidepresivos/farmacología , Conducta Animal/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/farmacología , Ketamina/farmacología , Pruebas Neuropsicológicas/normas , Recompensa , Investigación Biomédica Traslacional/normas , Anhedonia/efectos de los fármacos , Animales , Antidepresivos/administración & dosificación , Callithrix , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Ketamina/administración & dosificación , Masculino , Fenciclidina/farmacología , Aprendizaje por ProbabilidadRESUMEN
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 Me4 CB[8] toward ten drugs of abuse (3-9, 12-14) by a combination of 1 Hâ NMR spectroscopy and isothermal titration calorimetry in phosphate buffered water. We find that the cavity of CB[8] and Me4 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 Kd values ≤50â 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 Me4 CB[8] indicated good tolerability. The tightest hostâ guest pair (Me4 CB[8]â PCP; Kd =2â nm) was advanced to in vivo efficacy studies. The results of open field tests demonstrate that pretreatment of mice with Me4 CB[8] prevents subsequent hyperlocomotion induction by PCP and also that treatment of animals previously dosed with PCP with Me4 CB[8] significantly reduces the locomotion levels.
Asunto(s)
Hidrocarburos Aromáticos con Puentes/química , Imidazoles/química , Fenciclidina/análisis , Fenciclidina/química , Animales , Hidrocarburos Aromáticos con Puentes/administración & dosificación , Hidrocarburos Aromáticos con Puentes/farmacología , Células HEK293 , Células Hep G2 , Humanos , Imidazoles/administración & dosificación , Imidazoles/farmacología , Locomoción/efectos de los fármacos , Ratones , Fenciclidina/administración & dosificación , Fenciclidina/farmacologíaRESUMEN
Methods to assess neuronal receptor functions are needed in toxicology and for drug development. Human-based test systems that allow studies on glutamate signalling are still scarce. To address this issue, we developed and characterized pluripotent stem cell (PSC)-based neural cultures capable of forming a functional network. Starting from a stably proliferating neuroepithelial stem cell (NESC) population, we generate "mixed cortical cultures" (MCC) within 24 days. Characterization by immunocytochemistry, gene expression profiling and functional tests (multi-electrode arrays) showed that MCC contain various functional neurotransmitter receptors, and in particular, the N-methyl-D-aspartate subtype of ionotropic glutamate receptors (NMDA-R). As this important receptor is found neither on conventional neural cell lines nor on most stem cell-derived neurons, we focused here on the characterization of rapid glutamate-triggered Ca2+ signalling. Changes of the intracellular free calcium ion concentration ([Ca2+]i) were measured by fluorescent imaging as the main endpoint, and a method to evaluate and quantify signals in hundreds of cells at the same time was developed. We observed responses to glutamate in the low µM range. MCC responded to kainate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and a subpopulation of 50% had functional NMDA-R. The receptor was modulated by Mg2+, Zn2+ and Pb2+ in the expected ways, and various toxicologically relevant agonists (quinolinic acid, ibotenic acid, domoic acid) triggered [Ca2+]i responses in MCC. Antagonists, such as phencyclidine, ketamine and dextromethorphan, were also readily identified. Thus, the MCC developed here may fill an important gap in the panel of test systems available to characterize the effects of chemicals on neurotransmitter receptors.
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N-Metilaspartato/metabolismo , Receptores de Glutamato/metabolismo , Animales , Calcio , Células Cultivadas , Agonistas de Aminoácidos Excitadores , Ácido Glutámico , Humanos , Ácido Kaínico/análogos & derivados , Células-Madre Neurales , Neuronas , Receptores AMPA , Receptores de N-Metil-D-Aspartato , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol PropiónicoRESUMEN
Schizophrenia is a complex psychopathology whose treatment is still challenging. Given the limitations of existing antipsychotics, there is urgent need for novel drugs with fewer side effects. SEP-363856 (SEP-856) is a novel psychotropic agent currently under phase III clinical investigation for schizophrenia treatment. In this study, we investigated the ability of an acute oral SEP-856 administration to modulate the functional activity of specific brain regions at basal levels and under glutamatergic or dopaminergic-perturbed conditions in adult rats. We found that immediate-early genes (IEGs) expression was strongly upregulated in the prefrontal cortex and, to a less extent, in the ventral hippocampus, suggesting an activation of these regions. Furthermore, SEP-856 was effective in preventing the hyperactivity induced by an acute injection of phencyclidine (PCP), but not of d-amphetamine (AMPH). The compound effectively normalized the PCP-induced increase in IEGs expression in the PFC at all doses tested, whereas only the highest dose determined the major modulations on AMPH-induced changes. Lastly, SEP-856 acute administration corrected the cognitive deficits produced by subchronic PCP administration. Taken together, our data provide further insights on SEP-856, suggesting that modulation of the PFC may represent an important mechanism for the functional and behavioural activity of this novel compound.
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Antipsicóticos/farmacología , Cognición , Genes Inmediatos-Precoces , Piranos/farmacología , Esquizofrenia/tratamiento farmacológico , Administración Oral , Animales , Antipsicóticos/administración & dosificación , Antipsicóticos/uso terapéutico , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Piranos/administración & dosificación , Piranos/uso terapéutico , Ratas , Ratas Sprague-DawleyRESUMEN
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.
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Abuso de Fenciclidina/metabolismo , Fenciclidina/análogos & derivados , Fenciclidina/farmacología , Animales , Conducta Adictiva/fisiopatología , Dopamina/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Núcleo Accumbens/metabolismo , Fenciclidina/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Desempeño Psicomotor/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D1/metabolismo , Refuerzo en Psicología , Recompensa , AutoadministraciónRESUMEN
Schizophrenia is a mental disorder characterized by positive symptoms, negative symptoms, and cognitive dysfunction. Phencyclidine (PCP)-a N-methyl-D-aspartate (NMDA) receptor antagonist-induces symptoms indistinguishable from those of schizophrenia. A reduction of the phosphoprotein synapsin II has also been implicated in schizophrenia and has a well-known role in the maintenance of the presynaptic reserve pool and vesicle mobilization. This study assessed the behavioral and biochemical outcomes of chronic NMDA receptor antagonism in rodents and its implications for the pathophysiology of schizophrenia. Sprague Dawley rats received saline or chronic PCP (5 mg/kg/day) for 14 days via surgically implanted Alzet® osmotic mini-pumps. Following the treatment period, rats were tested with a series of behavioral paradigms, including locomotor activity, social interaction, and sensorimotor gating. Following behavioral assessment, the medial prefrontal cortex (mPFC) of all rats was isolated for synapsin II protein analysis. Chronic PCP treatment yielded a hyper-locomotive state (p = 0.0256), reduced social interaction (p = 0.0005), and reduced pre-pulse inhibition (p < 0.0001) in comparison to saline-treated controls. Synapsin IIa (p < 0.0001) and IIb (p < 0.0071) levels in the mPFC of chronically treated PCP rats were reduced in comparison to the saline group. Study results confirm that rats subject to chronic PCP treatment display behavioral phenotypes similar to established preclinical animal models of schizophrenia. Reduction of synapsin II expression in this context implicates the role of this protein in the pathophysiology of schizophrenia and sheds light on the longer-term consequences of NMDA receptor antagonism facilitated by chronic PCP treatment.
Asunto(s)
Antagonistas de Aminoácidos Excitadores/toxicidad , Alucinógenos/toxicidad , Fenciclidina/toxicidad , Esquizofrenia/metabolismo , Sinapsinas/metabolismo , Animales , Modelos Animales de Enfermedad , Locomoción , Masculino , Corteza Prefrontal/metabolismo , Ratas , Ratas Sprague-Dawley , Esquizofrenia/etiología , Esquizofrenia/fisiopatología , Conducta Social , Sinapsinas/genéticaRESUMEN
Diminished glutamate neurotransmission via the N-methyl-D-aspartate type glutamate receptor (NMDAR) has been considered to be involved in the pathophysiology of schizophrenia based upon the observation that the antagonists and autoantibodies of NMDAR cause positive, negative and cognitive symptomatologies similar to those of schizophrenia. The possible reduced extracellular levels of D-serine by overstimulation of the calcium-permeable α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate glutamate receptor (CP-AMPAR) following the NMDAR hypofunction-induced compensatory increase in the glutamate release could aggravate the NMDAR hypofunction in the brain of the drug- or antibody-associated psychoses and schizophrenia, because D-serine is an intrinsic coagonist for the NMDAR. To obtain an insight into the therapeutic approach to such a glutamate-linked psychotic state, we have studied the effects of the systemic administration of the CP-AMPAR-selective antagonist, IEM 1460 (N,N,N-trimethyl-5- [(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]-1-pentanaminium bromide hydrobromide), on the hyperactivity following an injection of a schizophrenomimetic NMDAR antagonist, phencyclidine, in the mouse. The subcutaneous IEM 1460 application produced a dose-dependent inhibition of the increased movement counts after the subcutaneous injection of phencyclidine. This inhibiting influence was also seen on the hyperactivity elicited by another NMDAR antagonist, dizocilpine. Moreover, the IEM 1460 administration attenuated the ability of a schizophrenomimetic dopamine agonist, methamphetamine, to increase spontaneous movements. These findings indicate that dysregulation of the CP-AMPAR could, at least in part, be implicated in the glutamate pathology of schizophrenia and/or related psychotic symptoms and be a potential target for the development of their novel treatment.
Asunto(s)
Adamantano/análogos & derivados , Conducta Animal/efectos de los fármacos , Hipercinesia/metabolismo , Receptores AMPA/antagonistas & inhibidores , Esquizofrenia , Adamantano/farmacología , Animales , Antagonistas de Aminoácidos Excitadores/toxicidad , Hipercinesia/inducido químicamente , Masculino , Ratones , Ratones Endogámicos C57BL , Fenciclidina/toxicidadRESUMEN
The serendipitous discovery of phencyclidine (PCP) in 1956 sets the stage for significant research efforts that resulted in a plethora of analogs and derivatives designed to explore the biological effects of this class. PCP soon became the prototypical dissociative agent that eventually sneaked through the doors of clinical laboratories and became an established street drug. Estimations suggest that around 14 PCP analogs were identified as "street drugs" in the period between the 1960s and 1990s. Fast forward to the 2000s, and largely facilitated by advancements in electronic forms of communication made possible through the Internet, a variety of new PCP analogs began to attract the attention of communities interested in the collaborative exploration of these substances. Traditionally, as was the case with the first-generation analogs identified in previous decades, the substances explored represented compounds already known in the scientific literature. As the decade of the noughties unfolded, a number of new PCP-derived substances appeared on the scene, which included some analogs that have not been previously recorded in the published literature. The aim of this chapter is to present a brief introductory overview of substances that have materialized as PCP-derived new psychoactive substances (NPS) in recent years and their known pharmacology. Since N-methyl-D-aspartate receptor (NMDAR) antagonism is implicated in mediating the subjective and mind-altering effects of many dissociative drugs, additional data are included from other analogs not presently identified as NPS.
Asunto(s)
Drogas Ilícitas/farmacología , Fenciclidina/farmacología , Psicotrópicos/farmacología , Humanos , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidoresRESUMEN
Symptoms of schizophrenia have been linked to insults during neurodevelopment such as NMDA receptor (NMDAR) antagonist exposure. In animal models, this leads to schizophrenia-like behavioral symptoms as well as molecular and functional changes within hippocampal and prefrontal regions. The aim of this study was to determine how administration of the NMDAR antagonist phencyclidine (PCP) during neurodevelopment affects functional network activity within the hippocampus and medial prefrontal cortex (mPFC). We recorded field potentials in vivo after electrical brain stem stimulation and observed a suppression of evoked theta power in ventral hippocampus, while evoked gamma power in mPFC was enhanced in rats administered with PCP neonatally. In addition, increased gamma synchrony elicited by acute administration of the NMDAR antagonist MK-801 was exaggerated in neonatal PCP animals. These data suggest that NMDAR antagonist exposure during brain development alters functional networks within hippocampus and mPFC possibly contributing to the reported behavioral symptoms of this animal model of schizophrenia.NEW & NOTEWORTHY We show that insults with a NMDA receptor antagonist during neurodevelopment lead to suppressed evoked theta oscillations in ventral hippocampus in adult rats, while evoked gamma oscillations are enhanced and hypersensitive to an acute challenge with a NMDA receptor antagonist in prefrontal cortex. These observations reveal the significance of neurodevelopmental disturbances in the evolvement of schizophrenia-like symptoms and contribute to the understanding of the functional deficits underlying aberrant behavior in this disease.