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1.
Physiol Behav ; 263: 114117, 2023 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-36781093

RESUMO

Treatments for schizophrenia are not effective in ameliorating cognitive deficits. Therefore, novel therapies are needed to treat cognitive impairments associated with schizophrenia (CIAS), which are modelled in rats through administration of sub-chronic phencyclidine (scPCP). We have previously shown that enrichment via voluntary exercise prevents and reverses impairments in novel object recognition (NOR) in this model. The present study aimed to investigate if handling could prevent delay-induced NOR deficits and prevent and reverse scPCP-induced NOR deficits. Two cohorts of adult female Lister Hooded rats were used. In experiment one, handling (five minutes/day, five days/week for two weeks), took place before scPCP administration (2 mg/kg, i.p. twice-daily for seven days). NOR tests were conducted at two, four, and seven weeks post-handling with a one-minute inter-trial interval (ITI) and at five weeks post-dosing with a six-hour ITI. In experiment two, rats were handled after scPCP administration and tested immediately in the one-minute ITI NOR task and again at two weeks post-handling. In both handling regimens, the scPCP control groups failed to discriminate novelty, conversely the scPCP handled groups significantly discriminated in this task. In the 6 h ITI test, vehicle control and scPCP control failed to discriminate novelty; however, the vehicle handled and scPCP handled groups did significantly discriminate. Handling rats prevented and reversed scPCP-induced deficits and prevented delay-induced NOR deficits. These findings add to evidence that environmental enrichment is a viable treatment for cognitive deficits in rodent tests and models of relevance to schizophrenia, with potential to translate into effective treatments for CIAS.


Assuntos
Transtornos Cognitivos , Disfunção Cognitiva , Esquizofrenia , Ratos , Feminino , Animais , Fenciclidina/efeitos adversos , Esquizofrenia/induzido quimicamente , Disfunção Cognitiva/induzido quimicamente , Cognição , Modelos Animais de Doenças
2.
Pharmacol Biochem Behav ; 223: 173532, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36822254

RESUMO

Aberrant cortical oscillations in the beta and gamma range are associated with symptoms of schizophrenia and other psychiatric conditions. We have thus investigated the ability of anterior cingulate cortex (ACC) in vitro to generate beta and gamma oscillations, and how these are affected by Group II metabotropic glutamate (mGlu) receptor activation and blockade of N-methyl-d-aspartate (NMDA) receptors. Activation of Group II mGlu receptors, and mGlu2 specifically, with orthosteric agonists reduced the power of both beta and gamma oscillations in ACC without a significant effect on oscillation peak frequencies. The NMDA receptor blocker phencyclidine (PCP), known to evoke certain schizophrenia-like symptoms in humans, elevated the power of beta oscillations in ACC and caused a shift in oscillation frequency from the gamma range to the beta range. These enhanced beta oscillations were reduced by the Group II mGlu receptor agonists. These results show that Group II mGlu receptors, and specifically mGlu2, modulate network oscillations. Furthermore, attenuation of the effect of PCP suggests that mGlu2 receptors may stabilise aberrant network activity. These results underline the importance of Group II mGlu receptors, and particularly mGlu2, as targets for the treatment of neuropsychiatric and neurodegenerative diseases.


Assuntos
Receptores de Glutamato Metabotrópico , Humanos , Ratos , Animais , Receptores de Glutamato Metabotrópico/agonistas , Fenciclidina , Giro do Cíngulo/metabolismo , N-Metilaspartato
4.
Int J Mol Sci ; 23(24)2022 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-36555217

RESUMO

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.


Assuntos
Ketamina , Ketamina/farmacologia , Fenciclidina , Receptores de N-Metil-D-Aspartato , Ásia , Europa (Continente)
5.
Toxicol Appl Pharmacol ; 456: 116282, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36252887

RESUMO

The association between schizophrenia and nicotine addiction becomes evident during adolescence. Here, to investigate interactive events that might underlie the early establishment of this comorbidity, we used phencyclidine-evoked locomotor sensitization, a proxy model of psychotic behavior, and nicotine minipump infusions in adolescent mice. Considering the involvement of dopamine D2 receptors in both schizophrenia and addiction, we further tested their role by exposing mice to raclopride. Adolescent mice that were either exposed to nicotine (24 mg/Kg/day) or not, received single daily raclopride (0.5 mg/kg, s.c.) or saline followed by phencyclidine injections (10 mg/Kg, s.c.) during open field testing for 6 consecutive days (Acquisition phase, ACQ). Phencyclidine and nicotine challenges (Sensitization Test, ST) were carried out after a 5-day withdrawal. Ambulation escalated in response to repeated phencyclidine exposure during ACQ and was increased after phencyclidine challenge, evidencing development and expression of locomotor sensitization. Raclopride prevented phencyclidine-evoked development of sensitization. However, raclopride pre-exposure during ACQ only shortened its expression in phencyclidine-challenged mice. Nicotine failed to interfere with phencyclidine stimulatory effects during ACQ but potentiated raclopride inhibition during the first ACQ days. During ST, nicotine history shortened the expression of phencyclidine-evoked sensitization. Nicotine challenge had no impact on locomotion, which is consistent with a lack of nicotine/phencyclidine cross-sensitization. In conclusion, our results show that nicotine does not worsen, and may even ameliorate phencyclidine-sensitized psychotic-like behavior in adolescent mice. The potentiation of raclopride-mediated inhibition further suggests that nicotine transiently improves the therapeutic efficacy of medication on psychotic symptoms through mechanisms that converge on D2 receptors.


Assuntos
Nicotina , Fenciclidina , Camundongos , Animais , Fenciclidina/toxicidade , Nicotina/toxicidade , Racloprida/farmacologia , Locomoção , Atividade Motora , Receptores Dopaminérgicos
6.
Biochem Biophys Res Commun ; 629: 142-151, 2022 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-36116377

RESUMO

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.


Assuntos
Quinurenina 3-Mono-Oxigenase , Cinurenina , Animais , Ácido Cinurênico/metabolismo , Cinurenina/metabolismo , Quinurenina 3-Mono-Oxigenase/genética , Quinurenina 3-Mono-Oxigenase/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fenciclidina , Inibição Pré-Pulso , Ácido Quinolínico/metabolismo , RNA Mensageiro
7.
Anal Chim Acta ; 1226: 340170, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36068050

RESUMO

The nail is an alternative matrix to complement hair analysis in proving drug intake over several months in forensic toxicology investigations. However, because of the high hardness and toughness of nails, the existing pretreatment procedures for nails have the disadvantages of either a high degree of time consumption (from hours to days), or low extraction recoveries. This study aims to propose a high-throughput nail sample preparation method and provide a quantitative analytical method for 106 drugs and their metabolites present in nail. We developed cryogenic grinding, coupled with high-speed grinding in the extraction solvent method, which could improve the extraction recovery by thoroughly destroying the nail keratin for approximately 18 min. Subsequently, an ultra-high-performance liquid chromatography-tandem mass spectrometry method was developed for the identification and quantification of 34 synthetic cannabinoids, 26 fentanyls, 18 synthetic cathinones, 10 phenylethylamines, eight opioids, three phencyclidine, two tryptamines, two piperazine, cocaine, benzoylecgonine, and tetrahydrocannabinol (THC). Nail samples were collected from people with a history of drug abuse from five different regions of China. The analysis of 294 authentic samples resulted in 213 detected samples, and showed a broad concentration range including 5.04-67.26 pg/mg for nine synthetic cannabinoids, 109.29-250.29 pg/mg for a synthetic cathinone, 5.06-434291 pg/mg for four phenylethylamines, 5.06-464278 pg/mg for three phencyclidine, 5.50-192195 pg/mg for six opioids, 19.44-36.11 pg/mg for cocaine, and 50.53 pg/mg for THC in nail. Furthermore, up to 10 different compounds were detected in a single nail sample. This nail analysis method serves as a useful tool for the large-scale surveillance of illicit drugs abuse.


Assuntos
Cocaína , Espectrometria de Massas em Tandem , Analgésicos Opioides/análise , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida/métodos , Cocaína/análise , Dronabinol/análise , Cabelo/química , Humanos , Fenciclidina/análise , Fenetilaminas/análise , Detecção do Abuso de Substâncias/métodos , Espectrometria de Massas em Tandem/métodos
8.
Am J Emerg Med ; 61: 234.e5-234.e6, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35961834

RESUMO

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.


Assuntos
Canabinoides , Fenciclidina , Humanos , Masculino , Pessoa de Meia-Idade , Lamotrigina , Mirtazapina , Cloridrato de Duloxetina , Palmitato de Paliperidona , Lisinopril , Hidroxizina
9.
Int J Neuropsychopharmacol ; 25(9): 786-793, 2022 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-35882205

RESUMO

BACKGROUND: Fragile X syndrome (FXS) is a genetic condition that causes a range of developmental problems, including intellectual disability, aggressive behavior, anxiety, abnormal sensory processing, and cognitive impairment. Despite intensive preclinical research in Fmr1-targeted transgenic mice, an effective treatment for FXS has yet to be developed. We previously demonstrated that ASP5736, a 5-Hydroxytryptamine (serotonin) receptor 5A receptor antagonist, ameliorated scopolamine-induced working memory deficits in mice, reference memory impairment in aged rats, and methamphetamine-induced positive symptoms and phencyclidine-induced cognitive impairment in animal models of schizophrenia. We hypothesized that ASP5736 may be effective for ameliorating similar behavior deficits in male Fmr1-targeted transgenic rats as a preclinical model of FXS. METHODS: We evaluated the effect of acute oral administration of ASP5736 on the abnormal behavior of hyperactivity (0.01, 0.1 mg/kg), prepulse inhibition (0.01, 0.03, 0.1 mg/kg), and the novel object recognition task (0.1 mg/kg) in Frmr1-knockout (KO) rats. RESULTS: Fmr1-KO rats showed body weight gain, hyperactivity, abnormal sensory motor gating, and cognitive impairment. ASP5736 (0.1 mg/kg) reversed the hyperactivity and ameliorated the sensory motor gating deficits (0.03-0.1 mg/kg). ASP5736 (0.01 mg/kg) also improved cognitive impairment. CONCLUSIONS: ASP5736 is a potential drug candidate for FXS. Further studies are needed to confirm its clinical efficacy.


Assuntos
Síndrome do Cromossomo X Frágil , Metanfetamina , Animais , Modelos Animais de Doenças , Proteína do X Frágil de Retardo Mental/genética , Proteína do X Frágil de Retardo Mental/uso terapêutico , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Síndrome do Cromossomo X Frágil/genética , Guanidinas , Isoquinolinas , Masculino , Transtornos da Memória/tratamento farmacológico , Camundongos , Camundongos Knockout , Fenciclidina/uso terapêutico , Ratos , Ratos Transgênicos , Receptores de Serotonina , Escopolamina/uso terapêutico , Serotonina , Antagonistas da Serotonina/farmacologia
10.
Behav Brain Res ; 432: 113964, 2022 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-35718230

RESUMO

Rapastinel, a positive N-methyl-D-aspartate receptor (NMDAR) modulator with rapid-acting antidepressant properties, rescues memory deficits in rodents. We have previously reported that a single intravenous dose of rapastinel, significantly, but only transiently, prevented and rescued deficits in the novel object recognition (NOR) test, a measure of episodic memory, produced by acute or subchronic administration of the NMDAR antagonists, phencyclidine (PCP) and ketamine. Here, we tested the ability of single and multiple subcutaneous doses per day of rapastinel to restore NOR and operant reversal learning (ORL) deficits in subchronic PCP-treated mice. Rapastinel, 1 or 3 mg/kg, administered subcutaneously, 30 min before NOR or ORL testing, respectively, transiently rescued both deficits in subchronic PCP mice. This effect of rapastinel on NOR and ORL was mammalian target of rapamycin (mTOR)-dependent. Most importantly, 1 mg/kg rapastinel given twice daily for 3 or 5 days, but not 1 day, restored NOR for at least 9 and 10 weeks, respectively, which is an indication of neuroplastic effects on learning and memory. Both rapastinel (3 mg/kg) and ketamine (30 mg/kg), moderately increased the efflux of dopamine, norepinephrine, and serotonin in medial prefrontal cortex; however, only ketamine increased cortical glutamate efflux. This observation was likely the basis for the contrasting effects of the two drugs on cognition.


Assuntos
Ketamina , Fenciclidina , Animais , Ketamina/farmacologia , Ketamina/uso terapêutico , Mamíferos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Camundongos , Oligopeptídeos/farmacologia , Fenciclidina/farmacologia
11.
Neuropharmacology ; 216: 109171, 2022 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-35764129

RESUMO

Ketamine (Ket) was developed in 1962 as a less hallucinogenic and shorter acting agent than phencyclidine. It was given to humans for the first time in 1964. However, Ket produces several adverse reactions such as raised intracranial and blood pressures along with seizures, and patients still show low acceptance due to hallucinations. As new volatile and intravenous anesthetic agents with good emergence and favorable side effect profiles were developed, Ket use markedly decreased. In the 1990s, as the ultrashort-acting opioid remifentanil was developed, high dose opioid could be used to reduce surgical stress in highly invasive procedures. However, high dose opioids can produce hyperalgesia and acute tolerance. As Ket can exert anti-hyperalgesic actions, the clinical use of low dose Ket has been reconsidered. Other beneficial effects of Ket such as; analgesia, anti-shock in hemorrhagic and septic insults, anti-inflammatory effects, anti-tumor effects, brain and spinal cord neuroprotection, and bronchodilation, have all been reported. Moreover, this anesthetic agent at low dose has been recently recognized to possess anti-depressive actions. This diverse profile extends Ket far beyond anesthesia practice and the operating room.


Assuntos
Anestésicos , Ketamina , Analgésicos Opioides/efeitos adversos , Anestésicos/farmacologia , Anestésicos/uso terapêutico , Humanos , Hiperalgesia/induzido quimicamente , Ketamina/farmacologia , Ketamina/uso terapêutico , Fenciclidina , Remifentanil
12.
Pharmacotherapy ; 42(7): 567-579, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35665948

RESUMO

Ketamine, an anesthetic available since 1970, and esketamine, its newer S-enantiomer, provide a novel approach for the treatment of depression and other psychiatric disorders. At subanesthetic doses, the two drugs, along with their older congener, phencyclidine (PCP), induce a transient, altered mental state by blocking the N-methyl-D-aspartate (NMDA) receptor for glutamate, the primary excitatory neurotransmitter in the mammalian central nervous system. This multidisciplinary review examines the pharmacology/direct effects on consciousness, effectiveness in depression and acute suicidality, and safety of these fast-acting NMDA antagonists. To capture the essence of 60 years of peer-reviewed literature, we used a semi-structured approach to the subtopics, each of which required a different search strategy. We review the evidence for the three primary reported benefits of the two clinical drugs when used for depression: success in difficult-to-treat patients, rapid onset of action within a day, and immediate effects on suicidality. Key safety issues include the evidence-and lack thereof-for the effects of repeatedly inducing this altered mental state, and whether an adequate safety margin exists to rule out the neurotoxic effects seen in animal studies. This review includes evidence from multiple sources that raise substantial questions about both safety and effectiveness of ketamine and esketamine for psychiatric disorders.


Assuntos
Depressão , Ketamina , Receptores de N-Metil-D-Aspartato , Animais , Depressão/tratamento farmacológico , Humanos , Ketamina/efeitos adversos , Mamíferos , N-Metilaspartato , Fenciclidina/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores
13.
J Anal Toxicol ; 46(8): 891-898, 2022 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-35689545

RESUMO

Presented are phencyclidine (PCP)-positive cases received by the Toxicology Laboratory at the Southwestern Institute of Forensic Sciences from local law enforcement agencies and the Office of the Medical Examiner (OME) between 1 January 2015 and 31 December 2020. Of the 43,940 requests for testing received during that time, 898 (2.04%) were positive for PCP. These cases were evaluated for PCP concentration, additional/concurrently reported drug concentrations and demographics. For ME cases, the cause and manner of death were also evaluated. Although the number of requests received by the Toxicology Laboratory increased each year, the percentage positive for PCP remained consistent. Subjects ranged from 18 to 71 years old (median 48 years) and were predominantly black (94.19%) and male (78.49%). PCP concentrations for all case types ranged from 0.02 to 2.33 mg/L (median 0.05 mg/L); driving while intoxicated (DWI) cases ranged from 0.02 to 0.14 mg/L (median 0.04 mg/L) and ME cases ranged from 0.02 to 2.33 mg/L (median 0.13 mg/L). In addition to PCP, one or more drug(s) or metabolite(s) was identified concurrently in 69.49% of cases. Cannabinoids were the most frequently detected (39.8%), followed by cocaine and its metabolites (22.0%) and ethanol (18.5%). Results were similar when comparing the additional drugs reported in ME and DWI cases. PCP concentrations in ME samples were generally higher, especially for stimulant drugs. Of the 264 ME cases positive for PCP, the manner of death was determined to be an accident for the majority of cases (62.54%), and the most common cause of death was drug toxicity (35.61%). The results from this study facilitate comparison of laboratory- or region-specific data sets, help determine whether laboratory scopes meet testing needs, contribute to reference ranges and provide the foundation for well-informed policy decisions.


Assuntos
Canabinoides , Cocaína , Adolescente , Adulto , Idoso , Etanol , Humanos , Masculino , Pessoa de Meia-Idade , Fenciclidina , Estudos Retrospectivos , Adulto Jovem
14.
Proc Natl Acad Sci U S A ; 119(21): e2122544119, 2022 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-35588456

RESUMO

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.


Assuntos
Alucinógenos , Fenciclidina , Células de Purkinje , Esquizofrenia , Animais , Fator de Crescimento do Tecido Conjuntivo/genética , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Modelos Animais de Doenças , Alucinógenos/administração & dosagem , Alucinógenos/efeitos adversos , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fenciclidina/administração & dosagem , Fenciclidina/efeitos adversos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Células de Purkinje/efeitos dos fármacos , Células de Purkinje/fisiologia , Células de Purkinje/ultraestrutura , Receptores da Fenciclidina/agonistas , Esquizofrenia/induzido quimicamente , Esquizofrenia/patologia , Sinapses/efeitos dos fármacos , Sinapses/ultraestrutura
15.
Neuropharmacology ; 213: 109079, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35561792

RESUMO

Non-competitive NMDA receptor (NMDA-R) antagonists like ketamine, phencyclidine (PCP) and MK-801 are routinely used as pharmacological models of schizophrenia. However, the NMDA-R subtypes, neuronal types (e.g., GABA vs. glutamatergic neurons) and brain regions involved in psychotomimetic actions are not fully understood. PCP activates thalamo-cortical circuits after NMDA-R blockade in reticular thalamic GABAergic neurons. GluN2C subunits are densely expressed in thalamus and cerebellum. Therefore, we examined their involvement in the behavioral and functional effects elicited by PCP and MK-801 using GluN2C knockout (GluN2CKO) and wild-type mice, under the working hypothesis that psychotomimetic effects should be attenuated in mutant mice. PCP and MK-801 induced a disorganized and meandered hyperlocomotion in both genotypes. Interestingly, stereotyped behaviors like circling/rotation, rearings and ataxia signs were dramatically reduced in GluN2CKO mice, indicating a better motor coordination in absence of GluN2C subunits. In contrast, other motor or sensorimotor (pre-pulse inhibition of the startle response) aspects of the behavioral syndrome remained unaltered by GluN2C deletion. PCP and MK-801 evoked a general pattern of c-fos activation in mouse brain (including thalamo-cortical networks) but not in the cerebellum, where they markedly reduced c-fos expression, with significant genotype differences paralleling those in motor coordination. Finally, resting-state fMRI showed an enhanced cortico-thalamic-cerebellar connectivity in GluN2CKO mice, less affected by MK-801 than controls. Hence, the GluN2C subunit allows the dissection of the behavioral alterations induced by PCP and MK-801, showing that some motor effects (in particular, motor incoordination), but not deficits in sensorimotor gating, likely depend on GluN2C-containing NMDA-R blockade in cerebellar circuits.


Assuntos
Maleato de Dizocilpina , Transtornos Psicóticos , Animais , Maleato de Dizocilpina/farmacologia , Neurônios GABAérgicos/metabolismo , Camundongos , Camundongos Knockout , N-Metilaspartato , Fenciclidina/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo
16.
J Anal Toxicol ; 46(8): 899-904, 2022 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-35640884

RESUMO

A rapid, simple extraction method followed by qualitative screening using liquid chromatography-tandem mass spectrometry (LC-MS-MS) for drugs in oral fluid is presented. The decision points were selected to be at, or lower, than those recommended as Tier I compounds by the National Safety Council's Alcohol, Drugs and Impairment Division for toxicological investigation of driving under the influence of drug (DUID) cases and were also at, or lower, than those recommended by Substance Abuse and Mental Health Service Administration and the Department of Transportation for Federal workplace drug testing programs. The method included 30 drugs: delta-9-tetrahydrocannabinol, amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine, 3,4-methylenedioxyamphetamine, cocaine, benzoylecgonine, carisoprodol, meprobamate, zolpidem, alprazolam, clonazepam, 7-aminoclonazepam, diazepam, nordiazepam, lorazepam, oxazepam, temazepam, codeine, morphine, 6-acetylmorphine, buprenorphine, fentanyl, hydrocodone, hydromorphone, oxycodone, oxymorphone, methadone, tramadol and phencyclidine. Phencyclidine was included because it is in the Federal workplace program even though it is considered a Tier II drug for DUID cases. A liquid-liquid extraction method using isopropanol, hexane and ethyl acetate to extract drugs from the oral fluid-buffer mix collected in a Quantisal™ device, followed by LC-MS-MS screening, was developed and validated according to ANSI/ASB 2019 Standard Practices for Method Validation in Forensic Toxicology. Interference studies, limit of detection, precision at the decision point, ionization suppression/enhancement and processed sample stability were determined for each drug. The method was successfully applied to proficiency specimens and routine samples received in the laboratory.


Assuntos
3,4-Metilenodioxianfetamina , Buprenorfina , Carisoprodol , Cocaína , Meprobamato , Metanfetamina , N-Metil-3,4-Metilenodioxianfetamina , Tramadol , 2-Propanol , Alprazolam , Anfetaminas , Clonazepam , Codeína , Dronabinol , Fentanila , Hexanos , Hidrocodona , Hidromorfona , Lorazepam , Metadona , Derivados da Morfina , Nordazepam , Oxazepam , Oxicodona , Oximorfona , Preparações Farmacêuticas/análise , Fenciclidina , Espectrometria de Massas em Tandem , Temazepam , Zolpidem
17.
Biomed Pharmacother ; 150: 113022, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35483195

RESUMO

GABAA receptors containing α6 subunits (α6GABAARs) in the cerebellum have -been implicated in schizophrenia. It was reported that the GABA synthesizing enzymes were downregulated whereas α6GABAARs were upregulated in postmortem cerebellar tissues of patients with schizophrenia and in a rat model induced by chronic phencyclidine (PCP). We have previously demonstrated that pyrazoloquinolinone Compound 6, an α6GABAAR-highly selective positive allosteric modulator (PAM), can rescue the disrupted prepulse inhibition (PPI) induced by methamphetamine (METH), an animal model mimicking the sensorimotor gating deficit based on the hyper-dopaminergic hypothesis of schizophrenia. Here, we demonstrate that not only Compound 6, but also its structural analogues, LAU463 and LAU159, with similarly high α6GABAAR selectivity and their respective deuterated derivatives (DK-I-56-1, DK-I-58-1 and DK-I-59-1) can rescue METH-induced PPI disruption. Besides, Compound 6 and DK-I-56-I can also rescue the PPI disruption induced by acute administration of PCP, an animal model based on the hypo-glutamatergic hypothesis of schizophrenia. Importantly, Compound 6 and DK-I-56-I, at doses not affecting spontaneous locomotor activity, can also rescue impairments of social interaction and novel object recognition in mice induced by chronic PCP treatments. At similar doses, Compound 6 did not induce sedation but significantly suppressed METH-induced hyperlocomotion. Thus, α6GABAAR-selective PAMs can rescue not only disrupted PPI but also hyperlocomotion, social withdrawal, and cognitive impairment, in both METH- and PCP-induced animal models mimicking schizophrenia, suggesting that they are a potential novel therapy for the three core symptoms, i.e. positive symptoms, negative symptoms, and cognitive impairment, of schizophrenia.


Assuntos
Metanfetamina , Esquizofrenia , Animais , Modelos Animais de Doenças , Humanos , Metanfetamina/efeitos adversos , Camundongos , Fenciclidina/efeitos adversos , Ratos , Receptores de GABA-A , Esquizofrenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Ácido gama-Aminobutírico/uso terapêutico
18.
Int J Legal Med ; 136(5): 1297-1301, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35359189

RESUMO

Over the past few years, the new psychoactive substances' phenomenon has been continuously studied. Its dynamic context is characterized by a broad diversity of substances, including several groups, such as synthetic cathinones, synthetic opiates, and synthetic cannabinoids. However, and due both to this diversity and to the low number of detected cases, information on intoxication reports is always important, in order to understand their biological mechanisms. In this case, a male individual was found unresponsive, with some different powders and paraphernalia near him. After toxicological analysis to the powders, paraphernalia, and whole blood samples, five different compounds were identified. From these, two of them (3-MeO-PCP and o-desmethyltramadol) were identified and quantitated in the whole blood sample. The obtained results suggested that death was due to the presence and action of these two substances, in what may be considered an unusual mix of NPS. This case highlights the value of evaluating all the traces found in the scene investigation and the need of sending all the paraphernalia found for toxicological examination, together with all the possible information obtained on the scene, namely by relatives or witnesses. On the other hand, this case shows the significance of broad-spectrum analytical methods, in order to detect and identify, as specifically as possible, eventual substances present and used by victims.


Assuntos
Fenciclidina , Tramadol , Humanos , Masculino , Fenciclidina/análogos & derivados , Fenciclidina/análise , Psicotrópicos/análise , Tramadol/análogos & derivados
19.
J Anal Toxicol ; 46(5): 461-470, 2022 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-35246686

RESUMO

The phencyclidine derivative 3-methoxyphencyclidine (3-MeO-PCP) is a potent dissociative hallucinogen. Sought for recreational use as a novel psychoactive substance, it can also induce acute psychological agitation and pathophysiological cardiorespiratory effects. Due to the harms associated with its use, 3-MeO-PCP was added to the "Green List" of materials covered by the 1971 Convention on Psychotropic Substances as a Schedule II substance by the United Nations Commission on Narcotic Drugs in April 2021. There have been 15 previous reports of fatal intoxications following 3-MeO-PCP use, but only one was attributable to 3-MeO-PCP intoxication alone. In this report, we detail the first fatality due to 3-MeO-PCP intoxication to be reported in the UK, along with a review of the surrounding literature. While the blood concentrations associated with 3-MeO-PCP toxicity and fatality remain unclear, by providing details of sample collection and storage conditions, this case will aid in future interpretations. Furthermore, this case suggests that 3-MeO-PCP toxicity may be exacerbated by exercise. Users of 3-MeO-PCP should be cautioned against its use as a "club drug" or in a similar setting where elevations in heart rate, body temperature and blood pressure may occur.


Assuntos
Alucinógenos , Fenciclidina , Cromatografia Líquida , Alucinógenos/toxicidade , Fenciclidina/análogos & derivados , Reino Unido
20.
J Integr Neurosci ; 21(1): 17, 2022 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-35164453

RESUMO

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.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Acatisia Induzida por Medicamentos/prevenção & controle , Anfetamina/farmacologia , Comportamento Animal/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Antagonistas de Dopamina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Fenciclidina/farmacologia , Psicoses Induzidas por Substâncias/prevenção & controle , Antagonistas da Serotonina/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 1/administração & dosagem , Acatisia Induzida por Medicamentos/etiologia , Anfetamina/administração & dosagem , Animais , Estimulantes do Sistema Nervoso Central/administração & dosagem , Modelos Animais de Doenças , Antagonistas de Dopamina/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Masculino , Fenciclidina/administração & dosagem , Psicoses Induzidas por Substâncias/etiologia , Ratos , Ratos Sprague-Dawley , Antagonistas da Serotonina/administração & dosagem
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