RESUMO
BACKGROUND: The abuse of the Phencyclidine-type substances, especially ketamine is a serious problem worldwide, and retrospective analysis are important for both the analysis and the identification of forms of drug abuse. The current major analytical methods, while all excellent in terms of accuracy, are time- and reagent-consuming. This depletion is made even more unfortunate by the fact that a large number of samples are negative in retrospective analyses. It is clear that a set of methods that can be analyzed both accurately and quickly need to be developed and applied to the screening and analysis of large quantities of samples. RESULTS: We described a urine test based on acoustic ejection mass spectrometry, which allows precise injection at very low volumes and near 1 ejection s-1 and data acquisition. The confidence in identification was increased by the characterization of the abundance ratio of the two pairs of ions. Urine samples could be diluted with water and loaded into a 384-well plate for sampling without complicated sample preparation. The sample in the transparent 384-well plate was pre-scanned by the laser, and then 20 nL droplets were ejected into the ion source for targeted analysis of 2 ion transitions per droplet totaling 9 targeted analytes in the sequence of acquisition methods. It took 90 min to screen 250 samples in this approach, yielding 10 ng mL-1 detection limits. Positive samples were further analyzed by UHPLC-MS/MS for confirmation and quantification of up to 36 analytes. SIGNIFICANCE: This was the first fast screening method for phencyclidine-type substances based on acoustic ejection mass spectrometry, which greatly reduces the analytical time, and can accomplish in 1.5 h what UHPLC-MS/MS needs 3 days to complete. And the samples can be analyzed without complicated sample preparation, and also can obtain good detectability. It was applied to a short-term retrospective analysis in Shanghai, and its accuracy was also extremely high.
Assuntos
Ensaios de Triagem em Larga Escala , Fenciclidina , Espectrometria de Massas em Tandem , Espectrometria de Massas em Tandem/métodos , Fenciclidina/urina , Humanos , Detecção do Abuso de Substâncias/métodos , AcústicaRESUMO
BACKGROUND: Phencyclidine, an NMDA receptor antagonist, is frequently used to model behavioral and neurochemical changes correlated with schizophrenia in laboratory animals. The present study aimed to examine the effects of repeated administration of phencyclidine during early postnatal development on the contents of glutathione and sulfur-containing amino acids, as well as the activity of antioxidant enzymes in the brain of 12-day-old rats, and schizophrenia-like symptoms in adulthood. METHODS: Male Sprague-Dawley pups were administered phencyclidine (10 mg/kg) or saline subcutaneously on the postnatal days p2, p6, p9 and p12. In 12-day-old pups, 4 h after the last dose of phencyclidine, the levels of glutathione, cysteine, methionine, and homocysteine, and the enzymatic activity of superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GR) were measured in the frontal cortex, hippocampus, and striatum. In 70-72-day-old rats, schizophrenia-like symptoms were assessed using behavioral tests. RESULTS: Biochemical data showed that perinatal phencyclidine treatment significantly reduced glutathione and cysteine levels in all brain structures studied, methionine was diminished in the striatum, and homocysteine in both the frontal cortex and striatum. GR activity was increased in the frontal cortex while SODactivity was decreased in the hippocampus. Behaviorally, perinatal phencyclidine induced long-term deficits in social and cognitive function and a decrease in locomotor activity assessed as the time of walking. Finally, perinatal treatment with phencyclidine resulted in a significant reduction in body weight gain over time. CONCLUSION: Our research provides further evidence for the usefulness of the phencyclidine-induced neurodevelopmental model of schizophrenia for studying the pathogenesis of schizophrenia.
Assuntos
Encéfalo , Glutationa , Fenciclidina , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato , Esquizofrenia , Animais , Fenciclidina/toxicidade , Fenciclidina/farmacologia , Esquizofrenia/metabolismo , Esquizofrenia/tratamento farmacológico , Esquizofrenia/induzido quimicamente , Glutationa/metabolismo , Masculino , Receptores de N-Metil-D-Aspartato/metabolismo , Ratos , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Aminoácidos Sulfúricos/metabolismo , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Animais Recém-NascidosRESUMO
Pharmacological approaches to induce N-methyl-d-aspartate receptor (NMDAR) hypofunction have been intensively used to understand the aetiology and pathophysiology of schizophrenia. Yet, the precise cellular and molecular mechanisms that relate to brain network dysfunction remain largely unknown. Here, we used a set of complementary approaches to assess the functional network abnormalities present in male mice that underwent a 7-day subchronic phencyclidine (PCP 10 mg/kg, subcutaneously, once daily) treatment. Our data revealed that pharmacological intervention with PCP affected cognitive performance and auditory evoked gamma oscillations in the prefrontal cortex (PFC) mimicking endophenotypes of some schizophrenia patients. We further assessed PFC cellular function and identified altered neuronal intrinsic membrane properties, reduced parvalbumin (PV) immunostaining and diminished inhibition onto L5 PFC pyramidal cells. A decrease in the strength of optogenetically-evoked glutamatergic current at the ventral hippocampus to PFC synapse was also demonstrated, along with a weaker shunt of excitatory transmission by local PFC interneurons. On a macrocircuit level, functional ultrasound measurements indicated compromised functional connectivity within several brain regions particularly involving PFC and frontostriatal circuits. Herein, we reproduced a panel of schizophrenia endophenotypes induced by subchronic PCP application in mice. We further recapitulated electrophysiological signatures associated with schizophrenia and provided an anatomical reference to critical elements in the brain circuitry. Together, our findings contribute to a better understanding of the physiological underpinnings of deficits induced by subchronic NMDAR antagonist regimes and provide a test system for characterization of pharmacological compounds.
Assuntos
Modelos Animais de Doenças , Fenciclidina , Córtex Pré-Frontal , Receptores de N-Metil-D-Aspartato , Animais , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Masculino , Fenciclidina/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo , Camundongos , Esquizofrenia/induzido quimicamente , Esquizofrenia/fisiopatologia , Esquizofrenia/metabolismo , Camundongos Endogâmicos C57BL , Parvalbuminas/metabolismo , Adaptação Fisiológica/efeitos dos fármacos , Adaptação Fisiológica/fisiologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/fisiologia , Ritmo Gama/efeitos dos fármacos , Ritmo Gama/fisiologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Antagonistas de Aminoácidos Excitatórios/farmacologiaRESUMO
AIMS: We aimed to evaluate the potential of a novel selective α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) potentiator, LT-102, in treating cognitive impairments associated with schizophrenia (CIAS) and elucidating its mechanism of action. METHODS: The activity of LT-102 was examined by Ca2+ influx assays and patch-clamp in rat primary hippocampal neurons. The structure of the complex was determined by X-ray crystallography. The selectivity of LT-102 was evaluated by hERG tail current recording and kinase-inhibition assays. The electrophysiological characterization of LT-102 was characterized by patch-clamp recording in mouse hippocampal slices. The expression and phosphorylation levels of proteins were examined by Western blotting. Cognitive function was assessed using the Morris water maze and novel object recognition tests. RESULTS: LT-102 is a novel and selective AMPAR potentiator with little agonistic effect, which binds to the allosteric site formed by the intradimer interface of AMPAR's GluA2 subunit. Treatment with LT-102 facilitated long-term potentiation in mouse hippocampal slices and reversed cognitive deficits in a phencyclidine-induced mouse model. Additionally, LT-102 treatment increased the protein level of brain-derived neurotrophic factor and the phosphorylation of GluA1 in primary neurons and hippocampal tissues. CONCLUSION: We conclude that LT-102 ameliorates cognitive impairments in a phencyclidine-induced model of schizophrenia by enhancing synaptic function, which could make it a potential therapeutic candidate for CIAS.
Assuntos
Disfunção Cognitiva , Propionatos , Esquizofrenia , Animais , Camundongos , Ratos , Fenciclidina , Esquizofrenia/complicações , Esquizofrenia/tratamento farmacológico , Disfunção Cognitiva/tratamento farmacológico , IsoxazóisRESUMO
Hypofunctioning of NMDA receptors, and the resulting shift in the balance between excitation and inhibition, is considered a key process in the pathophysiology of schizophrenia. One important manifestation of this phenomenon is changes in neural oscillations, those above 30 Hz (i.e., gamma-band oscillations), in particular. Although both preclinical and clinical studies observed increased gamma activity following acute administration of NMDA receptor antagonists, the relevance of this phenomenon has been recently questioned given the reduced gamma oscillations typically observed during sensory and cognitive tasks in schizophrenia. However, there is emerging, yet contradictory, evidence for increased spontaneous gamma-band activity (i.e., at rest or under baseline conditions). Here, we use the sub-chronic phencyclidine (PCP) rat model for schizophrenia, which has been argued to model the pathophysiology of schizophrenia more closely than acute NMDA antagonism, to investigate gamma oscillations (30-100 Hz) in the medial prefrontal cortex of anesthetized animals. While baseline gamma oscillations were not affected, oscillations induced by train stimulation of the posterior dorsal CA1 (pdCA1) field of the hippocampus were enhanced in PCP-treated animals (5 mg/kg, twice daily for 7 days, followed by a 7-day washout period). This effect was reversed by pharmacological enhancement of endocannabinoid levels via systemic administration of URB597 (0.3 mg/kg), an inhibitor of the catabolic enzyme of the endocannabinoid anandamide. Intriguingly, the pharmacological blockade of CB1 receptors by AM251 unmasked a reduced gamma oscillatory activity in PCP-treated animals. The findings are consistent with the observed effects of URB597 and AM251 on behavioral deficits reminiscent of the symptoms of schizophrenia and further validate the potential for cannabinoid-based drugs as a treatment for schizophrenia.
Assuntos
Amidoidrolases , Benzamidas , Carbamatos , Fenciclidina , Piperidinas , Esquizofrenia , Animais , Masculino , Ratos , Amidoidrolases/antagonistas & inibidores , Amidoidrolases/metabolismo , Ácidos Araquidônicos/metabolismo , Ácidos Araquidônicos/farmacologia , Benzamidas/farmacologia , Carbamatos/farmacologia , Modelos Animais de Doenças , Endocanabinoides/metabolismo , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Ritmo Gama/fisiologia , Ritmo Gama/efeitos dos fármacos , Fenciclidina/farmacologia , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/metabolismo , Alcamidas Poli-Insaturadas/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiopatologia , Pirazóis/farmacologia , Ratos Sprague-Dawley , Esquizofrenia/fisiopatologia , Esquizofrenia/metabolismo , Esquizofrenia/tratamento farmacológicoRESUMO
The pathogenesis of schizophrenia begins in early neurodevelopment and leads to excitatory-inhibitory imbalance. It is therefore essential that preclinical models used to understand disease, select drug targets and evaluate novel therapeutics encompass similar neurochemical deficits. One approach to improved preclinical modelling incorporates dual-hit neurodevelopmental insults, like neonatal administration of phencyclidine (PCP, to disrupt development of glutamatergic circuitry) then post-weaning isolation (Iso, to mimic adolescent social stress). We recently showed that male Lister-hooded rats exposed to PCP-Iso exhibit reduced hippocampal expression of the GABA interneuron marker calbindin. The current study expanded on this by investigating changes to additional populations of GABAergic interneurons in frontal cortical and hippocampal tissue from the same animals (by immunohistochemistry) as well as levels of GABA itself (via ELISA). Because inflammatory changes are also implicated in schizophrenia, we performed additional immunohistochemical evaluations of Iba-1 positive microglia as well as ELISA analysis of IL-6 in the same brain regions. Single-hit isolation-reared and dual-hit PCP-Iso rats both showed reduced parvalbumin immunoreactivity in the prelimbic/infralimbic region of the frontal cortex. However, this was more widespread in PCP-Iso, extending to the medial/ventral and lateral/dorsolateral orbitofrontal cortices. Loss of GABAergic markers was accompanied by increased microglial activation in the medial/ventral orbitofrontal cortices of PCP-Iso, together with frontal cortical IL-6 elevations not seen following single-hit isolation rearing. These findings enhance the face validity of PCP-Iso, and we advocate the use of this preclinical model for future evaluation of novel therapeutics-especially those designed to normalise excitatory-inhibitory imbalance or reduce neuroinflammation.
Assuntos
Animais Recém-Nascidos , Modelos Animais de Doenças , Lobo Frontal , Fenciclidina , Esquizofrenia , Isolamento Social , Ácido gama-Aminobutírico , Animais , Esquizofrenia/metabolismo , Esquizofrenia/patologia , Esquizofrenia/induzido quimicamente , Masculino , Lobo Frontal/metabolismo , Lobo Frontal/patologia , Lobo Frontal/efeitos dos fármacos , Ratos , Fenciclidina/toxicidade , Ácido gama-Aminobutírico/metabolismo , Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/patologia , Parvalbuminas/metabolismo , Microglia/metabolismo , Microglia/patologia , Microglia/efeitos dos fármacos , Inflamação/patologia , Inflamação/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Interleucina-6/metabolismo , Interneurônios/metabolismo , Interneurônios/patologia , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas dos MicrofilamentosRESUMO
KPNA1 is a mediator of nucleocytoplasmic transport that is abundantly expressed in the mammalian brain and regulates neuronal differentiation and synaptic function. De novo mutations in Kpna1 have been identified using genome-wide association studies in humans with schizophrenia; however, it remains unclear how KPNA1 contributes to schizophrenia pathogenesis. Recent studies have suggested a complex combination of genetic and environmental factors that are closely related to psychiatric disorders. Here, we found that subchronic administration of phencyclidine, a psychotropic drug, induced vulnerability and behavioral abnormalities consistent with the symptoms of schizophrenia in Kpna1-deficient mice. Microarray assessment revealed that the expression levels of dopamine d1/d2 receptors, an RNA editing enzyme, and a cytoplasmic dynein component were significantly altered in the nucleus accumbens brain region in a gene-environment (G × E) interaction-dependent manner. Our findings demonstrate that Kpna1-deficient mice may be useful as a G × E interaction mouse model for psychiatric disorders and for further investigation into the pathogenesis of such diseases and disorders.
Assuntos
Esquizofrenia , Humanos , Camundongos , Animais , Esquizofrenia/induzido quimicamente , Esquizofrenia/genética , Interação Gene-Ambiente , Estudo de Associação Genômica Ampla , Psicotrópicos/farmacologia , Fenciclidina/farmacologia , Núcleo Accumbens/metabolismo , Mamíferos/metabolismo , alfa Carioferinas/genética , alfa Carioferinas/metabolismoRESUMO
A safe and productive workplace requires a sober workforce, free from substances that impair judgment and concentration. Although drug monitoring programs already exist, the scope and loopholes of standard workplace testing panels are well known, allowing other substances to remain a source of risk. Therefore, a high-throughput urine screening method for psilocin, mitragynine, phencyclidine, ketamine, norketamine and dehydronorketamine was developed and validated in conjunction with a urine and blood confirmation method. There are analytical challenges to overcome with psilocin and mitragynine, particularly when it comes to drug stability and unambiguous identification in authentic specimens. Screening and confirmation methods were validated according to the American National Standards Institute/Academy Standards Board (ANSI/ASB) Standard 036, Standard Practices for Method Validation in Forensic Toxicology. An automated liquid handling system equipped with dispersive pipette extraction tips was utilized for preparing screening samples, whereas an offline solid-phase extraction method was used for confirmation sample preparation. Both methods utilized liquid chromatography-tandem mass spectrometry to achieve limits of detection between 1-5 ng/mL for the screening method and 1 ng/mL for the confirmation method. Automation allows for faster throughput and enhanced quality assurance, which improves turnaround time. Compared to previous in-house methods, specimen volumes were substantially decreased for both blood and urine, which is an advantage when volume is limited. This screening technique is well suited for evaluating large numbers of specimens from those employed in safety-sensitive workforce positions. This method can be utilized by workplace drug testing, human performance and postmortem laboratories seeking robust qualitative screening and confirmation methods for analytes that have traditionally been challenging to routinely analyze.
Assuntos
Ketamina , Psilocibina/análogos & derivados , Alcaloides de Triptamina e Secologanina , Humanos , Fenciclidina , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida/métodosRESUMO
Abuse of novel arylcyclohexylamines (ACX) poses risks for toxicities, including adverse neurocognitive effects. In vivo effects of ring-substituted analogs of phencyclidine (PCP), eticyclidine (PCE), and ketamine are understudied. Adult male National Institutes of Health Swiss mice were used to assess locomotor effects of PCP and its 3-OH, 3-MeO, 3-Cl, and 4-MeO analogs, PCE and its 3-OH and 3-MeO analogs, and ketamine and its deschloro and 2F-deschloro analogs, in comparison with those of methamphetamine (METH), 3,4-methylenedioxymethamphetamine (MDMA), and two benzofuran analogs of MDMA. PCP-like interoceptive effects for all of these ACXs were determined using a food-reinforced drug discrimination procedure in adult male Sprague Dawley rats. A novel operant assay of rule-governed behavior incorporating aspects of attentional set-shifting was used to profile psychosis-like neurocognitive effects of PCP and 3-Cl-PCP in rats, in comparison with cocaine and morphine. PCP-like ACXs were more effective locomotor stimulants than the amphetamines, PCE-like ACXs were as effective as the amphetamines, and ketamine-like ACXs were less effective than the amphetamines. Addition of -Cl, -OH, or -OMe at the 3-position on the aromatic ring did not impact locomotor effectiveness, but addition of -OMe at the 4-position reduced locomotor effectiveness. Lethal effects were induced by drugs with -OH at the 3-position or -OMe at the 3- or 4-position. All novel ACXs substituted at least partially for PCP, and PCP and 3-Cl-PCP elicited dose-dependent psychosis-like neurocognitive deficits in the rule-governed behavior task not observed with cocaine or morphine. Novel ACXs exhibit substantial abuse liability and toxicities not necessarily observed with their parent drugs. SIGNIFICANCE STATEMENT: Novel arylcyclohexylamine analogs of PCP, PCE, and ketamine are appearing on the illicit market, and abuse of these drugs poses risks for toxicities, including adverse neurocognitive effects. These studies demonstrate that the novel ACXs exhibit PCP-like abuse liability in the drug discrimination assay, elicit varied locomotor stimulant and lethal effects in mice, and induce psychosis-like neurocognitive effects in rats.
Assuntos
Fenciclidina , Ratos Sprague-Dawley , Animais , Masculino , Camundongos , Fenciclidina/análogos & derivados , Fenciclidina/toxicidade , Ratos , Psicoses Induzidas por Substâncias/etiologia , Cicloexilaminas , Atividade Motora/efeitos dos fármacos , Cognição/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Drogas Ilícitas/efeitos adversos , Drogas Ilícitas/toxicidade , Ketamina/análogos & derivados , Ketamina/toxicidade , Transtornos Relacionados ao Uso de Substâncias/psicologia , Abuso de FenciclidinaRESUMO
Introducción: La ketamina es utilizada como anestésico general, de inducción y como analgésico. Objetivos: Evaluar los cambios en la presión arterial sistólica (PAS), diastólica (PAD) y frecuencia del pulso (FP) producidos por la ketamina, y la influencia de la succinilcolina. Diseño: Comparativo y de observación. Institución: Clínica Maison de Santé, Lima, Perú. Participantes: Pacientes que recibieron ketamina. Intervenciones: La ketamina fue empleada como anestésico general único y de inducción. Por cada modalidad, se consideró doce pacientes. Los doce primeros recibieron ketamina 2 mg/kg endovenosa, con medición de la PAS, PAD y FP antes y después de la anestesia. Los otros doce recibieron ketamina más succinilcolina, midiéndose los parámetros antes y después. Se comparó los cambios. Principales medidas de resultados: Variaciones en la PAS, PAD y FP. Resultados: En los primeros doce pacientes, la ketamina elevó la PAS 26 ± 3 mmHg, p < 0,001, la PAD 19 ± 3 mmHg, p < 0,001, y la FP 15 ± 3 por minuto, p < 0,001. En los otros doce, la ketamina más succinilcolina elevaron la PAS 28 ± 3 mmHg, p < 0,001, la PAD 18 ± 2 mmHg, p < 0,001 y la FP 13 ± 1 por minuto, p < 0,001. Comparándolos porcentualmente, la succinilcolina no afectó esos cambios. Conclusiones: El incremento de la presión arterial y pulso producidos por la ketamina no fueron afectados por la succinilcolina.
Introduction: Ketamine is used as a general anesthetic as well as for anesthesia induction and analgesia. Objectives: To assess modifications in systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) caused by ketamine, and if there is any influence of succinylcholine. Design: Comparative and observational study. Setting: Maison de Santé Clinic, Lima, Peru. Participants: Patients receiving ketamine. Interventions: Ketamine was used as a single drug for general anesthesia and for induction. Twelve patients were considered for each modality. The twelve first patients received ketamine, 2 mg/kg IV, and SBP, DBP and HR were measured before and after administering the drug. The second group received ketamine plus succinylcholine, and same parameters were measured. Main outcome measures: SBP, DBP, and HR variations. Results: Following ketamine injection in the first twelve patients there were elevations in SBP 26 ± 3 mmHg, p < 0,001, DBP 19 ± 3 mmHg, p < 0,001, and HR 15 ± 3 per minute, p < 0,001. In the second group after ketamine plus succinylcholine administration there were increases in SBP 28 ± 3 mmHg, p < 0,001, DBP 18 ± 2 mmHg, p < 0,001, and HR 13 ± 1 per minute, p < 0,001. There were no statistically significant differences when comparing both groups, i.e. succinlycholine did not have any influence in modifying the aforementioned parameters. Conclusions: Increases in blood pressure and heart rate induced by ketamine were not affected by succinylcholine.
Assuntos
Humanos , Masculino , Feminino , Adulto , Anestesia , Fenciclidina/análogos & derivados , Pressão Sanguínea , Pulso Arterial , Succinilcolina , Estudos Observacionais como AssuntoRESUMO
A pesar de los avances en el conocimiento de las bases biológicas de la conducta, los mecanismos neurobiológicos precisos involucrados en la esquizofrenia permanecen desconocidos. Como consecuencia de esto las terapias farmacológicas actuales descansan más sobre bases empíricas que sobre explicaciones fisiopatológicas. En el presente trabajo se propone un modelo de la esquizofrenia que podría ser de utilidad en el diseño de nuevas estrategias terapéuticas. Este modelo intenta integrar recientes hallazgos neuropsicológicos y de neuroimagen con lo que hoy sabemos respecto a la biología del desarrollo y plasticidad cerebral normal. Se propone que la esquizofrenia es una enfermedad del neurodesarrollo caracterizada por una neurotransmisión glutamatérgica inadecuadamente modulada a consecuencia de la disfunción de interneuronas GABAérgicas en múltiples regiones del cerebro. Anormalidades sutiles en el balance entre GABA y Glutamato explicarían los defectos en la cognición, la conducta social y la coordinación motora reportados en las etapas pre-psicóticas de la esquizofrenia. Más tarde en la historia natural de la enfermedad, estados hiperglutamatérgicos desencadenados por la incrementada neurotransmisión dopaminérgica propia de la peri-adolescencia y adultez temprana llevarían a la psicosis. Esta excesiva actividad glutamatérgica conduciría a su vez a las reducciones progresivas en sustancia gris y blanca observadas en recientes estudios prospectivos. En apoyo a esta hipótesis, se describen estudios propios y de otros laboratorios con pacientes esquizofrénicos, así como en un modelo animal de exposición intermitente a fenciclidina. Como corolario, drogas moduladoras de la neurotransmisión glutamatérgica, tales como acamprosato y lamotrigina, son propuestas como estrategias terapéuticas potencialmente utilizables en las etapas tempranas de la esquizofrenia.
Assuntos
Animais , Humanos , Esquizofrenia/genética , Esquizofrenia/metabolismo , Ácido Glutâmico/metabolismo , Ácido gama-Aminobutírico/metabolismo , Antipsicóticos/uso terapêutico , Modelos Animais de Doenças , Dopamina/metabolismo , Esquizofrenia/fisiopatologia , Esquizofrenia/tratamento farmacológico , Fenciclidina/farmacologia , Neurotransmissores , Psicoses Induzidas por Substâncias , Receptores de N-Metil-D-Aspartato/antagonistas & inibidoresRESUMO
La disponibilidad de agentes intravenosos sedativos, hipnóticos, opioides y relajantes musculares de corta duración de acción ha promovido el avance de técnicas de anestesia intravenosa total (TIVA). La TIVA provee una inducción suave, con mínima tos o hipo, con rápido control de la profundidad anestésica y rápida emergencia con poca resaca. Es la mejor opción para pacientes de cirugía laringotraqueal, endoscopía de vías aéreas, anestesia en lugares remotos, pacientes susceptibles de hipertermia maligna o injuria radiactiva o química. La ketamina, un derivado de la fenciclidina, es el único anestésico i.v. con propiedades hipnóticas, analgésicas y amnésicas. Produce una rápida hipnosis con profunda analgesia y amnesia luego de la administración intravenosa de 0,5 a 2 mg/kg o la administración i.m. de 4-6 mg/kg (gran constante keO y rápido equilibrio entre el compartimiento donde ejerce su acción y el plasma). Niveles plasmáticos de 0,2 a 2u/ml de plasma se asocian con anestesia general. Es metabolizada en el hígado a norketamina (30 por ciento de la actividad de la droga madre) y a hidroxinorketamina, y excretada por el riñón. Interactúa con el receptor N metil D aspartato produciendo un antagonismo no competitivo e inhibiendo la actividad del glutamato y del aspartato, bloqueando la producción de óxido nítrico e inhibiendo la liberación intracelular de GMPc. Por otro lado, interactúa con el receptor opioide sigma, produciendo reacciones disfóricas. Interactúa con receptores muscarínicos M, produciendo acciones sobre la memoria, la conciencia, amnesia, dando incremento del tono simpático, broncodilatación y midriasis. La ketamina aumenta la presión intracraneal y la presión intraocular, y está contraindicada en pacientes con aumento de la presión intracraneana (trauma cerebral, masa intracraneal o hemorragia) y en trauma ocular abierto. La ketamina produce estimulación cardiovascular, con aumento de la frecuencia cardíaca, de la presión arterial y del índice cardíaco por liberación de noradrenalina, pero tiene un efecto negativo sobre la contractilidad miocárdica. La ketamina deprime la respiración a dosis mayores de 2 mg/kg o con el uso concomitante de otros depresores...
Assuntos
Humanos , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/farmacologia , Analgésicos Opioides/uso terapêutico , Anestesia Intravenosa , Fenciclidina , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Período de Recuperação da Anestesia , Bombas de Infusão , Interações MedicamentosasRESUMO
Este experimento teve por objetivo avaliar a viabilidade do emprego da levomepromazina no bloqueio da atividade arritmogênica da adrenalina, em cäes anestesiados pela quetamina. Para tal, foram utilizados 30 cäes adultos, machos e fêmeas, considerados sadios, com pesos compreendidos entre 7 e 14kg. Estes foram divididos em 3 grupos de 10 animais (G1, G2 e G3). Aos cäes de G1 foi administrada, por via intravenosa, adrenalina em doses de 3, 6, 9, 12 e 15µg/kg, em intervalos de 10 minutos. Deste grupo, foram colhidos o tempo de duraçäo do efeito da catecolamina (TA), estabelecido pela contagem da freqüência cardíaca e o número total de batimentos cardíacos de origem ectópica, produzidos pela adrenalina (ESV). Aos animais do G2, foi administrada soluçäo salina a 0,9 porcento, na dose de 0,2ml/kg, por via intravenosa, seguida, 10 minutos após, da injeçäo, pela mesma via, de quetamina, na dose de 2mg/kg. Decorridos 5 minutos, iniciou-se a infusäo contínua de quetamina, por via intravenosa, na dose de 0,2mg/kg/min. Aguardou-se 5 minutos e iniciou-se a adminstraçäo de adrenalina e colheita das variáveis, conforme protocolado para o G1. Aos animais do G3, aplicou-se a mesma metodologia, substituindo-se o placebo pela levomepromazina, administrada por via intravenosa, na dose de 1mg/kg. A análise dos resultados mostrou que a levomepromazina reduz a duraçäo do efeito da catecolamina e minimiza o aparecimento de batimentos cardíacos de origem ectópica. Os achados permitiram concluir que a levomepromazina é útil no bloqueio da arritmia produzida pela adrenalina em cäes anestesiados pela quetamina.
Assuntos
Animais , Masculino , Feminino , Cães , Antipsicóticos/farmacologia , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/veterinária , Coração , Epinefrina/efeitos adversos , Inibidores Enzimáticos/farmacologia , Metotrimeprazina/farmacologia , Fenciclidina/farmacologia , Vasoconstritores/efeitos adversos , Anestesia/veterináriaRESUMO
La hipótesis glutamatérgica de la esquizofrenia, que está recién en sus inicios, plantea que existe una alteración de la neurotransmisión glutamatérgica en esta enfermedad. La hipótesis se basa en los efectos psicoticomiméticos de la fenciclidina (PCF) y en las evidencias de actividad glutamatérgica anormal en pacientes esquizofrénicos. En este artículo se discute la posibilidad de que una deficiencia en la actividad de vías glutamatérgicas corticoestriatales pueda tener un papel fisiopatológico importante en la esquizofrenia. Se analizan las estrategias terapéuticas que se derivan de la hipótesis, como el empleo de agonistas glutamatérgicos y otros fármacos que pueden corregir la anormalidad planteada
Assuntos
Humanos , Ácido Glutâmico/deficiência , Dopamina/farmacocinética , Esquizofrenia/fisiopatologia , Ácido Glutâmico/farmacocinética , Interações Medicamentosas/fisiologia , Haloperidol/farmacocinética , Fenciclidina/efeitos adversos , Psicoses Induzidas por Substâncias , Esquizofrenia/tratamento farmacológicoRESUMO
La fenciclidina (PCP) produce psicosis muy similares a la esquizofrenia. Mientras las psicosis inducidas por anfetamina presentan sólo síntomas positivos como delirio y alucinaciones, las psicosis inducidas por PCP presentan tanto síntomas positivos como negativos (aplanamiento afectivo, retardo psicomotor, empobrecimiento del discurso). De este modo las psicosis anfetamínicas se ajustan a un modelo schneideriano y las psicosis por PCP a un modelo bleuleriano de esquizofrenia. La PCP se une selectivamente a un sitio de unión específico, el receptor a aminoácidos excitatorios N-metil-D-aspaertato (NMDA). Estos hallazgos sugieren que una disfunción de la neurotransmisión mediada por el receptor NMDA puede contribuir a la etiopatogenia de la esquizofrenia
Assuntos
Humanos , Fenciclidina/farmacocinética , Esquizofrenia/induzido quimicamente , Anfetamina/efeitos adversos , Abuso de Fenciclidina/fisiopatologia , Fenciclidina/efeitos adversos , Psicoses Induzidas por Substâncias/fisiopatologia , Transtornos Psicóticos/fisiopatologiaRESUMO
En la patologia esquizofrénica, los modelos bioquímicos explicativos mas comunes son: El de la Dopamina y el de la Fenciclidina. El neurotransmisor Dopamina actúa sobre los diversos receptores específicos, y la Fenciclidina sobre los llamados receptores de aminoácidos excitatorios. Otra hipótesis, como la de la Glicina o la de las Poliaminas, también tienen que ver con la acción sobre receptores de aminoacidos excitatorios. Esta revisión estudia algunos eventos neuroquímicos y neuropatológicos relacionados con los modelos mencionados. Conclusion: La esquizofrenia no puede ser explicada por un modelo simple, y mas bien es el resultado de una compleja interacción de disfunciones en los sistemas de neurotransmisión.
Assuntos
Humanos , Neurotransmissores/metabolismo , Esquizofrenia/metabolismo , Dopamina/metabolismo , Aminoácidos Excitatórios , Glicina/metabolismo , N-Metilaspartato , Fenciclidina/metabolismo , Poliaminas/metabolismo , Receptores DopaminérgicosRESUMO
En el daño neuronal isquémico, uno de los mecanismos finales de la lesión celular es la entrada abrupta de calcio al interior de la célula mediada por canales depredientes de voltaje o por activación de receptores NMDA (N-metil D-aspartato), que origina destrucción de las membranas y el citoesqueleto. Se probó la utilidad terapeútica de un bloqueador no competitivo del receptor NMDA (MK-801, 2mg/kg intraperitoneal), para reducir la extensión del daño neuronal en un modelo de oclusión de la arteria cerebral media en rata. El MK-801 se administró 10 minutos antes (grupo 3) y una hora después de la oclusión (grupo 4), y los resultados se compararon con un grupo de oclusión sin medicamento (grupo 2) y un grupo control (grupo 1). Se encontró que la administración de MK-801 redujo significativamente el área de infarto en relación al grupo de oclusión sin medicamento (p < 0.05), con mayor efectividad cuando se administró de forma profiláctica (10 minutos antes de la oclusión) (grupo 3). Estos resultados sugieren que el MK-801 puede ser efectivo en la prevención de daño neurológico post-isquémico. Sin embargo, antes de recomendar su aplicación clínica, deberán definirse sus posibles efectos colaterales
Assuntos
Animais , Ratos , Artéria Carótida Externa/cirurgia , Encefalopatias/mortalidade , Transtornos Cerebrovasculares/complicações , Maleato de Dizocilpina/análogos & derivados , Glutamatos/antagonistas & inibidores , Hipercapnia/diagnóstico , Ataque Isquêmico Transitório/induzido quimicamente , Ketamina/antagonistas & inibidores , N-Metilaspartato/antagonistas & inibidores , Fenciclidina/antagonistas & inibidoresRESUMO
En este estudio se utilizó una mezcla de dos fármacos para inmovilizar carnívoros silvestres en condiciones de campo: el clohidrato de xilacina (XHC1), un analgésico, sedante y relajante muscular, ye el clorhidrato de Ketamina (KHC1), útil para inducir anestesia disociativa. Se aplicaron por vía intramuscular a cuatro lobos mexicanos (canis lupus baileyi), doce coyotes (Canis latrans), dos zorras grises (Urocyon cinereoargenteus), tres zorrillos (Mephitis macroura) y dos mapaches (Procyon lotor). Los datos obtenidos de los animales capturados se agruparon en tres categorías, debido a las comparaciones que se realizaron, de tal manera que a los carnívoros pequeños cuyo peso varió de 1 Kg a 6.6 Kg, se les administró una dosis promedio de 36.1 mg/kg p.c. de KHC1 y 6.5 mg/kg p.c. de XHC1.Los coyotes pesaron de 7.5 a 16 kg, se les aplicó una dosis promedio de 4.7 mg/kg p.c. de KHC1 y 1.6 mg/kg p.c. de XHC1. Por último, los lobos, que pesaron de 23 Kg a 28 Kg, recibieron dosis promedio de 4.2 mg/kg p.c. de KHC1 y 2.3 mg/kg p.c. de XHC1. Las dosis utilizadas variaron por individuo en función de su talla y mantuvieron inmovilizados a los animales el tiempo suficiente para obtener datos de sus medidad corporales, peso, marcaje y la colocación de un collar radiotransmisor. No se presentaron vómitos, sangrados, arritmia cardiaca, pero respiratorio o muerte en ninguno de los casos tratados con esta mezcla, dando como resultado un método accesible y, sobre todo,seguro para el animal, así como para el capturador. Se discute el efecto inmediato de los fármacos en función el tiempo de manejo obtenido con las dosis aplicadas, al hacer correlaciones entre estas variables. Se recomienda el uso de la mezcla a los profesionistas relacionados con el manejo de fauna silvestre.
Assuntos
Animais , Fenciclidina/administração & dosagem , Fenciclidina/análogos & derivados , Xilazina/administração & dosagem , Injeções Intramusculares , Animais Selvagens , Carnívoros , Hipnóticos e Sedativos/administração & dosagem , ImobilizaçãoRESUMO
Se realizaron ensayos preliminares de la decocción de Justicia pectoralis en ratones de la cepa C-57, donde se evaluaron los posible efectos de dichas decocciones sobre la conducta exploratoria, la conducta agresiva y las convulsiones inducidas por pentilentetrazol en ratones. También se estudió el efecto de J. pectoralis sobre la excitación producida por fenciclidina (droga esquizofrenomimética) en ratas infantiles. Los resultados obtenidos sugieren que Justicia pectoralis reduce la conducta agresiva y la actividad exploratoria en ratones, bloquea la excitación inducida por fenciclidina en ratas infantiles y no previene las convulsiones inducidas por pentilentetrazol
Assuntos
Camundongos , Animais , Masculino , Neurofarmacologia , Pentilenotetrazol/efeitos adversos , Fenciclidina/efeitos adversos , Plantas Medicinais , Convulsões/induzido quimicamenteRESUMO
En este trabajo se analiza el conocimiento actual sobre los receptores sigma y PCP/NMDA. Se enfatiza que el haloperidol y muchos otros antipsicóticos similares presentan una afinidad relativamente alta por el receptor sigma. Esto sugiere que el efecto farmacológico de estas drogas pudiera ser debido a un efecto no tan solo en el receptor D2, sino que también a través del receptor sigma. Además se analizan los posibles mecanismos fisiopatológicos de algunos cuadros como las psicosis esquizomorfas epilépticas, el efecto de hormonas esteroidales y estimulantes cerebrales y la implicancia de este conocimiento para su manejo terapéutico. La conclusión más importante de este trabajo es que los receptores sigma y PCP/NMDA parecen estar involucrados en la génesis de los síntomas psicóticos productivos, lo que permite una mejor clasificación de estos cuadros y el desarrollo de antipsicóticos específicos para cada disfunción