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1.
Int J Mol Sci ; 24(2)2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36674542

RESUMO

Schizophrenia (SZ) is a heterogeneous mental disorder, affecting ~1% of the worldwide population. One of the main pathophysiological theories of SZ is the imbalance of excitatory glutamatergic pyramidal neurons and inhibitory GABAergic interneurons, involving N-methyl-D-aspartate receptors (NMDAr). This may lead to local glutamate storms coupled with excessive dendritic pruning and subsequent cellular stress, including nitrosative stress, during a critical period of neurodevelopment, such as adolescence. Nitrosative stress is mediated by nitric oxide (NO), which is released by NO synthases (NOS) and has emerged as a key signaling molecule implicated in SZ. Regarding glutamatergic models of SZ, the administration of NMDAr antagonists has been found to increase NOS levels in the prefrontal cortex (PFC) and ventral hippocampus (HPC). We hypothesized that suboptimal NOS function in adolescence could be a target for early treatments, including clozapine (CLZ) and the novel metabotropic glutamate receptor modulator JNJ-46356479 (JNJ). We analyzed the protein levels of NOS isoforms in adult PFC and HPC of a postnatal ketamine induced murine model of SZ receiving CLZ or JNJ during adolescence by western blot. Endothelial NOS and neuronal NOS increased under ketamine administration in PFC and decreased in CLZ or JNJ treatments. The same trends were found in the HPC in neuronal NOS. In contrast, inducible NOS was increased under JNJ treatment with respect to ketamine induction in the HPC, and the same trends were found in the PFC. Taken together, our findings suggest a misbalance of the NOS system following NMDAr antagonist administration, which was then modulated under early CLZ and JNJ treatments.


Assuntos
Clozapina , Ketamina , Esquizofrenia , Humanos , Adulto , Camundongos , Animais , Clozapina/farmacologia , Ketamina/farmacologia , Ketamina/metabolismo , Esquizofrenia/metabolismo , Ácido Glutâmico/metabolismo , Estresse Nitrosativo , Córtex Pré-Frontal/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo
2.
ACS Chem Neurosci ; 14(3): 468-480, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36630309

RESUMO

Psilocybin is a psychedelic with therapeutic potential. While there is growing evidence that psilocybin exerts its beneficial effects through enhancing neural plasticity, the exact brain regions involved are not completely understood. Determining the impact of psilocybin on plasticity-related gene expression throughout the brain can broaden our understanding of the neural circuits involved in psychedelic-evoked neural plasticity. In this study, whole-brain serial two-photon microscopy and light sheet microscopy were employed to map the expression of the immediate early gene, c-Fos, in male and female mice. The drug-induced c-Fos expression following psilocybin administration was compared to that of subanesthetic ketamine and saline control. Psilocybin and ketamine produced acutely comparable elevations in c-Fos expression in numerous brain regions, including anterior cingulate cortex, locus coeruleus, primary visual cortex, central and basolateral amygdala, medial and lateral habenula, and claustrum. Select regions exhibited drug-preferential differences, such as dorsal raphe and insular cortex for psilocybin and the CA1 subfield of hippocampus for ketamine. To gain insights into the contributions of receptors and cell types, the c-Fos expression maps were related to brain-wide in situ hybridization data. The transcript analyses showed that the endogenous levels of Grin2a and Grin2b predict whether a cortical region is sensitive to drug-evoked neural plasticity for both ketamine and psilocybin. Collectively, the systematic mapping approach produced an unbiased list of brain regions impacted by psilocybin and ketamine. The data are a resource that highlights previously underappreciated regions for future investigations. Furthermore, the robust relationships between drug-evoked c-Fos expression and endogenous transcript distributions suggest glutamatergic receptors as a potential convergent target for how psilocybin and ketamine produce their rapid-acting and long-lasting therapeutic effects.


Assuntos
Alucinógenos , Ketamina , Masculino , Feminino , Camundongos , Animais , Ketamina/farmacologia , Psilocibina/farmacologia , Alucinógenos/farmacologia , Alucinógenos/metabolismo , Genes Precoces , Encéfalo/metabolismo , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Núcleo Dorsal da Rafe/metabolismo
3.
Med Gas Res ; 13(3): 112-117, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36571375

RESUMO

Electroconvulsive therapy (ECT) is one of the therapeutic opportunities for patients with psychological disorders when they may decline to take medication. We sought to systematically compare the anesthetic efficacy of ketamine, propofol, and dexmedetomidine for electroconvulsive therapy in treatment-resistant major depressive disorder patients. This double-blind trial enrolled treatment-resistant major depressive disorder patients (n = 85) who had been hospitalized for ECT in the Amir Kabir Hospital's psychiatric ward (Arak, Iran). The ketamine, propofol, and dexmedetomidine groups received a dose of 0.2 µg/kg ketamine, 1.5 mg/kg propofol, and 0.8 mg/kg dexmedetomidine, respectively. In all intervention groups, 10 mL of interventional drugs was injected intravenously for 10 minutes, and in the placebo group, 10 mL of normal saline was given over the same period. The dexmedetomidine group's blood pressure was revealed comparatively lower at all times. Dexmedetomidine-treated patients showed their marked satisfaction, while those treated with propofol had shorter recovery time, shorter seizure duration, and shorter time to achieve an Aldrete score of 9-10 and increased relaxation, and next dexmedetomidine produced deeper relaxation. Propofol could shorten recovery time and seizure duration, and enhance relaxation, while dexmedetomidine was associated with higher patient satisfaction. Considering that any anesthetic which does not shorten seizure duration may serve efficiently for ECT and that ketamine-treated patients had more prolonged seizure duration, the preferred drug can hence be considered from various angles, thereby offering anesthetic agents with highly favorable efficacy in treatment-resistant major depressive disorder patients needing ECT. The drug choice thus depends on physical conditions, underlying diseases, and psychiatrist consultation.


Assuntos
Anestesia , Transtorno Depressivo Maior , Dexmedetomidina , Eletroconvulsoterapia , Ketamina , Propofol , Humanos , Propofol/efeitos adversos , Ketamina/farmacologia , Ketamina/uso terapêutico , Eletroconvulsoterapia/efeitos adversos , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/psicologia , Dexmedetomidina/farmacologia , Dexmedetomidina/uso terapêutico , Anestésicos Intravenosos/efeitos adversos , Resultado do Tratamento , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico
4.
Neuropharmacology ; 225: 109374, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36516891

RESUMO

Depression is a complex and highly heterogeneous disorder which diagnosis is based on an exceedingly variable set of clinical symptoms. Current treatments focus almost exclusively on the manipulation of monoamine neurotransmitter systems, but despite considerable efforts, these remain inadequate for a significant proportion of those afflicted by the disorder. The emergence of racemic (R, S)-ketamine as a fast-acting antidepressant has provided an exciting new path for the study of major depressive disorder (MDD) and the search for better therapeutics for its treatment. Previous work suggested that ketamine's mechanism of action is primarily mediated via blockaded of N-methyl-d-aspartate (NMDA) receptors, however, this is an area of active research and clinical and preclinical evidence now indicate that ketamine acts on multiple systems. The last couple of decades have cemented the mesolimbic dopamine reward pathway's involvement in the pathogenesis of MDD and related mood disorders. Exposure to negative stress dysregulates dopamine neuronal activity disrupting reward and motivational processes resulting in anhedonia (lack of pleasure), a hallmark symptom of depression. Although the mechanism(s) underlying ketamine's antidepressant activity continue to be elucidated, current evidence indicate that its therapeutic effects are mediated, at least in part, via long-lasting synaptic changes and subsequent molecular adaptations in brain regions within the mesolimbic dopamine system. Notwithstanding, ketamine is a drug of abuse, and this liability may pose limitations for long term use as an antidepressant. This review outlines the current knowledge of ketamine's actions within the mesolimbic dopamine system and its abuse potential. This article is part of the Special Issue on 'Ketamine and its Metabolites'.


Assuntos
Transtorno Depressivo Maior , Ketamina , Humanos , Ketamina/farmacologia , Ketamina/uso terapêutico , Ketamina/metabolismo , Transtorno Depressivo Maior/tratamento farmacológico , Dopamina , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Antidepressivos/metabolismo , Encéfalo/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo
5.
Neuropharmacology ; 225: 109378, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36539011

RESUMO

Ketamine, functioning as a channel blocker of the excitatory glutamate-gated N-methyl-d-aspartate (NMDA) receptors, displays compelling fast-acting and sustained antidepressant effects for treatment-resistant depression. Over the past decades, clinical and preclinical studies have implied that the pathology of depression is associated with dysfunction of glutamatergic transmission. In particular, the discovery of antidepressant agents modulating NMDA receptor function has prompted breakthroughs for depression treatment compared with conventional antidepressants targeting the monoaminergic system. In this review, we first summarized the signalling pathway of the ketamine-mediated antidepressant effects, based on the glutamate hypothesis of depression. Second, we reviewed the hypotheses of the synaptic mechanism and network of ketamine antidepressant effects within different brain areas and distinct subcellular localizations, including NMDA receptor antagonism on GABAergic interneurons, extrasynaptic and synaptic NMDA receptor-mediated antagonism, and ketamine blocking bursting activities in the lateral habenula. Third, we reviewed the different roles of NMDA receptor subunits in ketamine-mediated cognitive and psychiatric behaviours in genetically-manipulated rodent models. Finally, we summarized the structural basis of NMDA receptor channel blockers and discussed NMDA receptor modulators that have been reported to exert potential antidepressant effects in animal models or in clinical trials. Integrating the cutting-edge technologies of cryo-EM and artificial intelligence-based drug design (AIDD), we expect that the next generation of first-in-class rapid antidepressants targeting NMDA receptors would be an emerging direction for depression therapeutics. This article is part of the Special Issue on 'Ketamine and its Metabolites'.


Assuntos
Depressão , Ketamina , Animais , Depressão/tratamento farmacológico , Receptores de N-Metil-D-Aspartato/metabolismo , Ketamina/farmacologia , Ketamina/uso terapêutico , Ketamina/metabolismo , Inteligência Artificial , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Antidepressivos/metabolismo , Ácido Glutâmico/metabolismo
6.
Neuropharmacology ; 225: 109403, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36565852

RESUMO

Benzethonium chloride (BZT) is an excipient used in numerous products including (R,S)-ketamine (ketamine) drug formulations for human and veterinary use. Emerging evidence indicates BZT is pharmacologically active. BZT may therefore contribute to some of the clinical or preclinical effects observed with ketamine. In the present study, we evaluated: (i) the affinity of BZT for neurotransmitter receptors and transporters, (ii) the effects of BZT on hippocampal synaptic transmission in vitro, and (iii) plasma and brain concentrations of BZT following its intraperitoneal administration to male CD1 mice. Radioligand binding assays determined the affinity of BZT for neurotransmitter targets. Effects of BZT on field excitatory postsynaptic potentials (fEPSPs) were established via electrophysiological recordings from slices collected from male C57BL/6J mice. The binding assays revealed that BZT binds to numerous receptors (e.g., σ2 Ki = 7 nM) and transporters (e.g., dopamine transporter Ki = 545 nM). Bath application of BZT potentiated hippocampal fEPSPs in mouse hippocampal slices with an EC50 of 2.03 nM. Following intraperitoneal administration, BZT was detected in the plasma, but not in the brain of mice. These data highlight that studies measuring peripheral endpoints or directly exposing systems, in vitro, intracerebroventricularly, or intracortically, to BZT-containing formulations should account for the direct effects of BZT. Our findings also suggest that earlier data attributing pharmacological effects to ketamine may be confounded by BZT and that additional investigation into the functional impact of BZT is warranted. This article is part of the Special Issue on 'Ketamine and its Metabolites'.


Assuntos
Ketamina , Humanos , Camundongos , Masculino , Animais , Ketamina/farmacologia , Ketamina/metabolismo , Benzetônio/metabolismo , Benzetônio/farmacologia , Camundongos Endogâmicos C57BL , Hipocampo , Transmissão Sináptica , Receptores de Neurotransmissores/metabolismo
7.
Brain Res Bull ; 193: 84-94, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36539101

RESUMO

Auditory steady-state responses (ASSRs) are recurrent neural activities entrained to regular cyclic auditory stimulation. ASSRs are altered in individuals with schizophrenia, and may be related to hypofunction of the N-methyl-D-aspartate (NMDA) glutamate receptor. Noncompetitive NMDA receptor antagonists, including ketamine, have been used in ASSR studies of rodent models of schizophrenia. Although animal studies using non-human primates are required to complement rodent studies, the effects of ketamine on ASSRs are unknown in intact awake non-human primates. In this study, after administration of vehicle or ketamine, click trains at 20-83.3 Hz were presented to elicit ASSRs during recording of electroencephalograms in intact, awake macaque monkeys. The results indicated that ASSRs quantified by event-related spectral perturbation and inter-trial coherence were maximal at 83.3 Hz after vehicle administration, and that ketamine reduced ASSRs at 58.8 and 83.3 Hz, but not at 20 and 40 Hz. The present results demonstrated a reduction of ASSRs by the NMDA receptor antagonist at optimal frequencies with maximal responses in intact, awake macaques, comparable to ASSR reduction in patients with schizophrenia. These findings suggest that ASSR can be used as a neurophysiological biomarker of the disturbance of gamma-oscillatory neural circuits in this ketamine model of schizophrenia using intact, awake macaques. Thus, this model with ASSRs would be useful in the investigation of human brain pathophysiology as well as in preclinical translational research.


Assuntos
Ketamina , Esquizofrenia , Animais , Estimulação Acústica/métodos , Eletroencefalografia/métodos , Potenciais Evocados Auditivos/fisiologia , Ketamina/farmacologia , Primatas , Receptores de N-Metil-D-Aspartato , Esquizofrenia/tratamento farmacológico , Vigília
8.
Biomed Pharmacother ; 158: 114079, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36521250

RESUMO

Positive allosteric modulators of the metabotropic glutamate receptor 2 (mGluR2), such as JNJ-46356479 (JNJ), may mitigate the glutamate storm during the early stages of schizophrenia (SZ), which could be especially useful in the treatment of cognitive and negative symptoms. We evaluated the efficacy of early treatment with JNJ or clozapine (CLZ) in reversing behavioral and neuropathological deficits induced in a postnatal ketamine (KET) mouse model of SZ. Mice exposed to KET (30 mg/kg) on postnatal days (PND) 7, 9, and 11 received JNJ or CLZ (10 mg/kg) daily in the adolescent period (PND 35-60). Mice exposed to KET did not show the expected preference for a novel object or for social novelty, but they recovered this preference with JNJ treatment. Similarly, KET group did not show the expected dishabituation in the fifth trial, but mice treated with JNJ or CLZ recovered an interest in the novel animal. Neuronal immunoreactivity also differed between treatment groups with mice exposed to KET showing a reduction in parvalbumin positive cells in the prefrontal cortex and decreased c-Fos expression in the hippocampus, which was normalized with the pharmacological treatment. JNJ-46356479 treatment in early stages may help improve the cognitive and negative symptoms, as well as certain neuropathological deficits, and may even obtain a better response than CLZ treatment. This may have relevant clinical translational applications since early treatment with mGluR2 modulators that inhibit glutamate release at the onset of critical phases of SZ may prevent or slow down the clinical deterioration of the disease.


Assuntos
Clozapina , Ketamina , Receptores de Glutamato Metabotrópico , Esquizofrenia , Camundongos , Animais , Ketamina/farmacologia , Ketamina/uso terapêutico , Esquizofrenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Receptores de Glutamato Metabotrópico/uso terapêutico , Clozapina/uso terapêutico
9.
Neuropharmacology ; 222: 109308, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36341809

RESUMO

Ketamine exerts rapid and long-lasting antidepressant effects in patients with treatment-resistant depression. However, its clinical use is limited by its undesirable psychotomimetic side effects. Accumulating evidence from preclinical studies has shown that the antidepressant effects of ketamine are dependent on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R) activation, which triggers activation of the mechanistic target of rapamycin pathway and brain-derived neurotrophic factor release. Thus, AMPA-R has emerged as a promising new target for novel antidepressants with a rapid onset of action. However, almost all known AMPA-R potentiators carry the risk of a narrow bell-shaped dose-response curve and a poor safety margin against seizures. Our data suggest that agonistic activity is not only related to the risks of bell-shaped dose-response curves and seizures but also to the reduced synaptic transmission and procognitive effects of AMPA-R potentiators. In this review, we describe our original screening approach that led to the discovery of an investigational AMPA-R potentiator with low agonistic activity, TAK-653. We further review the in vitro and in vivo profiles of TAK-653, including its procognitive and antidepressant-like effects, as well as its safety profile, in comparison with known AMPA-R potentiators with agonistic activity and AMPA, an AMPA-R agonist. The low agnostic activity of TAK-653 may overcome limitations of known AMPA-R potentiators. This article is part of the Special Issue on 'Ketamine and its Metabolites'.


Assuntos
Ketamina , Humanos , Ketamina/farmacologia , Ketamina/uso terapêutico , Receptores de AMPA , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico , Antidepressivos/farmacologia , Convulsões/tratamento farmacológico
10.
Neuropharmacology ; 222: 109305, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36354092

RESUMO

Depression is a well-known serious mental illness, and the onset of treatment using traditional antidepressants is frequently delayed by several weeks. Moreover, numerous patients with depression fail to respond to therapy. One major breakthrough in antidepressant therapy is that subanesthetic ketamine doses can rapidly alleviate depressive symptoms within hours of administering a single dose, even in treatment-resistant patients. However, specific mechanisms through which ketamine exerts its antidepressant effects remain elusive, leading to concerns regarding its rapid and long-lasting antidepressant effects. N-methyl-d-aspartate receptor (NMDAR) antagonists like ketamine are reportedly associated with serious side effects, such as dissociative symptoms, cognitive impairment, and abuse potential, limiting the large-scale clinical use of ketamine as an antidepressant. Herein, we reviewed the pharmacological properties of ketamine and the mechanisms of action underlying the rapid antidepressant efficacy, including the disinhibition hypothesis and synaptogenesis, along with common downstream effector pathways such as enhanced brain-derived neurotrophic factor and tropomyosin-related kinase B signaling, activation of the mechanistic target of rapamycin complex 1 and transforming growth factor ß1. We focused on evidence supporting the relevance of these potential mechanisms of ketamine and its metabolites in mediating the clinical efficacy of the drug. Given its reported antidepressant efficacy in preclinical studies and limited undesirable adverse effects, (R)-ketamine may be a safer, more controllable, rapid antidepressant. Overall, understanding the potential mechanisms of action of ketamine and its metabolites in combination with pharmacology may help develop a new generation of rapid antidepressants that maximize antidepressant effects while avoiding unfavorable adverse effects. This article is part of the Special Issue on 'Ketamine and its Metabolites'.


Assuntos
Disfunção Cognitiva , Ketamina , Humanos , Ketamina/farmacologia , Ketamina/uso terapêutico , Depressão , Psicoterapia , Transtornos Dissociativos
11.
Neuropsychopharmacology ; 48(1): 186-190, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-35768568

RESUMO

Major depressive disorder is a prevalent and heterogeneous disorder with treatment resistance in at least 50% of individuals. Most of the initial studies focused on the monoamine system; however, recently other mechanisms have come under investigation. Specific to the current issue, studies show synaptic involvement in depression. Other articles in this issue report on reductions in synaptic density, dendritic spines, boutons and glia associated with stress and depression. Importantly, it appears that some drugs (e.g., ketamine) may lead to rapid synaptic restoration or synaptogenesis. Direct evidence for this comes from preclinical work. However, neuroimaging studies, such as magnetic resonance imaging (MRI) and positron emission tomography (PET), have become useful in assessing these changes in vivo. Here, we describe the use of neuroimaging techniques in the evaluation of synaptic alterations associated with depression in humans, as well as measurement of synaptic restoration after administration of ketamine. Although more research is desired, use of these techniques widen our understanding of depression and move us further along the path to targeted and effective treatment for depression.


Assuntos
Transtorno Depressivo Maior , Ketamina , Humanos , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/tratamento farmacológico , Ketamina/farmacologia , Ketamina/uso terapêutico , Depressão/tratamento farmacológico , Neuroimagem , Tomografia por Emissão de Pósitrons
12.
Neuropsychopharmacology ; 48(1): 54-60, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-35995973

RESUMO

Neuronal and synaptic plasticity are widely used terms in the field of psychiatry. However, cellular neurophysiologists have identified two broad classes of plasticity. Hebbian forms of plasticity alter synaptic strength in a synapse specific manner in the same direction of the initial conditioning stimulation. In contrast, homeostatic plasticities act globally over longer time frames in a negative feedback manner to counter network level changes in activity or synaptic strength. Recent evidence suggests that homeostatic plasticity mechanisms can be rapidly engaged, particularly by fast-acting antidepressants such as ketamine to trigger behavioral effects. There is increasing evidence that several neuropsychoactive compounds either directly elicit changes in synaptic activity or indirectly tap into downstream signaling pathways to trigger homeostatic plasticity and subsequent behavioral effects. In this review, we discuss this recent work in the context of a wider paradigm where homeostatic synaptic plasticity mechanisms may provide novel targets for neuropsychiatric treatment advance.


Assuntos
Ketamina , Sinapses , Plasticidade Neuronal/fisiologia , Homeostase/fisiologia , Neurônios , Ketamina/farmacologia
13.
Eur Neuropsychopharmacol ; 67: 37-52, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36476352

RESUMO

(S)-ketamine-induced rapid-acting antidepressant effects have revolutionized the pharmacotherapy of major depression; however, this medication also produces psychotomimetic effects such as timing distortion. While (R)-ketamine produces fewer dissociative effects, its antidepressant actions are less studied. Depression is associated with time overestimation (i.e., subjectively, time passes slowly). Our recent report suggests that while (S)-ketamine induces an opposite effect, i.e., time underestimation, the (R)-isomer does not affect timing. It has been suggested that opioid receptors are involved in the antidepressant effect of ketamine. In the present study we tested (R)- and (S)-ketamine, and fluoxetine as a positive control in the differential-reinforcement-of-low-rate (DRL) 72-s schedule of reinforcement in male rats following naloxone pretreatment. DRL classic metrics as well as peak deviation analyses served to determine antidepressant-like actions and those associated with timing. We report antidepressant-like effects of (S)-ketamine (30-60 mg/kg) that resemble fluoxetine's (2.5-10 mg/kg), as both compounds increased reinforcement rate and peak location (suggesting increased performance), reduced premature responses (suggesting time underestimation) and decreased Weber's fraction (suggesting increased timing precision). (R)-ketamine (30, but not 60 mg/kg) increased only the reinforcement rate and peak location but did not affect timing. Only fluoxetine decreased burst responses, suggesting decreased impulsivity. Naloxone pretreatment did not block ketamine enantiomers' actions, but unexpectedly, increased fluoxetine' performance. Thus, while all three medications produced antidepressant-like effects in DRL 72-s, fluoxetine- and (S)- but not (R)- ketamine-induced time underestimation (the subject experiences the time as passing quickly). The potentiation of DRL performance of fluoxetine by naloxone was unexpected and warrants clinical studies.


Assuntos
Transtorno Depressivo , Ketamina , Ratos , Masculino , Animais , Fluoxetina/farmacologia , Ketamina/farmacologia , Reforço Psicológico , Antidepressivos/farmacologia , Esquema de Reforço
14.
Synapse ; 77(1): e22253, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36121749

RESUMO

Anorexia nervosa (AN) is a mental illness with the highest rates of mortality and relapse, and no approved pharmacological treatment. Using an animal model of AN, called activity-based anorexia (ABA), we showed earlier that a single intraperitoneal injection of ketamine at a dose of 30 mg/kg (30mgKET), but not 3 mg/kg (3mgKET), has a long-lasting effect upon adolescent females of ameliorating anorexia-like symptoms through the following changes: enhanced food consumption and body weight; reduced running and anxiety-like behavior. However, there were also individual differences in the drug's efficacy. We hypothesized that individual differences in ketamine's ameliorative effects involve drebrin A, an F-actin-binding protein known to be required for the activity-dependent trafficking of NMDA receptors (NMDARs). We tested this hypothesis by electron microscopic quantifications of drebrin A immunoreactivity at excitatory synapses of pyramidal neurons (PN) and GABAergic interneurons (GABA-IN) in deep layer 1 of prefrontal cortex (PFC) of these mice. Results reveal that (1) the areal density of excitatory synapses on GABA-IN is greater for the 30mgKET group than the 3mgKET group; (2) the proportion of drebrin A+ excitatory synapses is greater for both PN and GABA-IN of 30mgKET than 3mgKET group. Correlation analyses with behavioral measurements revealed that (3) 30mgKET's protection is associated with reduced levels of drebrin A in the cytoplasm of GABA-IN and higher levels at extrasynaptic membranous sites of PN and GABA-IN; (5) altogether pointing to 30mgKET-induced homeostatic plasticity that engages drebrin A at excitatory synapses of both PN and GABA-IN.


Assuntos
Anorexia Nervosa , Ketamina , Camundongos , Feminino , Animais , Ketamina/farmacologia , Anorexia Nervosa/tratamento farmacológico , Anorexia Nervosa/metabolismo , Anorexia/tratamento farmacológico , Anorexia/metabolismo , Individualidade , Sinapses/metabolismo , Modelos Animais de Doenças , Córtex Pré-Frontal/metabolismo , Citoplasma/metabolismo , Ácido gama-Aminobutírico/metabolismo
15.
J Affect Disord ; 323: 598-606, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-36521662

RESUMO

Ketamine is a NMDA receptor antagonist that has a rapid acting antidepressant effect with high efficacy in treatment-resistant patients. Ketamine is a beneficial antidepressant for many individuals with depression, but not all of the patients respond, and some even exhibit symptom deterioration. The discovery of repeatable and mechanistically relevant biomarkers would address a major gap in treatment response prediction. Numerous potential peripheral biomarkers have been reported, but their current utility is unclear. We conducted an umbrella review to evaluate the biomarkers of ketamine's antidepressant effect in individuals with depression. PubMed and copus were searched using terms appropriate to each area of research, from their inception until July 2022. Five systematic reviews and meta analyses including 108 studies with 4912 participants were included. Blood-based and neuroimaging biomarkers were investigated. The results of this review indicate that ketamine can produce an anti-inflammatory effect and decrease at least one inflammatory marker following administration. Data from neuroimaging studies demonstrated that the cingulate cortex is the key locus of ketamine's action. The majority of the blood-based, neuroimaging, and neurophysiological investigations reviewed herein indicate ketamine induced normalization of major depressive disorder pathogenesis via synaptic plasticity and functional connectivity. Currently, no biomarker/biosignature is sufficiently validated for clinical utility, but several are promising. Now that ketamine is more widely available, biomarker discovery and replication should be attempted in larger, real-world populations.


Assuntos
Transtorno Depressivo Maior , Ketamina , Humanos , Depressão/tratamento farmacológico , Ketamina/uso terapêutico , Ketamina/farmacologia , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/tratamento farmacológico , Antidepressivos/uso terapêutico , Antidepressivos/farmacologia , Biomarcadores
16.
Vet Anaesth Analg ; 50(1): 63-71, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36528512

RESUMO

OBJECTIVE: To compare the effect of propofol, alfaxalone and ketamine on intraocular pressure (IOP) in cats. STUDY DESIGN: Prospective, masked, randomized clinical trial. ANIMALS: A total of 43 ophthalmologically normal cats scheduled to undergo general anesthesia for various procedures. METHODS: Following baseline IOP measurements using applanation tonometry, anesthesia was induced with propofol (n = 15), alfaxalone (n = 14) or ketamine (n = 14) administered intravenously to effect. Then, midazolam (0.3 mg kg-1) was administered intravenously and endotracheal intubation was performed without application of topical anesthesia. The IOP was measured following each intervention. Data was analyzed using one-way anova and repeated-measures mixed design with post hoc analysis. A p-value <0.05 was considered significant. RESULTS: Mean ± standard error IOP at baseline was not different among groups (propofol, 18 ± 0.6; alfaxalone, 18 ± 0.7; ketamine, 17 ± 0.5 mmHg). Following induction of anesthesia, IOP increased significantly compared with baseline in the propofol (20 ± 0.7 mmHg), but not in the alfaxalone (19 ± 0.8 mmHg) or ketamine (16 ± 0.7 mmHg) groups. Midazolam administration resulted in significant decrease from the previous measurement in the alfaxalone group (16 ± 0.7 mmHg), but not in the propofol group (19 ± 0.7 mmHg) or the ketamine (16 ± 0.8 mmHg) group. A further decrease was measured after intubation in the alfaxalone group (15 ± 0.9 mmHg). CONCLUSIONS AND CLINICAL RELEVANCE: Propofol should be used with caution in cats predisposed to perforation or glaucoma, as any increase in IOP should be avoided.


Assuntos
Anestésicos , Ketamina , Pregnanodionas , Propofol , Gatos , Animais , Propofol/farmacologia , Ketamina/farmacologia , Midazolam , Pressão Intraocular , Estudos Prospectivos , Pregnanodionas/farmacologia , Anestésicos/farmacologia
17.
Artigo em Inglês | MEDLINE | ID: mdl-36209771

RESUMO

The NMDA antagonist ketamine demonstrated a fast antidepressant activity in treatment-resistant depression. Pre-clinical studies suggest that de novo synthesis of the brain-derived neurotrophic factor (BDNF) in the PFC might be involved in the rapid antidepressant action of ketamine. Applying a genetic model of impaired glutamate release, this study aims to further identify the molecular mechanisms that could modulate antidepressant action and resistance to treatment. To that end, mice knocked-down for the vesicular glutamate transporter 1 (VGLUT1+/-) were used. We analyzed anhedonia and helpless behavior as well as the expression of the proteins linked to glutamate transmission in the PFC of mice treated with ketamine or the reference antidepressant reboxetine. Moreover, we analyzed the acute effects of ketamine in VGLUT1+/- mice pretreated with chronic reboxetine or those that received a PFC rescue expression of VGLUT1. Chronic reboxetine rescued the depressive-like phenotype of the VGLUT1+/- mice. In addition, it enhanced the expression of the proteins linked to the AMPA signaling pathway as well as the immature form of BDNF (pro-BDNF). Unlike WT mice, ketamine had no effect on anhedonia or pro-BDNF expression in VGLUT1+/- mice; it also failed to decrease phosphorylated eukaryote elongation factor 2 (p-eEF2). Nevertheless, we found that reboxetine administered as pretreatment or PFC overexpression of VGLUT1 did rescue the antidepressant-like activity of acute ketamine in the mice. Our results strongly suggest that not only do PFC VGLUT1 levels modulate the rapid-antidepressant action of ketamine, but also highlight a possible mechanism for antidepressant resistance in some patients.


Assuntos
Ketamina , Proteína Vesicular 1 de Transporte de Glutamato , Animais , Camundongos , Anedonia , Antidepressivos/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Depressão/metabolismo , Modelos Animais de Doenças , Ácido Glutâmico/metabolismo , Ketamina/farmacologia , Neurônios/metabolismo , Córtex Pré-Frontal/metabolismo , Reboxetina/farmacologia , Proteína Vesicular 1 de Transporte de Glutamato/metabolismo
18.
Pharmacol Biochem Behav ; 222: 173500, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36476377

RESUMO

Classical psychedelics with 5-hydroxytryptamine-2A receptor (5-HT2AR) agonism have rapid antidepressant actions in patients with depression. However, there is an ongoing debate over the role of 5-HT2AR in the antidepressant-like actions of psychedelics. In this study, we compared the effects of DOI (2,5-dimethoxy-4-iodoamphetamine: a hallucinogenic psychedelic drug with potent 5-HT2AR agonism), lisuride (non-hallucinogenic psychedelic analog with 5-HT2AR and 5-HT1AR agonisms), and the novel antidepressant (R)-ketamine on depression-like behavior and the decreased dendritic spine density in the brain of lipopolysaccharide (LPS)-treated mice. Saline (10 ml/kg), DOI (2.0 mg/kg), lisuride (1.0 mg/kg), or (R)-ketamine (10 mg/kg) was administered intraperitoneally to LPS (0.5 mg/kg, 23 h before)-treated mice. Both lisuride and (R)-ketamine significantly ameliorated the increased immobility time of forced swimming test, and the decreased dendritic spine density in the prelimbic region of medial prefrontal cortex, CA3 and dentate gyrus of hippocampus of LPS-treated mice. In contrast, DOI did not improve these changes produced after LPS administration. This study suggests that antidepressant-like effect of lisuride in LPS-treated mice is not associated with 5-HT2AR-related psychedelic effects. It is, therefore, unlikely that 5-HT2AR may play a major role in rapid-acting antidepressant actions of psychedelics although further detailed study is needed.


Assuntos
Alucinógenos , Ketamina , Camundongos , Animais , Alucinógenos/farmacologia , Lipopolissacarídeos/farmacologia , Lisurida , Ketamina/farmacologia , Serotonina , Antidepressivos/farmacologia , Depressão/tratamento farmacológico
19.
Transl Psychiatry ; 12(1): 500, 2022 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-36463316

RESUMO

The NMDA-R hypofunction model of schizophrenia started with the clinical observation of the precipitation of psychotic symptoms in patients with schizophrenia exposed to PCP or ketamine. Healthy volunteers exposed to acute low doses of ketamine experienced mild psychosis but also negative and cognitive type symptoms reminiscent of the full clinical picture of schizophrenia. In rodents, acute systemic ketamine resulted in a paradoxical increase in extracellular frontal glutamate as well as of dopamine. Similar increase in prefrontal glutamate was documented with acute ketamine in healthy volunteers with 1H-MRS. Furthermore, sub-chronic low dose PCP lead to reductions in frontal dendritic tree density in rodents. In post-mortem ultrastructural studies in schizophrenia, a broad reduction in dendritic complexity and somal volume of pyramidal cells has been repeatedly described. This most likely accounts for the broad, subtle progressive cortical thinning described with MRI in- vivo. Additionally, prefrontal reductions in the obligatory GluN1 subunit of the NMDA-R has been repeatedly found in post-mortem tissue. The vast 1H-MRS literature in schizophrenia has documented trait-like small increases in glutamate concentrations in striatum very early in the illness, before antipsychotic treatment (the same structure where increased pre-synaptic release of dopamine has been reported with PET). The more recent genetic literature has reliably detected very small risk effects for common variants involving several glutamate-related genes. The pharmacological literature has followed two main tracks, directly informed by the NMDA-R hypo model: agonism at the glycine site (as mostly add-on studies targeting negative and cognitive symptoms); and pre-synaptic modulation of glutamatergic release (as single agents for acute psychosis). Unfortunately, both approaches have failed so far. There is little doubt that brain glutamatergic abnormalities are present in schizophrenia and that some of these are related to the etiology of the illness. The genetic literature directly supports a non- specific etiological role for glutamatergic dysfunction. Whether NMDA-R hypofunction as a specific mechanism accounts for any important component of the illness is still not evident. However, a glutamatergic model still has heuristic value to guide future research in schizophrenia. New tools to jointly examine brain glutamatergic, GABA-ergic and dopaminergic systems in-vivo, early in the illness, may lay the ground for a next generation of clinical trials that go beyond dopamine D2 blockade.


Assuntos
Ketamina , Esquizofrenia , Humanos , Dopamina , Ketamina/farmacologia , N-Metilaspartato , Ácido Glutâmico
20.
J Avian Med Surg ; 36(3): 242-249, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36468801

RESUMO

The purpose of this study was to measure the effects of detomidine and medetomidine alone or in combination with ketamine on Schirmer tear test I (STT I) results and intraocular pressures (IOPs) in the common buzzard (Buteo buteo). Fourteen ophthalmologically healthy common buzzards were randomly assigned to 1 of 2 α-2 adrenoreceptor agonist groups: a detomidine group (group 1) and a medetomidine group (group 2). The detomidine group had 2 subgroups, detomidine alone or in combination with ketamine. Similarly, the medetomidine group had 2 subgroups, medetomidine alone or in combination with ketamine. Five minutes after α-2 adrenoreceptor agonist administration, the first measurements of STT I and IOP were collected. Ketamine was injected intramuscularly immediately after the first measurements were recorded. Schirmer tear test I and IOP measurements were repeated 5 minutes after ketamine administration. Measurements were obtained for 3 subgroups per agonist grouping: baseline 1, detomidine alone and detomidine with ketamine for group 1, and baseline 2, medetomidine alone and medetomidine with ketamine for group 2. Both IOP and STT I decreased significantly after sedation, anesthesia, or both. Intraocular pressure was significantly lower in the detomidine-ketamine group compared with the detomidine alone group. The IOP and STT I significantly decreased in both the medetomidine alone and medetomidine-ketamine groups when compared with those for all 14 unanesthetized animals before administering the α-2 adrenoreceptor agonist and ketamine. When α-2 adrenoreceptor agonists were considered as a single group (groups 1 and 2 combined), IOP also showed a significant decrease in the α-2 adrenoreceptor agonist-ketamine groups compared with the α-2 adrenoreceptor agonists alone, but STT I did not. According to the results obtained from these common buzzards, no statistical differences were found between the detomidine and medetomidine (alone) groups or detomidine-ketamine and medetomidine-ketamine groups in terms of STT I and IOP.


Assuntos
Falconiformes , Ketamina , Animais , Pressão Intraocular , Medetomidina/farmacologia , Ketamina/farmacologia , Tonometria Ocular/veterinária
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