RESUMO
Numerous findings confirm that the metabotropic glutamate receptors (mGluRs) are involved in the conditioned place preference (CPP) induced by morphine. Here we focused on the role of mGluR5 in the nucleus accumbens (NAc) as a main site of glutamate action on the rewarding effects of morphine. Firstly, we investigated the effects of intra-NAc administrating mGluR5 antagonist 3-((2-Methyl-1,3-thiazol-4-yl) ethynyl) pyridine hydrochloride (MTEP; 1, 3, and 10 µg/µl saline) on the extinction and the reinstatement phase of morphine CPP. Moreover, to determine the downstream signaling cascades of mGluR5 in morphine CPP, the protein levels of stromal interaction molecules (STIM1 and 2) in the NAc and hippocampus (HPC) were measured by western blotting. The behavioral data indicated that the mGluR5 blockade by MTEP at the high doses of 3 and 10 µg facilitated the extinction of morphine-induced CPP and attenuated the reinstatement to morphine in extinguished rats. Molecular results showed that the morphine led to increased levels of STIM proteins in the HPC and increased the level of STIM1 without affecting STIM2 in the NAc. Furthermore, intra-NAc microinjection of MTEP (10 µg) in the reinstatement phase decreased STIM1 in the NAc and HPC and reduced the STIM2 in the HPC. Collectively, our data show that morphine could facilitate brain reward function in part by increasing glutamate-mediated transmission through activation of mGluR5 and modulation of STIM proteins. Therefore, these results highlight the therapeutic potential of mGluR5 antagonists in morphine use disorder.
Assuntos
Extinção Psicológica , Morfina , Núcleo Accumbens , Piridinas , Receptor de Glutamato Metabotrópico 5 , Tiazóis , Animais , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Receptor de Glutamato Metabotrópico 5/metabolismo , Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores , Masculino , Extinção Psicológica/efeitos dos fármacos , Extinção Psicológica/fisiologia , Morfina/farmacologia , Morfina/administração & dosagem , Tiazóis/farmacologia , Tiazóis/administração & dosagem , Ratos , Piridinas/farmacologia , Piridinas/administração & dosagem , Ratos Sprague-Dawley , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Entorpecentes/farmacologia , Entorpecentes/administração & dosagem , Relação Dose-Resposta a DrogaRESUMO
BACKGROUND: The NMDA antagonist S-ketamine is gaining increasing use as a rapid-acting antidepressant, although its exact mechanisms of action are still unknown. In this study, we investigated ketamine in respect to its properties toward central noradrenergic mechanisms and how they influence alertness behavior. METHODS: We investigated the influence of S-ketamine on the locus coeruleus (LC) brain network in a placebo-controlled, cross-over, 7T functional, pharmacological MRI study in 35 healthy male participants (25.1 ± 4.2 years) in conjunction with the attention network task to measure LC-related alertness behavioral changes. RESULTS: We could show that acute disruption of the LC alertness network to the thalamus by ketamine is related to a behavioral alertness reduction. CONCLUSION: The results shed new light on the neural correlates of ketamine beyond the glutamatergic system and underpin a new concept of how it may unfold its antidepressant effects.
Assuntos
Atenção , Estudos Cross-Over , Ketamina , Locus Cerúleo , Imageamento por Ressonância Magnética , Humanos , Ketamina/farmacologia , Ketamina/administração & dosagem , Locus Cerúleo/efeitos dos fármacos , Locus Cerúleo/diagnóstico por imagem , Locus Cerúleo/fisiologia , Masculino , Adulto , Adulto Jovem , Atenção/efeitos dos fármacos , Atenção/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Método Duplo-Cego , Antidepressivos/farmacologia , Antidepressivos/administração & dosagemRESUMO
Neuroimaging studies have identified the anterior cingulate cortex (ACC) as one of the major targets of ketamine in the human brain, which may be related to ketamine's antidepressant (AD) mechanisms of action. However, due to different methodological approaches, different investigated populations, and varying measurement timepoints, results are not consistent, and the functional significance of the observed brain changes remains a matter of open debate. Inhibition of glutamate release during acute ketamine administration by lamotrigine provides the opportunity to gain additional insight into the functional significance of ketamine-induced brain changes. Furthermore, the assessment of trait negative emotionality holds promise to link findings in healthy participants to potential AD mechanisms of ketamine. In this double-blind, placebo-controlled, randomized, single dose, parallel-group study, we collected resting-state fMRI data before, during, and 24 h after ketamine administration in a sample of 75 healthy male and female participants who were randomly allocated to one of three treatment conditions (ketamine, ketamine with lamotrigine pre- treatment, placebo). Spontaneous brain activity was extracted from two ventral and one dorsal subregions of the ACC. Our results showed activity decreases during the administration of ketamine in all three ACC subregions. However, only in the ventral subregions of the ACC this effect was attenuated by lamotrigine. 24 h after administration, ACC activity returned to baseline levels, but group differences were observed between the lamotrigine and the ketamine group. Trait negative emotionality was closely linked to activity changes in the subgenual ACC after ketamine administration. These results contribute to an understanding of the functional significance of ketamine effects in different subregions of the ACC by combining an approach to modulate glutamate release with the assessment of multiple timepoints and associations with trait negative emotionality in healthy participants.
Assuntos
Emoções , Giro do Cíngulo , Ketamina , Lamotrigina , Imageamento por Ressonância Magnética , Humanos , Ketamina/farmacologia , Ketamina/administração & dosagem , Lamotrigina/farmacologia , Lamotrigina/administração & dosagem , Giro do Cíngulo/efeitos dos fármacos , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/metabolismo , Masculino , Feminino , Método Duplo-Cego , Adulto , Emoções/efeitos dos fármacos , Adulto Jovem , Antidepressivos/farmacologia , Antidepressivos/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/administração & dosagemRESUMO
The study introduced and evaluated learning paradigms for Maylandia callainos cichlids using a modified version of the rodent T-maze, filled with tank water (the "sunken" modification). Both male and female fish underwent training in two distinct conditioning paradigms. Firstly, simple operant conditioning involved placing a food reward in either the right or left compartment. Cichlids demonstrated the ability to purposefully find the bait within 6 days of training, with a persistent place preference lasting up to 6 days. Additionally, the learning dynamics varied with sex: female cichlids exhibited reduction in latency to visit the target compartment and consume the bait, along with a decrease in the number of errors 3 and 4 days earlier than males, respectively. Secondly, visually-cued operant conditioning was conducted, with a food reward exclusively placed in the yellow compartment, randomly positioned on the left or right side of the maze during each training session. Visual learning persisted for 10 days until reaction time improvement plateaued. Color preference disappeared after 4 consecutive check-ups, with no sex-related interference. For further validation of visually-cued operant conditioning paradigm, drugs MK-801 (dizocilpine) and caffeine, known to affect performance in learning tasks, were administered intraperitoneally. Chronic MK-801 (0.17â¯mg/kg) impaired maze learning, resulting in no color preference development. Conversely, caffeine administration enhanced test performance, increasing precision in fish. This developed paradigm offers a viable approach for studying learning and memory and presents an effective alternative to rodent-based drug screening tools, exhibiting good face and predictive validity.
Assuntos
Ciclídeos , Condicionamento Operante , Maleato de Dizocilpina , Aprendizagem em Labirinto , Animais , Ciclídeos/fisiologia , Masculino , Feminino , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Maleato de Dizocilpina/farmacologia , Recompensa , Aprendizagem por Associação/fisiologia , Aprendizagem por Associação/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Sinais (Psicologia)RESUMO
Ketamine (KET), a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, has rapid onset of antidepressant effects in Treatment-Resistant Depression patients and repeated infusions are required to sustain its antidepressant properties. However, KET is an addictive drug, and so more preclinical and clinical research is needed to assess the safety of recurring treatments in both sexes. Thus, the aim of this study was to investigate the reinforcing properties of various doses of KET (0-, 0.125-, 0.25-, 0.5 mg/kg/infusion) and assess KET's cue-induced reinstatement and neuronal activation in both sexes of Long Evans rats. Neuronal activation was assessed using the protein expression of the immediate early gene cFos in the nucleus accumbens (Nac), an important brain area implicated in reward, reinforcement and reinstatement to most drug-related cues. Our findings show that KET has reinforcing effects in both male and female rats, albeit exclusively at the highest two doses (0.25 and 0.5 mg/kg/infusion). Furthermore, we noted sex differences, particularly at the highest dose of ketamine, with female rats displaying a higher rate of self-administration. Interestingly, all groups that self-administered KET reinstated to drug-cues. Following drug cue-induced reinstatement test in rats exposed to KET (0.25 mg/kg/infusion) or saline, there was higher cFos protein expression in KET-treated animals compared to saline controls, and higher cFos expression in the core compared to the shell subregions of the Nac. As for reinstatement, there were no notable sex differences reported for cFos expression in the Nac. These findings reveal some sex and dose dependent effects in KET's reinforcing properties and that KET at all doses induced similar reinstatement in both sexes. This study also demonstrated that cues associated with ketamine induce comparable neuronal activation in the Nac of both male and female rats. This work warrants further research into the potential addictive properties of KET, especially when administered at lower doses which are now being used in the clinic for treating various psychopathologies.
Assuntos
Sinais (Psicologia) , Relação Dose-Resposta a Droga , Ketamina , Núcleo Accumbens , Ratos Long-Evans , Reforço Psicológico , Animais , Ketamina/farmacologia , Ketamina/administração & dosagem , Masculino , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Feminino , Proteínas Proto-Oncogênicas c-fos/metabolismo , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Ratos , Caracteres Sexuais , Autoadministração , Condicionamento Operante/efeitos dos fármacosAssuntos
Eletroconvulsoterapia , Ketamina , Estimulação Magnética Transcraniana , Humanos , Ketamina/efeitos adversos , Ketamina/farmacologia , Eletroconvulsoterapia/efeitos adversos , Estereoisomerismo , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/efeitos adversosRESUMO
BACKGROUND: Despite its widespread use, the adverse effects (AEs) of memantine have not been well documented, and there is a need to find new ways to analyze the AEs of memantine. RESEARCH DESIGN AND METHODS: AEs in which the primary suspected drug was memantine were retrieved from the FAERS database. The proportional report ratio (PRR), reporting odds ratio (ROR), Bayesian confidence propagation neural network (BCPNN), and empirical Bayesian geometric mean (EBGM) were used to detect potential positive signals between memantine and AEs. SAS, MySQL, EXCEL, and R language software were used for data processing and statistical analysis. RESULTS: This study gathered a total of 5808 reports of AEs associated with memantine. Of these reports, a greater proportion of female patients (51.17%) than male patients (36.33%) had AEs. The AEs reported by FAERS were mainly in psychiatric category (n = 2157, IC025 = 2.69), various neurologic disorders (n = 1608, IC025 = 2.04), systemic disorders and various site reactions (n = 842, IC025 = 1.29). Unexpected ocular adverse events have been reported, ophthalmic vein thrombosis (n = 4, IC025 = 3.47) and scleral discolouration (n = 7, IC025 = 3.1), which may worsen glaucoma. CONCLUSIONS: This study observed conceivable new AEs signals and may supply important assist for scientific monitoring and threat identification of memantine.
Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos , Teorema de Bayes , Memantina , United States Food and Drug Administration , Memantina/efeitos adversos , Memantina/administração & dosagem , Humanos , Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Estados Unidos , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Adulto , Bases de Dados Factuais , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Adulto Jovem , Redes Neurais de Computação , Adolescente , Idoso de 80 Anos ou maisRESUMO
Hypofunctioning of NMDA receptors, and the resulting shift in the balance between excitation and inhibition, is considered a key process in the pathophysiology of schizophrenia. One important manifestation of this phenomenon is changes in neural oscillations, those above 30 Hz (i.e., gamma-band oscillations), in particular. Although both preclinical and clinical studies observed increased gamma activity following acute administration of NMDA receptor antagonists, the relevance of this phenomenon has been recently questioned given the reduced gamma oscillations typically observed during sensory and cognitive tasks in schizophrenia. However, there is emerging, yet contradictory, evidence for increased spontaneous gamma-band activity (i.e., at rest or under baseline conditions). Here, we use the sub-chronic phencyclidine (PCP) rat model for schizophrenia, which has been argued to model the pathophysiology of schizophrenia more closely than acute NMDA antagonism, to investigate gamma oscillations (30-100 Hz) in the medial prefrontal cortex of anesthetized animals. While baseline gamma oscillations were not affected, oscillations induced by train stimulation of the posterior dorsal CA1 (pdCA1) field of the hippocampus were enhanced in PCP-treated animals (5 mg/kg, twice daily for 7 days, followed by a 7-day washout period). This effect was reversed by pharmacological enhancement of endocannabinoid levels via systemic administration of URB597 (0.3 mg/kg), an inhibitor of the catabolic enzyme of the endocannabinoid anandamide. Intriguingly, the pharmacological blockade of CB1 receptors by AM251 unmasked a reduced gamma oscillatory activity in PCP-treated animals. The findings are consistent with the observed effects of URB597 and AM251 on behavioral deficits reminiscent of the symptoms of schizophrenia and further validate the potential for cannabinoid-based drugs as a treatment for schizophrenia.
Assuntos
Amidoidrolases , Benzamidas , Carbamatos , Fenciclidina , Piperidinas , Esquizofrenia , Animais , Masculino , Ratos , Amidoidrolases/antagonistas & inibidores , Amidoidrolases/metabolismo , Ácidos Araquidônicos/metabolismo , Ácidos Araquidônicos/farmacologia , Benzamidas/farmacologia , Carbamatos/farmacologia , Modelos Animais de Doenças , Endocanabinoides/metabolismo , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Ritmo Gama/fisiologia , Ritmo Gama/efeitos dos fármacos , Fenciclidina/farmacologia , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/metabolismo , Alcamidas Poli-Insaturadas/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiopatologia , Pirazóis/farmacologia , Ratos Sprague-Dawley , Esquizofrenia/fisiopatologia , Esquizofrenia/metabolismo , Esquizofrenia/tratamento farmacológicoRESUMO
RATIONALE: Ketamine produces dissociative, psychomimetic, anxiolytic, antidepressant, and anesthetic effects in a dose dependent manner. It has a complex mechanism of action that involve alterations in other glutamate receptors. The metabotropic glutamate receptor 5 (mGluR5) has been investigated in relation to the psychotic and anesthetic properties of ketamine, while its role in mediating the therapeutic effects of ketamine remains unknown. OBJECTIVES: We investigated the role of mGluR5 on the antidepressant, anxiolytic and fear memory-related effects of ketamine in adult male Wistar rats. METHODS: Two sets of experiments were conducted. We first utilized the positive allosteric modulator CDPPB to investigate how acute mGluR5 activation regulates the therapeutic effects of ketamine (10 mg/kg). We then tested the synergistic antidepressant effect of mGluR5 antagonism and ketamine by combining MTEP with a sub-effective dose of ketamine (1 mg/kg). Behavioral despair, locomotor activity, anxiety-like behavior, and fear memory were respectively assessed in the forced swim test (FST), open field test (OFT), elevated plus maze (EPM), and auditory fear conditioning. RESULTS: Enhancing mGluR5 activity via CDPPB occluded the antidepressant effect of ketamine without changing locomotor activity. Furthermore, concomitant administration of MTEP and ketamine exhibited a robust synergistic antidepressant effect. The MTEP + ketamine treatment, however, blocked the anxiolytic effect observed by sole administration of MTEP or the low dose ketamine. CONCLUSIONS: These findings suggest that suppressed mGluR5 activity is required for the antidepressant effects of ketamine. Consequently, the antagonism of mGluR5 enhances the antidepressant effectiveness of low dose ketamine, but eliminates its anxiolytic effects.
Assuntos
Ansiolíticos , Antidepressivos , Ketamina , Ratos Wistar , Receptor de Glutamato Metabotrópico 5 , Animais , Ketamina/farmacologia , Ketamina/administração & dosagem , Receptor de Glutamato Metabotrópico 5/metabolismo , Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores , Masculino , Ratos , Ansiolíticos/farmacologia , Ansiolíticos/administração & dosagem , Antidepressivos/farmacologia , Antidepressivos/administração & dosagem , Piridinas/farmacologia , Piridinas/administração & dosagem , Medo/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Sinergismo Farmacológico , Relação Dose-Resposta a Droga , Memória/efeitos dos fármacos , Benzamidas/farmacologia , Benzamidas/administração & dosagem , Tiazóis/farmacologia , Tiazóis/administração & dosagem , Depressão/tratamento farmacológico , Ansiedade/tratamento farmacológico , PirazóisRESUMO
PURPOSE: There is insufficient evidence on the management of refractory status epilepticus (RSE) and super-RSE (SRSE). Ketamine is a N-methyl-d-aspartate receptor antagonist in the treatment of these entities. Our objectives were to study the effectiveness and safety of ketamine in the treatment of adult patients with RSE and SRSE, to determine the factors that can influence the response to ketamine, and to explore its use in patients without mechanical ventilation. METHODS: Adult patients who had received intravenous ketamine for the treatment of RSE or SRSE at Hospital Universitario Clínico San Carlos (Madrid, Spain) or Hospital Universitari Vall d'Hebron (Barcelona, Spain) from 2017 to 2023 were retrospectively analysed. RESULTS: This study included 58 adult patients, mean (standard deviation) age 60.2 (15.7) years, of whom 41 (70.7 %) were male; 33 (56.9 %) patients responded to ketamine without recurrence, with a low rate of adverse effects (8.6 %). The presence of SRSE at the time of ketamine initiation (OR 0.287, p = 0.028) and the time elapsed between status epilepticus onset and ketamine administration (OR 0.991, p = 0.034) were associated with worse response to ketamine. Patients treated without mechanical ventilation had similar rates of response without recurrence (62.5% vs 56.9 %) and lower mortality (37.5% vs 53.5 %) compared to the overall group. CONCLUSION: Ketamine is an effective drug with few adverse effects. Prompt administration should be considered in patients with RSE requiring anaesthesia, in patients with SRSE, and in patients with RSE who do not respond to standard antiseizure drugs and in whom mechanical ventilation is not advised.
Assuntos
Ketamina , Estado Epiléptico , Humanos , Ketamina/administração & dosagem , Ketamina/uso terapêutico , Estado Epiléptico/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso , Adulto , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Resultado do Tratamento , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/uso terapêuticoRESUMO
AIM: The therapeutic potential of N-methyl-D-aspartate glutamate receptor (NMDAR) antagonists, particularly ketamine, in mood disorders, is linked to their modulation of dopamine dynamics in the medial prefrontal cortex (mPFC). However, conflicting effects of distinct NMDAR antagonists, like ketamine and phencyclidine, on mPFC dopamine levels stem from variances in their receptor affinity profiles. This study investigates the impact of intermittent subchronic administration of an NMDAR antagonist on dopamine synthesis capacity and responsiveness within the mPFC, focusing on Dizocilpine (MK-801), a highly selective NMDAR antagonist. METHODS: In vivo microdialysis and high-performance liquid chromatography assessed extracellular dopamine levels in the mPFC following subchronic MK-801 treatment. Locomotor activity was measured using a computed video tracking system. RESULTS: Intermittent subchronic MK-801 administration, followed by a 24-h withdrawal, preserved both dopamine synthesis capacity and responsiveness to MK-801 challenge in the mPFC. However, altered locomotor activity was observed, deviating from previous findings indicating impaired dopamine synthesis and responsiveness in the mPFC with twice-daily subchronic NMDAR antagonist treatment. CONCLUSION: These findings offer crucial biochemical insights into the diverse impacts of NMDAR antagonists on dopamine dynamics and the distinct therapeutic mechanisms associated with ketamine in depression treatment. However, further investigation is imperative to pinpoint potential inconsistencies stemming from variances in drug type, dosage, or administration frequency.
Assuntos
Maleato de Dizocilpina , Dopamina , Antagonistas de Aminoácidos Excitatórios , Córtex Pré-Frontal , Maleato de Dizocilpina/farmacologia , Maleato de Dizocilpina/administração & dosagem , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Animais , Dopamina/metabolismo , Dopamina/biossíntese , Masculino , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Ratos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Locomoção/efeitos dos fármacos , Ratos Sprague-Dawley , Microdiálise/métodosRESUMO
This study investigates the influence of N-methyl-D-aspartate receptor (NMDAR) antagonists on the mismatch negativity (MMN) components of event-related potentials (ERPs) in healthy subjects and explores whether NMDAR antagonists have different effects on MMN components under different types of antagonists, drug dosages, and deviant stimuli. We conducted a comprehensive literature search of PubMed, EMBASE, and the Cochrane Library from inception to August 1, 2023 for studies comparing the MMN components between the NMDAR antagonist intervention group and the control group (or baseline). All statistical analyses were performed using Stata version 12.0 software. Sixteen articles were included in the systematic review: 13 articles were included in the meta-analysis of MMN amplitudes, and seven articles were included in the meta-analysis of MMN latencies. The pooled analysis showed that NMDAR antagonists reduced MMN amplitudes [SMD (95% CI) = 0.32 (0.16, 0.47), P < 0.01, I2 = 47.3%, p < 0.01] and prolonged MMN latencies [SMD (95% CI) = 0.31 (0.13, 0.49), P = 0.16, I2 = 28.3%, p < 0.01]. The type of antagonist drug regulates the effect of NMDAR antagonists on MMN amplitudes. Different antagonists, doses of antagonists, and types of deviant stimuli can also have different effects on MMN. These findings indicate a correlation between NMDAR and MMN, which may provide a foundation for the application of ERP-MMN in the early identification of NMDAR encephalitis.
Assuntos
Potenciais Evocados , Receptores de N-Metil-D-Aspartato , Humanos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Potenciais Evocados/efeitos dos fármacos , Potenciais Evocados/fisiologia , Eletroencefalografia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/administração & dosagemRESUMO
The NMDA receptor (NMDAR) antagonist ketamine has shown great potential as a rapid-acting antidepressant; however, its use is limited by poor oral bioavailability and a side effect profile that necessitates in-clinic dosing. GM-1020 is a novel NMDAR antagonist that was developed to address these limitations of ketamine as a treatment for depression. Here, we present the preclinical characterization of GM-1020 alongside ketamine, for comparison. In vitro, we profiled GM-1020 for binding to NMDAR and functional inhibition using patch-clamp electrophysiology. In vivo, GM-1020 was assessed for antidepressant-like efficacy using the Forced Swim Test (FST) and Chronic Mild Stress (CMS), while motor side effects were assessed in spontaneous locomotor activity and on the rotarod. The pharmacokinetic properties of GM-1020 were profiled across multiple preclinical species. Electroencephalography (EEG) was performed to determine indirect target engagement and provide a potentially translational biomarker. These results demonstrate that GM-1020 is an orally bioavailable NMDAR antagonist with antidepressant-like efficacy at exposures that do not produce unwanted motor effects.
Assuntos
Antidepressivos , Receptores de N-Metil-D-Aspartato , Animais , Antidepressivos/administração & dosagem , Antidepressivos/farmacologia , Antidepressivos/farmacocinética , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Masculino , Ratos , Camundongos , Administração Oral , Ratos Sprague-Dawley , Disponibilidade Biológica , Ketamina/administração & dosagem , Ketamina/farmacologia , Depressão/tratamento farmacológico , Atividade Motora/efeitos dos fármacos , Relação Dose-Resposta a Droga , Camundongos Endogâmicos C57BL , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacocinética , HumanosRESUMO
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 & dosagemRESUMO
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 , RatosRESUMO
Brainstem respiratory neuronal network significantly contributes to cough motor pattern generation. Neuronal populations in the pre-Bötzinger complex (PreBötC) represent a substantial component for respiratory rhythmogenesis. We studied the role of PreBötC neuronal excitation and inhibition on mechanically induced tracheobronchial cough in 15 spontaneously breathing, pentobarbital anesthetized adult cats (35 mg/kg, iv initially). Neuronal excitation by unilateral microinjection of glutamate analog d,l-homocysteic acid resulted in mild reduction of cough abdominal electromyogram (EMG) amplitudes and very limited temporal changes of cough compared with effects on breathing (very high respiratory rate, high amplitude inspiratory bursts with a short inspiratory phase, and tonic inspiratory motor component). Mean arterial blood pressure temporarily decreased. Blocking glutamate-related neuronal excitation by bilateral microinjections of nonspecific glutamate receptor antagonist kynurenic acid reduced cough inspiratory and expiratory EMG amplitude and shortened most cough temporal characteristics similarly to breathing temporal characteristics. Respiratory rate decreased and blood pressure temporarily increased. Limiting active neuronal inhibition by unilateral and bilateral microinjections of GABAA receptor antagonist gabazine resulted in lower cough number, reduced expiratory cough efforts, and prolongation of cough temporal features and breathing phases (with lower respiratory rate). The PreBötC is important for cough motor pattern generation. Excitatory glutamatergic neurotransmission in the PreBötC is involved in control of cough intensity and patterning. GABAA receptor-related inhibition in the PreBötC strongly affects breathing and coughing phase durations in the same manner, as well as cough expiratory efforts. In conclusion, differences in effects on cough and breathing are consistent with separate control of these behaviors.NEW & NOTEWORTHY This study is the first to explore the role of the inspiratory rhythm and pattern generator, the pre-Bötzinger complex (PreBötC), in cough motor pattern formation. In the PreBötC, excitatory glutamatergic neurotransmission affects cough intensity and patterning but not rhythm, and GABAA receptor-related inhibition affects coughing and breathing phase durations similarly to each other. Our data show that the PreBötC is important for cough motor pattern generation, but cough rhythmogenesis appears to be controlled elsewhere.
Assuntos
Geradores de Padrão Central , Tosse , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Receptores de GABA-A/farmacologia , Ácido Glutâmico/farmacologia , Inalação , Bulbo , Reflexo , Taxa Respiratória , Músculos Abdominais/efeitos dos fármacos , Músculos Abdominais/fisiopatologia , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Gatos , Geradores de Padrão Central/efeitos dos fármacos , Geradores de Padrão Central/metabolismo , Geradores de Padrão Central/fisiopatologia , Tosse/tratamento farmacológico , Tosse/metabolismo , Tosse/fisiopatologia , Eletromiografia , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Feminino , Antagonistas de Receptores de GABA-A/administração & dosagem , Ácido Glutâmico/administração & dosagem , Ácido Glutâmico/análise , Homocisteína/análogos & derivados , Homocisteína/farmacologia , Inalação/efeitos dos fármacos , Inalação/fisiologia , Ácido Cinurênico/farmacologia , Masculino , Bulbo/efeitos dos fármacos , Bulbo/metabolismo , Bulbo/fisiopatologia , Piridazinas/farmacologia , Reflexo/efeitos dos fármacos , Reflexo/fisiologia , Taxa Respiratória/efeitos dos fármacos , Taxa Respiratória/fisiologiaRESUMO
The striatal beat frequency model assumes that striatal medium spiny neurons encode duration via synaptic plasticity. Muscarinic 1 (M1) cholinergic receptors as well as dopamine and glutamate receptors are important for neural plasticity in the dorsal striatum. Therefore, we investigated the effect of inhibiting these receptors on the formation of duration memory. After sufficient training in a peak interval (PI)-20-s procedure, rats were administered a single or mixed infusion of a selective antagonist for the dopamine D1 receptor (SCH23390, 0.5 µg per side), N-methyl-D-aspartic acid (NMDA)-type glutamate receptor (D-AP5, 3 µg), or M1 receptor (pirenzepine, 10 µg) bilaterally in the dorsal striatum, immediately before initiating a PI-40 s session (shift session). The next day, the rats were tested for new duration memory (40 s) in a session in which no lever presses were reinforced (test session). In the shift session, the performance was comparable irrespective of the drug injected. However, in the test session, the mean peak time (an index of duration memory) of the M1 + NMDA co-blockade group, but not of the D1 + NMDA co-blockade group, was lower than that of the control group (Experiments 1 and 2). In Experiment 3, the effect of the co-blockade of M1 and NMDA receptors was replicated. Moreover, sole blockade of M1 receptors induced the same effect as M1 and NMDA blockade. These results suggest that in the dorsal striatum, the M1 receptor, but not the D1 or NMDA receptors, is involved in the consolidation of duration memory.
Assuntos
Antagonistas de Dopamina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Consolidação da Memória/efeitos dos fármacos , Antagonistas Muscarínicos/farmacologia , Neostriado/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Percepção do Tempo/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Antagonistas de Dopamina/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Masculino , Antagonistas Muscarínicos/administração & dosagem , Ratos , Ratos Wistar , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inibidoresRESUMO
Schizophrenia is severe neuropsychiatric disease, which is commonly accompanied not only by positive or negative symptoms, but also by cognitive impairment. To study neuronal mechanisms underlying cognitive distortions and mechanisms underlying schizophrenia, animal pharmacological models of cognitive symptoms are commonly used. Between various cognitive impairments in schizophrenia patients, disturbed time perception has often been reported. Here, we examined temporal and spatial cognition in a modified Carousel maze task in the animal model of schizophrenia induced by non-competitive NMDA-receptor antagonists MK-801. Male Long-Evans rats (n = 18) first learned to avoid the aversive sector on a rotating arena in both dark and light intervals. We verified that during dark, rats used temporal cues, while during light they relied predominantly on spatial cues. We demonstrated that the timing strategy depends on the stable rotation speed of the arena and on the repositioning clues such as aversive stimuli. During testing (both in light and dark intervals), half of the rats received MK-801 and the control half received saline solution. We observed dose-dependent disruptions of both temporal and spatial cognition. Namely, both doses of MK-801 (0.1 and 0.12 mg/kg) significantly impaired timing strategy in the dark and increased locomotor activity. MK-801 dose 0.1 mg/kg, but not 0.12, also impaired spatial avoidance strategy in light. We found that the timing strategy is more sensitive to NMDA antagonist MK-801 than the spatial strategy. To conclude, a modified version of the Carousel maze is a useful and sensitive tool for detecting timing impairments in the MK-801 induced rodent model of schizophrenia.
Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/fisiopatologia , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Esquizofrenia/induzido quimicamente , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Maleato de Dizocilpina/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Masculino , Ratos , Ratos Long-EvansRESUMO
Memantine's benefits in Alzheimer's disease (AD) are modest and heterogeneous. We tested the feasibility of using sensitivity to acute memantine challenge to predict an individual's clinical response. Eight participants completed a double-blind challenge study of memantine (placebo versus 20âmg) effects on autonomic, subjective, cognitive, and neurophysiological measures, followed by a 24-week unblinded active-dose therapeutic trial (10âmg bid). Study participation was well tolerated. Subgroups based on memantine sensitivity on specific laboratory measures differed in their clinical response to memantine, some by large effect sizes. It appears feasible to use biomarkers to predict clinical sensitivity to memantine.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Biomarcadores , Cognição/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Memantina/administração & dosagem , Idoso , Método Duplo-Cego , Feminino , Humanos , Masculino , Testes NeuropsicológicosRESUMO
We describe a clinical candidate molecule from a new series of glutamate N-methyl-d-aspartate receptor subunit 2B-selective inhibitors that shows enhanced inhibition at extracellular acidic pH values relative to physiologic pH. This property should render these compounds more effective inhibitors of N-methyl-d-aspartate receptors at synapses responding to a high frequency of action potentials, since glutamate-containing vesicles are acidic within their lumen. In addition, acidification of penumbral regions around ischemic tissue should also enhance selective drug action for improved neuroprotection. The aryl piperazine we describe here shows strong neuroprotective actions with minimal side effects in preclinical studies. The clinical candidate molecule NP10679 has high oral bioavailability with good brain penetration and is suitable for both intravenous and oral dosing for therapeutic use in humans. SIGNIFICANCE STATEMENT: This study identifies a new series of glutamate N-methyl-d-aspartate (NMDA) receptor subunit 2B-selective negative allosteric modulators with properties appropriate for clinical advancement. The compounds are more potent at acidic pH, associated with ischemic tissue, and this property should increase the therapeutic safety of this class by improving efficacy in affected tissue while sparing NMDA receptor block in healthy brain.