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1.
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
2.
Neuropharmacology ; 208: 108982, 2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-35151699

RESUMO

In schizophrenia, mGlu5 receptor hypofunction has been linked with neuropathology and cognitive deficits, making it an attractive therapeutic target. The cognitive impairment associated with schizophrenia remains an unmet clinical need, with existing antipsychotics primarily targeting positive symptoms, with weaker and more variable effects on cognitive deficits. Using the sub-chronic phencyclidine rat model, widely shown to mimic the cognitive impairment and neuropathology of schizophrenia, we have investigated two mGlu5 receptor positive allosteric modulators (PAMs), VU0409551 and VU0360172. We compared the efficacy of these compounds in restoring cognitive deficits and, since these two PAMs have reportedly distinct signalling mechanisms, changes in mGlu5 receptor signalling molecules AKT and MAPK in the PFC. Although not effective at 0.05 and 1 mg/kg, cognitive deficits were significantly alleviated by both PAMs at 10 and 20 mg/kg. The compounds appeared to have differential effects on the scPCP-induced increases in AKT and MAPK phosphorylation: VU0409551 induced a significant decrease in expression of p-AKT, whereas VU0360172 had this effect on p-MAPK levels. Thus, the beneficial effects of PAMs on scPCP-induced cognitive impairment are accompanied by at least partial reversal of scPCP-induced elevated levels of p-MAPK and p-AKT, whose dysfunction is strongly implicated in schizophrenia pathology. These promising data imply an important role for mGlu5 receptor signalling pathways in improving cognition in the scPCP model and provide support for mGlu5 receptor PAMs as a possible therapeutic intervention for schizophrenia.


Assuntos
Receptor de Glutamato Metabotrópico 5 , Esquizofrenia , Regulação Alostérica , Animais , Cognição , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Oxazóis , Fenciclidina/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piridinas , Ratos , Receptor de Glutamato Metabotrópico 5/metabolismo , Esquizofrenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo
3.
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
4.
J Psychopharmacol ; 36(2): 238-244, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35102781

RESUMO

BACKGROUND: N-methyl-d-aspartate receptor (NMDAR) dysfunction is implicated in schizophrenia, and NMDAR antagonists, such as phencyclidine (PCP), can induce behaviours that mimic aspects of the disorder. AIMS: We investigated DNA methylation of Grin1, Grin2a and Grin2b promoter region and NR1 and NR2 protein expression in the prefrontal cortex (PFC) and hippocampus of adult female Lister-hooded rats following subchronic PCP (scPCP) administration. We also determined whether any alterations were tissue-specific. METHODS: Rats were divided into two groups that received vehicle (0.9% saline) or 2 mg/kg PCP twice a day for 7 days (n = 10 per group). After behavioural testing (novel object recognition), to confirm a cognitive deficit, brains were dissected and NMDAR subunit DNA methylation and protein expression were analysed by pyrosequencing and ELISA. Line-1 methylation was determined as a measure of global methylation. Data were analysed using Student's t-test and Pearson correlation. RESULTS: The scPCP administration led to Grin1 and Grin2b hypermethylation and reduction in NR1 protein in both PFC and hippocampus. No significant differences were observed in Line-1 or Grin2a methylation and NR2 protein. CONCLUSIONS: The scPCP treatment resulted in increased DNA methylation at promoter sites of Grin1 and Grin2b NMDAR subunits in two brain areas implicated in schizophrenia, independent of any global change in DNA methylation, and are similar to our observations in a neurodevelopmental animal model of schizophrenia - social isolation rearing post-weaning. Moreover, these alterations may contribute to the changes in protein expression for NMDAR subunits demonstrating the potential importance of epigenetic mechanisms in schizophrenia.


Assuntos
Metilação de DNA/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Fenciclidina/farmacologia , Receptores de N-Metil-D-Aspartato/genética , Animais , Comportamento Animal/efeitos dos fármacos , Disfunção Cognitiva/genética , Disfunção Cognitiva/fisiopatologia , Modelos Animais de Doenças , Epigênese Genética , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Fenciclidina/administração & dosagem , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos
5.
Genes Brain Behav ; 21(4): e12797, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35075790

RESUMO

Genetic studies implicate disruption to the DLG2 gene in copy number variants as increasing risk for schizophrenia, autism spectrum disorders and intellectual disability. To investigate psychiatric endophenotypes associated with DLG2 haploinsufficiency (and concomitant PSD-93 protein reduction) a novel clinically relevant Dlg2+/- rat was assessed for abnormalities in anxiety, sensorimotor gating, hedonic reactions, social behaviour, and locomotor response to the N-Methyl-D-aspartic acid receptor antagonist phencyclidine. Dlg gene and protein expression were also investigated to assess model validity. Reductions in PSD-93 messenger RNA and protein were observed in the absence of compensation by other related genes or proteins. Behaviourally Dlg2+/- rats show a potentiated locomotor response to phencyclidine, as is typical of psychotic disorder models, in the absence of deficits in the other behavioural phenotypes assessed here. This shows that the behavioural effects of Dlg2 haploinsufficiency may specifically relate to psychosis vulnerability but are subtle, and partially dissimilar to behavioural deficits previously reported in Dlg2+/- mouse models demonstrating issues surrounding the comparison of models with different aetiology and species. Intact performance on many of the behavioural domains assessed here, such as anxiety and reward processing, will remove these as confounds when continuing investigation into this model using more complex cognitive tasks.


Assuntos
Guanilato Quinases , Haploinsuficiência , Esquizofrenia , Proteínas Supressoras de Tumor , Animais , Modelos Animais de Doenças , Guanilato Quinases/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas de Membrana , Camundongos , Fenciclidina/farmacologia , Ratos , Esquizofrenia/genética , Esquizofrenia/metabolismo , Comportamento Social , Proteínas Supressoras de Tumor/genética
6.
Neuropharmacology ; 205: 108896, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-34822815

RESUMO

There is compelling evidence that neonatal blockade of NMDA receptors by phencyclidine (PCP) is associated with cognitive impairment in adulthood but little is known about the effects of early life PCP treatment on synaptic function later in life. Here, we sought to determine whether early life exposure to PCP alters the electrophysiologic function of hippocampal CA1 neurons in adult rats. To this end, male and female Wistar rats received either saline or PCP (10 mg/kg) on postnatal days (PND) 7, 9, and 11, and then underwent separate behavioral and electrophysiology tests in adulthood. Neonatal PCP treatment did not alter basic synaptic transmission and had only a modest effect on frequency following (FF) capacity but significantly decreased the paired-pulse facilitation (PPF) in the Schaffer collateral (SC)-CA1 pathway. We found that PCP treatment significantly attenuated the long-term potentiation (LTP) and long-term depression (LTD) in CA1 neurons accompanied by pronounced alteration in complex response profile in adult rats. The electrophysiology data were comparable in male and female rats and reliably associated with impaired spatial reference and working memories in these animals. Overall, this study suggests that blockade of NMDA receptors during early life deteriorates the short-term and long-term synaptic plasticity and complex response profile of CA1 neurons in adulthood.


Assuntos
Região CA1 Hipocampal/efeitos dos fármacos , Disfunção Cognitiva/induzido quimicamente , Antagonistas de Aminoácidos Excitatórios/farmacologia , Aprendizagem/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Fenciclidina/farmacologia , Fatores Etários , Animais , Animais Recém-Nascidos , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Hipocampo/efeitos dos fármacos , Masculino , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Wistar
7.
PLoS One ; 16(9): e0257986, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34587208

RESUMO

The first symptoms of schizophrenia (SCHZ) are usually observed during adolescence, a developmental period during which first exposure to psychoactive drugs also occurs. These epidemiological findings point to adolescence as critical for nicotine addiction and SCHZ comorbidity, however it is not clear whether exposure to nicotine during this period has a detrimental impact on the development of SCHZ symptoms since there is a lack of studies that investigate the interactions between these conditions during this period of development. To elucidate the impact of a short course of nicotine exposure across the spectrum of SCHZ-like symptoms, we used a phencyclidine-induced adolescent mice model of SCHZ (2.5mg/Kg, s.c., daily, postnatal day (PN) 38-PN52; 10mg/Kg on PN53), combined with an established model of nicotine minipump infusions (24mg/Kg/day, PN37-44). Behavioral assessment began 4 days after the end of nicotine exposure (PN48) using the following tests: open field to assess the hyperlocomotion phenotype; novel object recognition, a declarative memory task; three-chamber sociability, to verify social interaction and prepulse inhibition, a measure of sensorimotor gating. Phencyclidine exposure evoked deficits in all analyzed behaviors. Nicotine history reduced the magnitude of phencyclidine-evoked hyperlocomotion and impeded the development of locomotor sensitization. It also mitigated the deficient sociability elicited by phencyclidine. In contrast, memory and sensorimotor gating deficits evoked by phencyclidine were neither improved nor worsened by nicotine history. In conclusion, our results show for the first time that nicotine history, restricted to a short period during adolescence, does not worsen SCHZ-like symptoms evoked by a phencyclidine-induced mice model.


Assuntos
Comportamento Animal/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Nicotina/farmacologia , Reconhecimento Psicológico/efeitos dos fármacos , Esquizofrenia/tratamento farmacológico , Filtro Sensorial/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Feminino , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Nicotina/uso terapêutico , Fenciclidina , Esquizofrenia/induzido quimicamente
8.
J Pharmacol Sci ; 147(1): 9-17, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34294378

RESUMO

Schizophrenia is one of the foremost psychological illness around the world, and recent evidence shows that inflammation and oxidative stress may play a critical role in the etiology of schizophrenia. Andrographolide is a diterpenoid lactone from Andrographis paniculate, which has shown anti-inflammation and anti-oxidative effects. In this study, we explored whether andrographolide can improve schizophrenia-like behaviors through its inhibition of inflammation and oxidative stress in Phencyclidine (PCP)-induced mouse model of schizophrenia. We found that abnormal behavioral including locomotor activity, forced swimming and novel object recognition were ameliorated following andrographolide administration (5 mg/kg and 10 mg/kg). Andrographolide inhibited PCP-induced production of inflammatory cytokines, decreased p-p65, p-IκBα, p-p38 and p-ERK1/2 in the prefrontal cortex. Andrographolide significantly declined the level of MDA and GSH, as well as elevated the activity of SOD, CAT and GCH-px. In addition, andrographolide increased expression of NRF-2, HO-1 and NQO-1, promoted nuclear translocation of NRF-2 through blocking the interaction between NRF-2 and KEAP1, which may be associated with directly binding to NRF-2. Furthermore, antioxidative effects and anti-schizophrenia-like behaviors of andrographolide were compromised by the application of NRF-2 inhibitor ML385. In conclusion, these results suggested that andrographolide improved oxidative stress and schizophrenia-like behaviors induced by PCP through increasing NRF-2 pathway.


Assuntos
Diterpenos/administração & dosagem , Diterpenos/farmacologia , Epistasia Genética/efeitos dos fármacos , Epistasia Genética/genética , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Fenciclidina/efeitos adversos , Fitoterapia , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , /química , Animais , Anti-Inflamatórios , Antioxidantes , Modelos Animais de Doenças , Diterpenos/isolamento & purificação , Inflamação , Masculino , Camundongos Endogâmicos ICR , Estresse Oxidativo/efeitos dos fármacos , Esquizofrenia/induzido quimicamente , Esquizofrenia/etiologia
9.
Int J Mol Sci ; 22(14)2021 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-34299276

RESUMO

1-cyclohexyl-x-methoxybenzene is a novel psychoactive substance (NPS), first discovered in Europe in 2012 as unknown racemic mixture of its three stereoisomers: ortho, meta and para. Each of these has structural similarities with the analgesic tramadol and the dissociative anesthetic phencyclidine. In light of these structural analogies, and based on the fact that both tramadol and phencyclidine are substances that cause toxic effects in humans, the aim of this study was to investigate the in vitro and in vivo pharmacodynamic profile of these molecules, and to compare them with those caused by tramadol and phencyclidine. In vitro studies demonstrated that tramadol, ortho, meta and para were inactive at mu, kappa and delta opioid receptors. Systemic administration of the three stereoisomers impairs sensorimotor responses, modulates spontaneous motor activity, induces modest analgesia, and alters thermoregulation and cardiorespiratory responses in the mouse in some cases, with a similar profile to that of tramadol and phencyclidine. Naloxone partially prevents only the visual sensorimotor impairments caused by three stereoisomers, without preventing other effects. The present data show that 1-cyclohexyl-x-methoxybenzene derivatives cause pharmaco-toxicological effects by activating both opioid and non-opioid mechanisms and suggest that their use could potentially lead to abuse and bodily harm.


Assuntos
Analgésicos Opioides/toxicidade , Anisóis/toxicidade , Derivados de Benzeno/toxicidade , Alucinógenos/toxicidade , Fenciclidina/toxicidade , Psicotrópicos/toxicidade , Receptores Opioides/metabolismo , Tramadol/toxicidade , Analgésicos Opioides/química , Animais , Anisóis/química , Derivados de Benzeno/química , Células Cultivadas , Cricetinae , Alucinógenos/química , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos ICR , Modelos Animais , Fenciclidina/química , Psicotrópicos/química , Tramadol/química
10.
J Chem Neuroanat ; 116: 101993, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34147620

RESUMO

OBJECTIVE: We studied the role of the P2X7 receptor on cognitive dysfunction in a mouse model of schizophrenia. METHODS: An adult mouse model was established by treatment with phencyclidine (PCP), an N-methyl-D-aspartate (NMDA) receptor antagonist. Young mice were divided into three groups: 1) the control (saline-injected) group; 2) experimental 5 mg/kg PCP-injected group; and 3) experimental 10 mg/kg PCP-injected group. The mice were subjected to the open-field and Morris water maze tests at 7 weeks. After intraperitoneal injection of the P2X7 receptor antagonist JNJ-47965567, the behaviour tests were performed again. Samples were taken after testing. The P2X7 receptor protein and mRNA expression levels were detected by immunohistochemistry, Western blotting and PCR. RESULTS: This study revealed that the infant sub-chronic PCP mice model showed severe spatial learning and memory impairment in the Morris water maze and schizophrenia-like symptoms (hypermotor behaviour) in the open-field test. The P2X7 receptor protein was highly expressed in the sub-chronic PCP mouse model and more highly expressed in the hippocampus than the prefrontal lobe. After the P2X7 receptor was blocked with JNJ-47965567, P2X7 receptor protein and mRNA expression in the frontal lobe were significantly increased, and the spatial memory impairment and hypermotor behaviour induced by PCP were reversed. CONCLUSION: PCP-induced cognitive impairment can be significantly improved by antagonizing the P2X7 receptor. Therefore, we believe that the P2X7 receptor plays an important role in the cognition of schizophrenic-like mice.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Fenciclidina/toxicidade , Antagonistas do Receptor Purinérgico P2X/administração & dosagem , Receptores Purinérgicos P2X7/metabolismo , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo , Animais , Animais Recém-Nascidos , Alucinógenos/toxicidade , Injeções Subcutâneas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Niacinamida/administração & dosagem , Niacinamida/análogos & derivados , Piperazinas/administração & dosagem , Roedores , Esquizofrenia/induzido quimicamente
11.
J Psychopharmacol ; 35(6): 730-743, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34008450

RESUMO

BACKGROUND: Cognitive deficits profoundly impact on the quality of life of patients with schizophrenia. Alterations in brain derived neurotrophic factor (BDNF) signalling, which regulates synaptic function through the activation of full-length tropomyosin-related kinase B receptors (TrkB-FL), are implicated in the aetiology of schizophrenia, as is N-methyl-D-aspartate receptor (NMDA-R) hypofunction. However, whether NMDA-R hypofunction contributes to the disrupted BDNF signalling seen in patients remains unknown. AIMS: The purpose of this study was to characterise BDNF signalling and function in a preclinical rodent model relevant to schizophrenia induced by prolonged NMDA-R hypofunction. METHODS: Using the subchronic phencyclidine (PCP) model, we performed electrophysiology approaches, molecular characterisation and behavioural analysis. RESULTS: The data showed that prolonged NMDA-R antagonism, induced by subchronic PCP treatment, impairs long-term potentiation (LTP) and the facilitatory effect of BDNF upon LTP in the medial prefrontal cortex (PFC) of adult mice. Additionally, TrkB-FL receptor expression is decreased in the PFC of these animals. By contrast, these changes were not present in the hippocampus of PCP-treated mice. Moreover, BDNF levels were not altered in the hippocampus or PFC of PCP-treated mice. Interestingly, these observations are paralleled by impaired performance in PFC-dependent cognitive tests in mice treated with PCP. CONCLUSIONS: Overall, these data suggest that NMDA-R hypofunction induces dysfunctional BDNF signalling in the PFC, but not in the hippocampus, which may contribute to the PFC-dependent cognitive deficits seen in the subchronic PCP model. Additionally, these data suggest that targeting BDNF signalling may be a mechanism to improve PFC-dependent cognitive dysfunction in schizophrenia.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Transtornos Cognitivos/fisiopatologia , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/fisiopatologia , Animais , Cognição/fisiologia , Modelos Animais de Doenças , Hipocampo/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Testes Neuropsicológicos , Fenciclidina , Córtex Pré-Frontal/patologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Transdução de Sinais/fisiologia
12.
J Neurosci Res ; 99(7): 1885-1901, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33848365

RESUMO

Dopamine signaling in nucleus accumbens (NAc) is modulated by γ-aminobutyric acid (GABA), acting through GABA-A and GABA-B receptors: dysregulation of GABAergic control of dopamine function may be important in behavioral deficits in schizophrenia. We investigated the effect of GABA-A (muscimol) and GABA-B (baclofen) receptor agonists on electrically stimulated dopamine release. Furthermore, we explored whether drug-induced changes were disrupted by pretreatment with phencyclidine, which provides a well-validated model of schizophrenia. Using brain slices from female rats, fast-scan cyclic voltammetry was used to measure electrically stimulated dopamine release in NAc shell. Both muscimol and baclofen caused concentration-dependent attenuation of evoked dopamine release: neither effect was changed by dihydro-ß-erythroidine, a nicotinic acetylcholine receptor antagonist, or the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), precluding indirect mechanisms using these transmitter systems in the GABAergic actions. In slices taken from rats pretreated with phencyclidine, the attenuation of evoked dopamine release by baclofen was abolished, but the attenuation by muscimol was unaffected. Since phencyclidine pretreatment was followed by drug-free washout period of at least a week, the drug was not present during recording. Therefore, disruption of GABA-B modulation of dopamine is due to long-term functional changes resulting from the treatment, rather than transient changes due to the drug's presence at test. This enduring dysregulation of GABA-B modulation of accumbal dopamine release provides a plausible mechanism through which GABA dysfunction influences accumbal dopamine leading to behavioral changes seen in schizophrenia and may provide a route for novel therapeutic strategies to treat the condition.


Assuntos
Dopamina/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Esquizofrenia/metabolismo , Ácido gama-Aminobutírico/metabolismo , Animais , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Agonistas GABAérgicos/farmacologia , Fenciclidina/farmacologia , Ratos , Ratos Wistar
13.
Behav Brain Res ; 409: 113308, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-33872663

RESUMO

Improved understanding of the neurophysiological and neurochemical mechanisms underlying schizophrenia is essential for the identification of biological markers and developing new therapeutic targets. The development of behaviorally faithful, predictive animal models is crucial to this endeavor. We have developed a novel two-hit paradigm designed to recapitulate in rodents the developmental process leading to appearance of human schizophrenia symptomatology. The model pairs neonatal administration of the NMDA receptor (NMDAR) open-channel blocker phencyclidine (PCP 10 mg/kg) to male rats at 7, 9 and 11 days of age, with later adolescent exposure (34 days of age) to a single prolonged stress paradigm consisting of 2 h restraint, followed by 20 min of forced swimming. Four experimental groups were examined: vehicle and no stress (VEH-NS), vehicle plus stress (VEH-S), PCP and no stress (PCP-NS), and PCP plus stress (PCP-S). Only pairing of neonatal PCP with single prolonged adolescent stress caused deficits in novel object recognition memory and increased anxiety-like behavior in the elevated plus maze task, without altering locomotor activity. In a separate cohort of animals, the PCP-S group showed significant reduction in magnitude of hippocampal long-term potentiation (LTP) at Schaffer collateral-CA1 synapses following a single pair of theta-burst stimuli (TBS), while LTP was diminished in both PCP treated groups when elicited by a second pair of TBS. These results suggest that the combination of neonatal PCP and acute adolescent stress are necessary for lasting cognitive impairment and anxiety-like phenotype, and that these behavioral impairments may be due to deficits in LTP in hippocampus, and perhaps elsewhere in the brain.


Assuntos
Comportamento Animal/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Fenciclidina/farmacologia , Esquizofrenia/etiologia , Esquizofrenia/fisiopatologia , Estresse Psicológico/complicações , Fatores Etários , Animais , Animais Recém-Nascidos , Comportamento Animal/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Masculino , Fenciclidina/administração & dosagem , Ratos , Ratos Sprague-Dawley , Esquizofrenia/induzido quimicamente
14.
Behav Brain Res ; 408: 113284, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-33819533

RESUMO

Habitual smoking in patients with schizophrenia (SCZ) is considered to improve their own psychoses or to develop a vulnerability to psychological dependence on (-)-nicotine ([-]-NIC) by stimulating nicotinic acetylcholine receptors (nAChRs) in the central nervous system. In the present study, we investigated whether habitual smoking is due to get therapeutic effect or to psychological dependence and which nAChR subunits are associated with them using mice that were repeatedly administered phencyclidine (PCP: 10 mg/kg/day, s.c. for 14 days) as SCZ-like model mice. Mice that were repeatedly administered PCP showed impairments in social or cognitive behaviors; decreased expression of α7 and/or α4 nAChR subunits in the prefrontal cortex (PFC); and increased expression of α7, α4, and ß2 nAChR subunits in the nucleus accumbens (NAc). These changes were attenuated by repeated administration of (-)-NIC. The attenuating effects on behavioral impairments were prevented by a selective α7 nAChR antagonist and a selective α4ß2 nAChR antagonist. At non- or weak effective dose by themselves, co-administration of (-)-NIC (0.03 mg/kg) and risperidone (0.03 mg/kg) showed synergistic effects on behavioral impairments in PCP-administered mice. Repeated (-)-NIC administration did not affect the performance of conditioned place preference, while it showed behavioral sensitization to (-)-NIC in the PCP-administered mice. Repeated (-)-NIC administration did not affect the performance of conditioned place preference, while it showed behavioral sensitization to (-)-NIC and attenuating effect on haloperidol-induced catalepsy in the PCP-administered mice. Our findings suggest that habitual smoking in SCZ might be attributed to get therapeutic and reduce side effects mediated by α7 and α4ß2 nAChR activation by (-)-NIC.


Assuntos
Comportamento Animal/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Núcleo Accumbens , Fenciclidina/farmacologia , Córtex Pré-Frontal , Receptores Nicotínicos , Comportamento Social , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Receptores Nicotínicos/efeitos dos fármacos , Receptores Nicotínicos/metabolismo , Esquizofrenia/metabolismo , Fumar/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/efeitos dos fármacos , Receptor Nicotínico de Acetilcolina alfa7/metabolismo
15.
Sci Adv ; 7(14)2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33789887

RESUMO

Cognitive impairment in schizophrenia (CIAS) is the most critical predictor of functional outcome. Limited understanding of the cellular mechanisms of CIAS hampers development of more effective treatments. We found that in subchronic phencyclidine (scPCP)-treated mice, an animal model that mimics CIAS, the reversal potential of GABAA currents in pyramidal neurons of the infralimbic prefrontal cortex (ILC) shifts from hyperpolarizing to depolarizing, the result of increased expression of the chloride transporter NKCC1. Further, we found that in scPCP mice, the NKCC1 antagonist bumetanide normalizes GABAA current polarity ex vivo and improves performance in multiple cognitive tasks in vivo. This behavioral effect was mimicked by selective, bilateral, NKCC1 knockdown in the ILC. Thus, we show that depolarizing GABAA currents in the ILC contributes to cognitive impairments in scPCP mice and suggest that bumetanide, an FDA-approved drug, has potential to treat or prevent CIAS and other components of the schizophrenia syndrome.


Assuntos
Disfunção Cognitiva , Esquizofrenia , Animais , Bumetanida/farmacologia , Bumetanida/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Modelos Animais de Doenças , Camundongos , Fenciclidina/farmacologia , Fenciclidina/uso terapêutico , Córtex Pré-Frontal/metabolismo , Esquizofrenia/tratamento farmacológico , Ácido gama-Aminobutírico
16.
Pharmacol Biochem Behav ; 203: 173129, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33515586

RESUMO

Adolescence is a period of profound developmental changes, which run the gamut from behavioral and neural to physiological and hormonal. It is also a time at which there is an increased propensity to engage in risk-taking and impulsive behaviors like drug use. This review examines the human and preclinical literature on adolescent drug use and its consequences, with a focus on dissociatives (PCP, ketamine, DXM), classic psychedelics (LSD, psilocybin), and MDMA. It is the case for all the substances reviewed here that very little is known about their effects in adolescent populations. An emerging aspect of the literature is that dissociatives and MDMA produce mixed reinforcing and aversive effects and that the balance between reinforcement and aversion may differ between adolescents and adults, with consequences for drug use and addiction. However, many studies have failed to directly compare adults and adolescents, which precludes definitive conclusions about these consequences. Other important areas that are largely unexplored are sex differences during adolescence and the long-term consequences of adolescent use of these substances. We provide suggestions for future work to address the gaps we identified in the literature. Given the widespread use of these drugs among adolescent users, and the potential for therapeutic use, this work will be crucial to understanding abuse potential and consequences of use in this developmental stage.


Assuntos
Dextrometorfano/administração & dosagem , Alucinógenos/administração & dosagem , Ketamina/administração & dosagem , Dietilamida do Ácido Lisérgico/administração & dosagem , N-Metil-3,4-Metilenodioxianfetamina/administração & dosagem , Fenciclidina/administração & dosagem , Psilocibina/administração & dosagem , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/psicologia , Adolescente , Adulto , Fatores Etários , Animais , Feminino , Humanos , Masculino , Assunção de Riscos
17.
Neuropharmacology ; 186: 108454, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33444639

RESUMO

Positive modulation of cAMP signalling by phosphodiesterase (PDE) inhibitors has recently been explored as a potential target for the reversal of cognitive and behavioural deficits implicating the corticoaccumbal circuit. Previous studies show that PDE type 1 isoform B (PDE1B) inhibition may improve memory function in rodent models; however, the contribution of PDE1B inhibition to impulsivity, attentional and motivational functions as well as its neurophysiological effects have not been investigated. To address this, we recorded single unit activity in medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) in Lister Hooded rats treated with the PDE1B inhibitor Lu AF64386 and tested in the 5-choice serial reaction time task (5-CSRTT). We also asked whether PDE1B inhibition modulates neurophysiological deficits produced by subchronic phencyclidine (PCP) treatment, a rat pharmacological model of schizophrenia. Lu AF64386 significantly affected behavioural parameters consistent with a reduction in goal-directed behaviour, however without affecting accuracy. Additionally, it reduced mPFC neuronal activity. Pre-treatment with PCP did not affect behavioural parameters, however it significantly disrupted overall neuronal firing while increasing phasic responses to reward-predicting cues and disrupting mPFC-NAc cross-talk. The latter two effects were reversed by Lu AF64386. These findings suggest PDE1B inhibition may be beneficial in disorders implicating a dysfunction of the mPFC-NAc network.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/antagonistas & inibidores , Objetivos , Fenciclidina/toxicidade , Inibidores de Fosfodiesterase/uso terapêutico , Córtex Pré-Frontal/enzimologia , Esquizofrenia/enzimologia , Animais , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/metabolismo , Modelos Animais de Doenças , Feminino , Alucinógenos/toxicidade , Inibidores de Fosfodiesterase/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiopatologia , Ratos , Esquizofrenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico
18.
Biochem Biophys Res Commun ; 534: 610-616, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33228965

RESUMO

Schizophrenia is probably ascribed to perinatal neurodevelopmental deficits, and its onset might be affected by environmental factors. Hypofrontality with glutamatergic and dopaminergic neuronal dysfunction are known factors, but a way to mitigate abnormalities remains unfound. An early enriched environment such as a wheel running in rodents may contribute to the prevention, but its clinical applicability is very limited. From our studies, low-intensity exercise training (LET) based on physiological indices, such as lactate threshold, easily translates to humans and positively affects the brains. Hence, LET during adolescence may ameliorate abnormalities in neurodevelopment and prevent the development of schizophrenia. In the current study, LET prevented sensitization to phencyclidine (PCP) treatment, impairment of cognition, and affective behavioral abnormalities in an animal model of schizophrenia induced by prenatal PCP treatment. Further, LET increased dopamine turnover and attenuated the impairment of phosphorylation of ERK1/2 after exposure to a novel object in the prenatal PCP-treated mice. These results suggest that LET during adolescence completely improves schizophrenia-like abnormal behaviors associated with improved glutamate uptake and the dopamine-induced ERK1/2 signaling pathway in the PFC.


Assuntos
Condicionamento Físico Animal/métodos , Esquizofrenia/prevenção & controle , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Fatores Etários , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Dopamina/metabolismo , Antagonistas de Aminoácidos Excitatórios/toxicidade , Feminino , Ácido Homovanílico/metabolismo , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos Endogâmicos ICR , Fenciclidina/toxicidade , Fosforilação , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/psicologia , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/induzido quimicamente , Esquizofrenia/fisiopatologia , Psicologia do Esquizofrênico
19.
Psychopharmacology (Berl) ; 238(2): 517-528, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33169202

RESUMO

RATIONALE: There is a need to develop animal models of schizophrenia-like behaviors that have both construct and predictive validity. Recently, a neonatal phencyclidine (PCP) and post-weaning social isolation dual-hit model was developed; however, its face and predictive validities need to be further investigated. OBJECTIVE: The aims of this study were to extend the characterization of the behavioral changes occurring in the neonatal PCP and post-weaning social isolation dual-hit rat model and to evaluate the effects of chronic treatment with clozapine on signs related to schizophrenia. METHODS: Male Wistar rat pups were treated with PCP (10 mg/kg s.c.) on postnatal days (PND) 7, 9, and 11. Starting from weaning, neonatal PCP-treated rat pups were socially isolated, while control saline-treated rats were group housed. At adulthood, rats were assessed using behavioral tasks evaluating locomotor activity, social recognition, prepulse inhibition, and reversal learning. Clozapine (3 mg/kg i.p.) was administered daily starting from a week before behavioral tests and until the end of the study. RESULTS: Neonatal PCP-treated and post-weaning social isolated (PCP-SI) rats displayed persistent and robust locomotor hyperactivity as well as social recognition impairment. The latter could not be explained by variations in the motivation to interact with a juvenile rat. Weak-to-moderate deficits in prepulse inhibition and reversal learning were also observed. Chronic treatment with clozapine attenuated the observed locomotor hyperactivity and social recognition deficits. CONCLUSION: The PCP-SI model presents enduring and robust deficits (hyperactivity and social recognition impairment) associated with positive symptoms and cognitive/social deficits of schizophrenia, respectively. These deficits are normalized by chronic treatment with clozapine, thereby confirming the predictive validity of this animal model.


Assuntos
Antipsicóticos/farmacologia , Clozapina/farmacologia , Função Executiva/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Fenciclidina/toxicidade , Inibição Pré-Pulso/efeitos dos fármacos , Reconhecimento Psicológico/efeitos dos fármacos , Isolamento Social/psicologia , Animais , Animais Recém-Nascidos , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Ratos , Ratos Wistar , Reversão de Aprendizagem/efeitos dos fármacos , Esquizofrenia , Psicologia do Esquizofrênico
20.
Chemistry ; 27(9): 3098-3105, 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33206421

RESUMO

We report investigations of the use of cucurbit[8]uril (CB[8]) macrocycles as an antidote to counteract the in vivo biological effects of phencyclidine. We investigate the binding of CB[8] and its derivative Me4 CB[8] toward ten drugs of abuse (3-9, 12-14) by a combination of 1 H NMR spectroscopy and isothermal titration calorimetry in phosphate buffered water. We find that the cavity of CB[8] and Me4 CB[8] are able to encapsulate the 1-amino-1-aryl-cyclohexane ring system of phencyclidine (PCP) and ketamine as well as the morphinan skeleton of morphine and hydromorphone with Kd values ≤50 nm. In vitro cytotoxicity (MTS metabolic and adenylate kinase cell death assays in HEK293 and HEPG2 cells) and in vivo maximum tolerated dose studies (Swiss Webster mice) which were performed for Me4 CB[8] indicated good tolerability. The tightest host⋅guest pair (Me4 CB[8]⋅PCP; Kd =2 nm) was advanced to in vivo efficacy studies. The results of open field tests demonstrate that pretreatment of mice with Me4 CB[8] prevents subsequent hyperlocomotion induction by PCP and also that treatment of animals previously dosed with PCP with Me4 CB[8] significantly reduces the locomotion levels.


Assuntos
Hidrocarbonetos Aromáticos com Pontes/química , Imidazóis/química , Fenciclidina/análise , Fenciclidina/química , Animais , Hidrocarbonetos Aromáticos com Pontes/administração & dosagem , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Células HEK293 , Células Hep G2 , Humanos , Imidazóis/administração & dosagem , Imidazóis/farmacologia , Locomoção/efeitos dos fármacos , Camundongos , Fenciclidina/administração & dosagem , Fenciclidina/farmacologia
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