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1.
Anal Chim Acta ; 1312: 342751, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38834265

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 , Acústica
2.
CNS Neurosci Ther ; 30(4): e14713, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38615362

RESUMO

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 , Isoxazóis
3.
Neuropharmacology ; 254: 109970, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-38685343

RESUMO

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/farmacologia
4.
Exp Brain Res ; 242(5): 1149-1160, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38489023

RESUMO

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 farmacológico
5.
Sci Rep ; 14(1): 3376, 2024 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-38336912

RESUMO

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/metabolismo
6.
J Anal Toxicol ; 48(2): 111-118, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38287693

RESUMO

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/métodos
7.
Drug Test Anal ; 16(1): 30-37, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37125436

RESUMO

3-Methoxyeticyclidine (3-MeO-PCE), a phencyclidine-type substance, has a higher N-methyl-D-aspartate receptor binding affinity than phencyclidine and an involvement in fatal intoxication cases. The aim of this study was to identify new biomarkers and biotransformation pathways for 3-MeO-PCE. In vitro models were established using zebrafish and human liver microsomes for analysis of the phases I and II metabolites of 3-MeO-PCE by liquid chromatography-high-resolution mass spectrometry. Urine samples of known 3-MeO-PCE consumers in forensic cases were then subjected to analysis. Overall, 14 metabolites were identified in zebrafish and human liver microsomes, allowing postulation of the following metabolic pathways: hydroxylation, O-demethylation, N-dealkylation, dehydrogenation, combination, and glucuronidation or sulfation. 3-MeO-PCE and three metabolites (M2, M3, and M6) were detected in urine. We recommended M2 (the hydroxylation product) as a potential biomarker for documenting 3-MeO-PCE intake in clinical and forensic cases.


Assuntos
Ketamina/análogos & derivados , Microssomos Hepáticos , Peixe-Zebra , Animais , Humanos , Microssomos Hepáticos/metabolismo , Fenciclidina , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida/métodos
8.
Neuropsychopharmacology ; 49(4): 720-730, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38049583

RESUMO

One of the critical unmet medical needs in schizophrenia is the treatment for cognitive deficits. However, the neural circuit mechanisms of them remain unresolved. Previous studies utilizing animal models of schizophrenia did not consider the fact that patients with schizophrenia generally cannot discontinue antipsychotic medication due to the high risk of relapse. Here, we used multi-dimensional approaches, including histological analysis of the prelimbic cortex (PL), LC-MS/MS-based in vivo dopamine D2 receptor occupancy analysis for antipsychotics, in vivo calcium imaging, and behavioral analyses of mice using chemogenetics to investigate neural mechanisms and potential therapeutic strategies for working memory deficit in a chronic phencyclidine (PCP) mouse model of schizophrenia. Chronic PCP administration led to alterations in excitatory and inhibitory synapses, specifically in dendritic spines of pyramidal neurons, vesicular glutamate transporter 1 (VGLUT1) positive terminals, and parvalbumin (PV) positive GABAergic interneurons located in layer 2-3 of the PL. Continuous administration of olanzapine, which achieved a sustained therapeutic window of dopamine D2 receptor occupancy (60-80%) in the striatum, did not ameliorate these synaptic abnormalities and working memory deficit in the chronic PCP-treated mice. We demonstrated that chemogenetic activation of PV neurons in the PL, as confirmed by in vivo calcium imaging, ameliorated working memory deficit in this model even under clinically comparable olanzapine treatment which by itself inhibited only PCP-induced psychomotor hyperactivity. Our study suggests that targeting prefrontal PV neurons could be a promising therapeutic intervention for cognitive deficits in schizophrenia in combination with antipsychotic medication.


Assuntos
Antipsicóticos , Esquizofrenia , Animais , Humanos , Camundongos , Antipsicóticos/uso terapêutico , Cálcio , Cromatografia Líquida , Modelos Animais de Doenças , Interneurônios/metabolismo , Transtornos da Memória/tratamento farmacológico , Olanzapina/efeitos adversos , Parvalbuminas/metabolismo , Fenciclidina/farmacologia , Córtex Pré-Frontal/metabolismo , Receptores de Dopamina D2 , Esquizofrenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Esquizofrenia/patologia , Espectrometria de Massas em Tandem
9.
J Neurosci Res ; 102(1): e25257, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37814998

RESUMO

Noncompetitive NMDA receptor (NMDAR) antagonists like phencyclidine (PCP) and ketamine cause psychosis-like symptoms in healthy humans, exacerbate schizophrenia symptoms in people with the disorder, and disrupt a range of schizophrenia-relevant behaviors in rodents, including hyperlocomotion. This is negated in mice lacking the GluN2D subunit of the NMDAR, suggesting the GluN2D subunit mediates the hyperlocomotor effects of these drugs. However, the role of GluN2D in mediating other schizophrenia-relevant NMDAR antagonist-induced behavioral disturbances, and in both sexes, is unclear. This study aimed to investigate the role of the GluN2D subunit in mediating schizophrenia-relevant behaviors induced by a range of NMDA receptor antagonists. Using both male and female GluN2D knockout (KO) mice, we examined the effects of the NMDAR antagonist's PCP, the S-ketamine enantiomer (S-ket), and the ketamine metabolite R-norketamine (R-norket) on locomotor activity, anxiety-related behavior, and recognition and short-term spatial memory. GluN2D-KO mice showed a blunted locomotor response to R-norket, S-ket, and PCP, a phenotype present in both sexes. GluN2D-KO mice of both sexes showed an anxious phenotype and S-ket, R-norket, and PCP showed anxiolytic effects that were dependent on sex and genotype. S-ket disrupted spatial recognition memory in females and novel object recognition memory in both sexes, independent of genotype. This datum identifies a role for the GluN2D subunit in sex-specific effects of NMDAR antagonists and on the differential effects of the R- and S-ket enantiomers.


Assuntos
Ketamina , Animais , Feminino , Humanos , Masculino , Camundongos , Ketamina/farmacologia , Fenciclidina/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo , Reconhecimento Psicológico
10.
J Addict Med ; 17(6): 695-701, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37934534

RESUMO

OBJECTIVES: Little contemporary research has explored phencyclidine (PCP) use in people with alcohol use disorder. Therefore, we sought to determine the prevalence of PCP positivity on urine toxicology screening among patients admitted for alcohol withdrawal, identify correlates of PCP positivity, and investigate PCP positivity's relationship to length of stay (LOS) and risk of facility readmission. METHODS: This was a retrospective study of patients admitted to a dual-diagnosis medically assisted withdrawal unit for alcohol withdrawal from 2014 to 2019. Univariate tests and logistic regression were used to investigate potential correlates of PCP positivity on admission toxicology screening (primary outcome). Multivariable linear regression models and survival analyses analyzing LOS and risk of readmission (secondary outcomes) were also developed. RESULTS: Ninety of 3731 patients (2.4%) screened positive for PCP. There were significant associations on univariate testing between PCP positivity and age, race, homeless status, and urine toxicology positivity for amphetamines, benzodiazepines, barbiturates, cocaine, tetrahydrocannabinol, and oxycodone. On multivariate logistic regression, only tetrahydrocannabinol, barbiturates, and cocaine positivity were associated with PCP positivity. Multivariate logistic regression and survival analysis found no statistically significant associations between PCP positivity and LOS or risk of readmission. CONCLUSIONS: This study provides rare analysis of contemporary data on PCP use among patients undergoing medically assisted alcohol withdrawal. Phencyclidine positivity was uncommon, but use appears considerably higher among this patient population than the general population. There was no significant association between PCP positivity and LOS or readmission risk.


Assuntos
Alcoolismo , Cocaína , Síndrome de Abstinência a Substâncias , Transtornos Relacionados ao Uso de Substâncias , Humanos , Fenciclidina , Dronabinol , Avaliação Pré-Clínica de Medicamentos , Estudos Retrospectivos , Barbitúricos
11.
Int J Mol Sci ; 24(19)2023 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-37834084

RESUMO

Tobacco misuse as a comorbidity of schizophrenia is frequently established during adolescence. However, comorbidity markers are still missing. Here, the method of label-free proteomics was used to identify deregulated proteins in the medial prefrontal cortex (prelimbic and infralimbic) of male and female mice modelled to schizophrenia with a history of nicotine exposure during adolescence. Phencyclidine (PCP), used to model schizophrenia (SCHZ), was combined with an established model of nicotine minipump infusions (NIC). The combined insults led to worse outcomes than each insult separately when considering the absolute number of deregulated proteins and that of exclusively deregulated ones. Partially shared Reactome pathways between sexes and between PCP, NIC and PCPNIC groups indicate functional overlaps. Distinctively, proteins differentially expressed exclusively in PCPNIC mice reveal unique effects associated with the comorbidity model. Interactome maps of these proteins identified sex-selective subnetworks, within which some proteins stood out: for females, peptidyl-prolyl cis-trans isomerase (Fkbp1a) and heat shock 70 kDa protein 1B (Hspa1b), both components of the oxidative stress subnetwork, and gamma-enolase (Eno2), a component of the energy metabolism subnetwork; and for males, amphiphysin (Amph), a component of the synaptic transmission subnetwork. These are proposed to be further investigated and validated as markers of the combined insult during adolescence.


Assuntos
Fenciclidina , Esquizofrenia , Camundongos , Animais , Masculino , Feminino , Fenciclidina/metabolismo , Esquizofrenia/metabolismo , Nicotina/farmacologia , Córtex Pré-Frontal/metabolismo , Transmissão Sináptica , Modelos Animais de Doenças
12.
Psychopharmacology (Berl) ; 240(10): 2111-2129, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37530885

RESUMO

Sex-biased differences in schizophrenia are evident in several features of the disease, including symptomatology and response to pharmacological treatments. As a neurodevelopmental disorder, these differences might originate early in life and emerge later during adolescence. Considering that the disruption of the glutamatergic system during development is known to contribute to schizophrenia, we hypothesized that the neonatal phencyclidine model could induce sex-dependent behavioral and neurochemical changes associated with this disorder during adolescence. C57BL/6 mice received either saline or phencyclidine (5, 10, or 20 mg/kg) on postnatal days (PN) 7, 9, and 11. Behavioral assessment occurred in late adolescence (PN48-50), when mice were submitted to the open field, social interaction, and prepulse inhibition tests. Either olanzapine or saline was administered before each test. The NMDAR obligatory GluN1 subunit and the postsynaptic density protein 95 (PSD-95) were evaluated in the frontal cortex and hippocampus at early (PN30) and late (PN50) adolescence. Neonatal phencyclidine evoked dose-dependent deficits in all analyzed behaviors and males were more susceptible. Males also had reduced GluN1 expression in the frontal cortex at PN30. There were late-emergent effects at PN50. Cortical GluN1 was increased in both sexes, while phencyclidine increased cortical and decreased hippocampal PSD-95 in females. Olanzapine failed to mitigate most phencyclidine-evoked alterations. In some instances, this antipsychotic aggravated the deficits or potentiated subthreshold effects. These results lend support to the use of neonatal phencyclidine as a sex-biased neurodevelopmental preclinical model of schizophrenia. Olanzapine null effects and deleterious outcomes suggest that its use during adolescence should be further evaluated.


Assuntos
Antipsicóticos , Esquizofrenia , Masculino , Feminino , Animais , Camundongos , Fenciclidina/farmacologia , Esquizofrenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Olanzapina/uso terapêutico , Camundongos Endogâmicos C57BL , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Modelos Animais de Doenças
13.
Behav Brain Res ; 454: 114614, 2023 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-37572758

RESUMO

The serotonin (5-HT)2 C receptor(R) is a widely distributed G-protein-coupled receptor, expressed abundantly in the central nervous system. Alstonine is a natural product that has significant properties of atypical antipsychotic drugs (AAPDs), in part attributed to 5-HT2 CR agonism. Based on alstonine, we developed NU-1223, a simplified ß carboline analog of alstonine, which shows efficacies comparable to alstonine and to other 5-HT2 CR agonists, Ro-60-0175 and lorcaserin. The 5-HT2 CR antagonism of some APDs, including olanzapine, contributes to weight gain, a major side effect which limits its tolerability, while the 5-HT2 CR agonists and/or modulators, may minimize weight gain. We used the well-established rodent subchronic phencyclidine (PCP) model to test the efficacy of NU-1223 on episodic memory, using novel object recognition (NOR) task, positive (locomotor activity), and negative symptoms (social interaction) of schizophrenia (SCH). We found that NU-1223 produced both transient and prolonged rescue of the subchronic PCP-induced deficits in NOR and SI. Further, NU-1223, but not Ro-60-0175, blocked PCP and amphetamine (AMPH)-induced increase in LMA in subchronic PCP mice. These transient efficacies in LMA were blocked by the 5-HT2 CR antagonist, SB242084. Sub-chronic NU-1223 treatment rescued NOR and SI deficits in subchronic PCP mice for at least 39 days after 3 days injection. Chronic treatment with NU-1223, ip, twice a day for 21 days, did not increase average body weight vs olanzapine. These findings clearly indicate NU-1223 as a class of small molecules with a possible 5-HT2 CR-agonist-like mechanism of action, attributing to its efficacy. Additional in-depth receptor mechanistic studies are warranted, as this small molecule, both transiently and chronically rescued PCP-induced deficits. Furthermore, NU-1223 did not induce weight gain post long-term administrations vs AAPDs such as olanzapine, making NU-1223 a putative therapeutic compound for SCH.


Assuntos
Antipsicóticos , Esquizofrenia , Animais , Camundongos , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Olanzapina/farmacologia , Fenciclidina/farmacologia , Esquizofrenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Serotonina/metabolismo , Serotonina/farmacologia , Alcaloides de Triptamina e Secologanina/farmacologia , Alcaloides de Triptamina e Secologanina/uso terapêutico
14.
J Pharm Biomed Anal ; 234: 115577, 2023 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-37480824

RESUMO

Phencyclidine (PCP) is a frequently abused dissociative agent. It causes confusion, increased tendencies toward violence, and concentration-dependent cytotoxicity after entry into the body. The parent nucleus of phencyclidine-type substances is arylcyclohexylamine, which is easy to modify; therefore, abusers and dealers can readily synthesize substitutes beyond the drug control catalog. An urgent need exists to establish screening methods for phencyclidine-type substances to provide technical support for abuse monitoring. In this study, 20 mg of hair was pulverized in 500 mL of methanol containing 0.5 ng/mL PCP-d5. After ultrasonication, centrifugation, and filtration, the supernatant was analyzed by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) operating in the multiple reaction monitoring mode. Phencyclidine-type substances were separated in 13 min on a biphenyl column using a mobile phase gradient composed of A (water, formic acid 0.1%, acetonitrile 5%, 20 mmol/L ammonium acetate) and B (acetonitrile). The developed and validated method showed good selectivity, sensitivity (limit of detection: 0.25-2 pg/mg and lower limit of quantitation: 0.5-4 pg/mg), linearity (R2 > 0.994), accuracy, and precision (< 20%), and a dilution effect. The method also showed good recovery and acceptable matrix effects for most of the targeted compounds. This analytical approach was successfully applied for the identification and quantification of phencyclidine-type substances in hair from 87 authentic forensic cases. Nine analytes were detected: ketamine (10.3-26211.3 pg/mg), 2-F-2-oxo-PCE (11.5-4034.9 pg/mg), 2-FDCK (14.0-43290.2 pg/mg), 2-BrDCK (10.6-21170.0 pg/mg), nor2-FDCK (10.1-16767.4 pg/mg), tiletamine (10.1-3250.8 pg/mg), O-PCE (43.3-166.1 pg/mg), DCK (10.2-90.4 pg/mg), and norDCK (24.9-103.0 pg/mg).


Assuntos
Fenciclidina , Espectrometria de Massas em Tandem , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Cabelo , Acetonitrilas
15.
Am J Drug Alcohol Abuse ; 49(4): 440-449, 2023 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-37433108

RESUMO

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.


Assuntos
Neoplasias de Cabeça e Pescoço , Drogas Ilícitas , Neoplasias Pulmonares , Humanos , Masculino , Feminino , Ópio , Fenciclidina , Fumar Cocaína , Los Angeles , Estudos de Casos e Controles , Neoplasias Pulmonares/epidemiologia , Pulmão , Fatores de Risco
16.
J Anal Toxicol ; 47(6): 552-556, 2023 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-37279962

RESUMO

3-Hydroxyphencyclidine (3-OH-PCP) is a hydroxy derivative of phencyclidine, synthesized in 1978 to investigate the structure-activity relationship of phencyclidine derivates. In vitro studies have shown that 3-OH-PCP, like phencyclidine, acts on the N-methyl-D-aspartate receptor and has a higher affinity for this receptor than phencyclidine. The authors report the case of a 38-year-old man, known for drug addiction, found dead at home with two plastic bags of powders found near his body. Using liquid chromatography coupled to tandem mass spectrometry, peripheral blood toxicological analysis revealed consumption of 3-OH-PCP with a concentration of 3-OH-PCP being 524 ng/mL. Blood also tested positive for nordiazepam, methylphenidate, amisulpride, methadone and benzoylecgonine, all at concentrations near those observed after recreational abuse. The blood concentration of 3-OH-PCP is the highest ever reported in the literature. Hair testing also revealed 3-OH-PCP, at 174 pg/mg, which may correspond to a chronic consumption of this molecule. A nuclear magnetic resonance analysis of the two powders highlighted 3-OH-PCP and 5-methoxy-dimethyltryptamine, estimated to have a purity of 85.4 and 91.3%, respectively, using the Electronic Reference To access In vivo Concentrations method.


Assuntos
Fenciclidina , Transtornos Relacionados ao Uso de Substâncias , Masculino , Humanos , Adulto , Pós/análise , Cabelo/química
17.
ACS Chem Neurosci ; 14(12): 2256-2270, 2023 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-37290117

RESUMO

Dextromethorphan (DXM) was introduced in 1958 as the first non-opioid cough suppressant and is indicated for multiple psychiatric disorders. It has been the most used over-the-counter cough suppressant since its emergence. However, individuals quickly noticed an intoxicating and psychedelic effect if they ingested large doses. DXM's antagonism at N-methyl-d-aspartate receptors (NMDAr) is thought to underly its efficacy in treating acute cough, but supratherapeutic doses mimic the activity of dissociative hallucinogens, such as phencyclidine and ketamine. In this Review we will discuss DXM's synthesis, manufacturing information, drug metabolism, pharmacology, adverse effects, recreational use, abuse potential, and its history and importance in therapy to present DXM as a true classic in chemical neuroscience.


Assuntos
Antitussígenos , Alucinógenos , Ketamina , Humanos , Antitussígenos/farmacologia , Antitussígenos/uso terapêutico , Dextrometorfano/farmacologia , Dextrometorfano/uso terapêutico , Alucinógenos/farmacologia , Alucinógenos/uso terapêutico , Fenciclidina , Ketamina/farmacologia , Ketamina/uso terapêutico , Receptores de N-Metil-D-Aspartato
18.
Eur J Pharmacol ; 953: 175802, 2023 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-37295763

RESUMO

Antipsychotic drugs of different chemical/pharmacological families show preferential dopamine (DA) D2 receptor (D2-R) vs. D1 receptor (D1-R) affinity, with the exception of clozapine, the gold standard of schizophrenia treatment, which shows a comparable affinity for both DA receptors. Here, we examined the ability of Lu AF35700 (preferential D1-R>D2-R antagonist), to reverse the alterations in thalamo-cortical activity induced by phencyclidine (PCP), used as a pharmacological model of schizophrenia. Lu AF35700 reversed the PCP-induced alteration of neuronal discharge and low frequency oscillation (LFO, 0.15-4 Hz) in thalamo-cortical networks. Likewise, Lu AF35700 prevented the increased c-fos mRNA expression induced by PCP in thalamo-cortical regions of awake rats. We next examined the contribution of D1-R and D2-R to the antipsychotic reversal of PCP effects. The D2-R antagonist haloperidol reversed PCP effects on thalamic discharge rate and LFO. Remarkably, the combination of sub-effective doses of haloperidol and SCH-23390 (DA D1-R antagonist) fully reversed the PCP-induced fall in thalamo-cortical LFO. However, unlike with haloperidol, SCH-23390 elicited different degrees of potentiation of the effects of low clozapine and Lu AF35700 doses. Overall, the present data support a synergistic interaction between both DA receptors to reverse the PCP-induced alterations of oscillatory activity in thalamo-cortical networks, possibly due to their simultaneous blockade in direct and indirect pathways of basal ganglia. The mild potentiation induced by SCH-23390 in the case of clozapine and Lu AF35700 suggests that, at effective doses, these agents reverse PCP effects through the simultaneous blockade of both DA receptors.


Assuntos
Antipsicóticos , Clozapina , Ratos , Animais , Fenciclidina/farmacologia , Clozapina/farmacologia , Haloperidol/farmacologia , Dopamina , Antipsicóticos/farmacologia , Antagonistas de Dopamina/farmacologia , Receptores de Dopamina D1
19.
Biochem Biophys Res Commun ; 667: 18-24, 2023 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-37201359

RESUMO

Repeated administration of drugs of abuse leads to progressively greater behavioral responses; this phenomenon is referred to as behavioral sensitization. MK-801 blocks the N-methyl-d-aspartate (NMDA) receptor and elicits behavioral sensitization. Ketamine and phencyclidine, are also NMDA antagonists and have well-documented abuse potential. This study investigated the characteristics of MK-801-induced behavioral sensitization and found that it induced sensitization rapidly; only five consecutive treatments were required. The optimal dose for robust sensitization was also identified, which corresponded to the typical doses of abused NMDA antagonists (i.e., between the doses inducing antidepressant and anesthetic effects). Following MK-801-induced behavioral sensitization, changes were observed in the expression and/or phosphorylation of NMDA receptor subunits. While the expression of early growth response protein 1, which serves as a marker of neuronal activation, was affected by MK-801 sensitization, extracellular signal-regulated kinase phosphorylation was not associated with MK-801 treatment.


Assuntos
Maleato de Dizocilpina , N-Metilaspartato , Animais , Maleato de Dizocilpina/farmacologia , N-Metilaspartato/farmacologia , Comportamento Animal , Fenciclidina , Receptores de N-Metil-D-Aspartato/metabolismo
20.
Mol Imaging Biol ; 25(4): 692-703, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-36944798

RESUMO

PURPOSE: NMDA receptors (NMDARs) dysfunction plays a central role in the physiopathology of psychiatric and neurodegenerative disorders whose mechanisms are still poorly understood. The development of a PET (positron emission tomography) tracer able to selectively bind to the NMDARs intra-channel PCP site may make it possible to visualize NMDARs in an open and active state. We describe the in vitro pharmacological characterization of [18F]-fluoroethylnormemantine ([18F]-FNM) and evaluate its ability to localize activated NMDA receptors in a rat preclinical model of excitotoxicity. PROCEDURES: The affinity of the non-radioactive analog for the intra-channel PCP site was determined in a radioligand competition assay using [3H]TCP ([3H]N-(1-[thienyl]cyclohexyl)piperidine) on rat brain homogenates. Selectivity was also investigated by the displacement of specific radioligands targeting various cerebral receptors. In vivo brain lesions were performed using stereotaxic quinolinic acid (QA) injections in the left motor area (M1) of seven Sprague Dawley rats. Each rat was imaged with a microPET/CT camera, 40 min after receiving a dose of 30 MBq + / - 20 of [18F]-FNM, 24 and 72 h after injury. Nine non-injured rats were also imaged using the same protocol. RESULTS: FNM displayed IC50 value of 13.0 ± 8.9 µM in rat forebrain homogenates but also showed significant bindings on opioid receptors. In the frontal and left somatosensory areas, [18F]FNM PET detected a mean of 37% and 41% increase in [18F]FNM uptake (p < 0,0001) 24 and 72 h after QA stereotaxic injection, respectively, compared to the control group. CONCLUSIONS: In spite of FNM's poor affinity for NMDAR PCP site, this study supports the ability of this tracer to track massive activation of NMDARs in neurological diseases.


Assuntos
Lesões Encefálicas , Receptores de N-Metil-D-Aspartato , Ratos , Animais , Receptores de N-Metil-D-Aspartato/metabolismo , Ratos Sprague-Dawley , Fenciclidina/metabolismo , Lesões Encefálicas/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo
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