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1.
Brain Res Bull ; 181: 175-182, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35124160

RESUMO

Previous studies showed a prominent role of the medial prefrontal cortex (mPFC), especially the prelimbic (PL) and infralimbic (IL) subregions, in behavioral and physiological responses to stressful stimuli. Nevertheless, the local neurochemical mechanisms involved are not completely understood. In this sense, previous studies identified cholinergic terminals within the mPFC, and stressful stimuli increased local acetylcholine release. Despite these pieces of evidence, the specific role of cholinergic neurotransmission in different subregions of the mPFC controlling the cardiovascular responses to stress has never been systematically evaluated. Therefore, the purpose of this study was to investigate the involvement of cholinergic neurotransmission present within PL and IL in cardiovascular responses to an acute session of restraint stress in rats. For this, rats received bilateral microinjection of the choline uptake inhibitor hemicholinium-3 before exposure to restraint stress. The arterial pressure and heart rate (HR) increases and the decrease in tail skin temperature as an indirect measurement of sympathetically-mediated cutaneous vasoconstriction were recorded throughout the restraint stress session. The results showed that the depletion of acetylcholine within the PL caused by local microinjection of hemicholinium-3 decreased the tachycardia to restraint stress, but without affecting the pressor response and the drop in tail skin temperature. Conversely, IL treatment with hemicholinium-3 decreased the restraint-evoked pressor response and the sympathetically-mediated cutaneous vasoconstriction without interfering with the HR response. Taken together, these results indicate functional differences of cholinergic neurotransmission within the PL and IL in control of cardiovascular and autonomic responses to stressful stimuli.


Assuntos
Acetilcolina/fisiologia , Sistema Nervoso Autônomo/fisiologia , Pressão Sanguínea/fisiologia , Colinérgicos/farmacologia , Frequência Cardíaca/fisiologia , Inibidores da Captação de Neurotransmissores/farmacologia , Córtex Pré-Frontal/fisiologia , Estresse Psicológico/fisiopatologia , Transmissão Sináptica/fisiologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Hemicolínio 3/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Restrição Física
2.
J Psychiatry Neurosci ; 46(1): E196-E207, 2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-33497170

RESUMO

Background: Depression is a common morbidity after traumatic brain injury. This network meta-analysis investigated the efficacy and tolerability of pharmacologic and nonpharmacologic interventions for depression after traumatic brain injury. Methods: We extracted randomized controlled trials examining pharmacologic or nonpharmacologic interventions with placebo- or active-controlled designs from PubMed, the Cochrane Library and ScienceDirect, from inception to October 30, 2018. We based study selection and extraction of a predefined list of variables on the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines, and conducted meta-analysis procedures using random effects modelling. Primary outcomes were changes in depressive symptom severity after pharmacologic or nonpharmacologic treatment; the secondary outcome was tolerability, reflected in overall patient dropout rates. Results: Our analysis of 27 randomized controlled trials (10 pharmacologic, total n = 483, mean age = 37.9 yr; 17 nonpharmacologic, total n = 1083, mean age = 38.0 yr) showed that methylphenidate had significantly superior efficacy compared to placebo or control (standardized mean difference -0.91, 95% confidence interval [CI] -1.49 to -0.33). Sertraline was associated with significantly lower tolerability (i.e., a higher dropout rate) compared to placebo or control (odds ratio 2.65, 95% CI 1.27 to 5.54). No nonpharmacologic treatment was more effective than the others, and we found no significant differences in tolerability (i.e., dropout rates) among the nonpharmacologic treatments. Limitations: Heterogeneity in participant characteristics (e.g., comorbidities), study designs (e.g., trial duration) and psychopathology assessment tools, as well as small trial numbers for some treatment arms, could have been confounders. Conclusion: The present network meta-analysis suggests that methylphenidate might be the best pharmacologic intervention for depressive symptoms related to traumatic brain injury. None of the nonpharmacologic interventions was associated with better improvement in depressive symptoms than the others or than control conditions. None of the pharmacologic or nonpharmacologic treatments had inferior tolerability compared to placebo or controls except for sertraline, which had significantly lower tolerability than placebo.


Assuntos
Lesões Encefálicas Traumáticas/complicações , Depressão/terapia , Transtorno Depressivo Maior/terapia , Metilfenidato/farmacologia , Inibidores da Captação de Neurotransmissores/farmacologia , Psicoterapia , Depressão/etiologia , Transtorno Depressivo Maior/etiologia , Humanos , Metanálise em Rede
3.
Pediatrics ; 147(2)2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33504611

RESUMO

Serotonergic medications are used for the prevention and treatment of depression during pregnancy. Selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors (SNRIs) can cause poor neonatal adaptation, which has been attributed to withdrawal versus toxicity. Bupropion, a norepinephrine-dopamine reuptake inhibitor, is often used as an adjunctive agent to selective serotonin reuptake inhibitors or SNRIs for refractory depression. Quetiapine, an atypical antipsychotic, may also be used in more complex cases. When combined with serotonergic drugs, bupropion and quetiapine are associated with increased risk of serotonin syndrome in adults. We describe a neonate exposed to venlafaxine (an SNRI), bupropion, and quetiapine in utero who presented nearly immediately after birth with encephalopathy and abnormal movements. The severity and rapidity of symptoms may be attributable to potentiation of venlafaxine's serotonergic effects by bupropion and quetiapine. Neonatal providers should be aware of maternal medications and prepare for possible adverse effects, particularly from common psychotropic exposures.


Assuntos
Antidepressivos/efeitos adversos , Transtorno Bipolar/tratamento farmacológico , Encefalopatias/induzido quimicamente , Discinesia Induzida por Medicamentos/etiologia , Inibidores da Captação de Neurotransmissores/efeitos adversos , Complicações na Gravidez/tratamento farmacológico , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Antidepressivos/uso terapêutico , Encefalopatias/congênito , Encefalopatias/diagnóstico , Bupropiona/efeitos adversos , Bupropiona/uso terapêutico , Quimioterapia Combinada , Discinesia Induzida por Medicamentos/congênito , Discinesia Induzida por Medicamentos/diagnóstico , Feminino , Humanos , Recém-Nascido , Masculino , Inibidores da Captação de Neurotransmissores/uso terapêutico , Gravidez , Fumarato de Quetiapina/efeitos adversos , Fumarato de Quetiapina/uso terapêutico , Cloridrato de Venlafaxina/efeitos adversos , Cloridrato de Venlafaxina/uso terapêutico
4.
Psychopharmacology (Berl) ; 238(2): 581-588, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33221932

RESUMO

RATIONALE: MDMA-assisted psychotherapy is under investigation as a novel treatment for posttraumatic stress disorder (PTSD). The primary mechanism of action of MDMA involves the same reuptake transporters targeted by antidepressant medications commonly prescribed for PTSD. OBJECTIVES: Data were pooled from four phase 2 trials of MDMA-assisted psychotherapy. To explore the effect of tapering antidepressant medications, participants who had been randomized to receive active doses of MDMA (75-125 mg) were divided into two groups (taper group (n = 16) or non-taper group (n = 34)). METHODS: Between-group comparisons were made for PTSD and depression symptom severity at the baseline and the primary endpoint, and for peak vital signs across two MDMA sessions. RESULTS: Demographics, baseline PTSD, and depression severity were similar between the taper and non-taper groups. At the primary endpoint, the non-taper group (mean = 45.7, SD = 27.17) had a significantly (p = 0.009) lower CAPS-IV total scores compared to the taper group (mean = 70.3, SD = 33.60). More participants in the non-taper group (63.6%) no longer met PTSD criteria at the primary endpoint than those in the taper group (25.0%). The non-taper group (mean = 12.7, SD = 10.17) had lower depression symptom severity scores (p = 0.010) compared to the taper group (mean = 22.6, SD = 16.69). There were significant differences between groups in peak systolic blood pressure (p = 0.043) and diastolic blood pressure (p = 0.032). CONCLUSIONS: Recent exposure to antidepressant drugs that target reuptake transporters may reduce treatment response to MDMA-assisted psychotherapy.


Assuntos
Antidepressivos/administração & dosagem , Redução da Medicação , N-Metil-3,4-Metilenodioxianfetamina/administração & dosagem , Inibidores da Captação de Neurotransmissores/administração & dosagem , Psicoterapia/métodos , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Adulto , Antidepressivos/uso terapêutico , Ensaios Clínicos Fase II como Assunto , Terapia Combinada , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Captação de Neurotransmissores/uso terapêutico , Escalas de Graduação Psiquiátrica , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
5.
Bioorg Chem ; 107: 104529, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33339665

RESUMO

In our screening program for new biologically active secondary metabolites, nine new polycyclic polyprenyled acylphloroglucinols, hyperscabins D-L, together with three known compounds, were obtained from the aerial parts of Hypericum scabrum. The chemical structures of 1-9 were characterized by extensive spectroscopic analyses, nuclear magnetic resonance calculation with DP4+ probability analysis, and the electronic circular dichroism spectra were calculated. Compound 1 was an unusual prenylated acylphloroglucinol decorated with a 5-oxaspiro [4,5] deca-1,9-dione skeleton. Compound 2 was a newly identified spirocyclic polyprenylated acylphloroglucinol possessing a rare 5,5-spiroketal segment. Compounds 3, 8, and 10 (10 µM) exhibited pronounced hepatoprotective activity against d-galactosamine-induced WB-F344 cell damage in vitro assays. All test compounds (1, 3, and 7-12) demonstrated potential inhibitory effects at 10 µM against noradrenalinet ([3H]-NE) reuptake in rat brain synaptosome.


Assuntos
Antidepressivos/farmacologia , Hemiterpenos/farmacologia , Hypericum/química , Floroglucinol/análogos & derivados , Floroglucinol/farmacologia , Substâncias Protetoras/farmacologia , Animais , Antidepressivos/síntese química , Antidepressivos/isolamento & purificação , Linhagem Celular , Hemiterpenos/síntese química , Hemiterpenos/isolamento & purificação , Inibidores da Captação de Neurotransmissores/síntese química , Inibidores da Captação de Neurotransmissores/isolamento & purificação , Inibidores da Captação de Neurotransmissores/farmacologia , Norepinefrina/metabolismo , Floroglucinol/isolamento & purificação , Componentes Aéreos da Planta/química , Substâncias Protetoras/síntese química , Substâncias Protetoras/isolamento & purificação , Ratos , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo
6.
Mol Neurobiol ; 57(5): 2144-2166, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31960362

RESUMO

Frontocortical NMDA receptors are pivotal in regulating cognition and mood, are hypofunctional in schizophrenia, and may contribute to autistic spectrum disorders. Despite extensive interest in agents potentiating activity at the co-agonist glycine modulatory site, few comparative functional studies exist. This study systematically compared the actions of the glycine reuptake inhibitors, sarcosine (40-200 mg/kg) and ORG24598 (0.63-5 mg/kg), the agonists, glycine (40-800 mg/kg), and D-serine (10-160 mg/kg) and the partial agonists, S18841 (2.5 mg/kg s.c.) and D-cycloserine (2.5-40 mg/kg) that all dose-dependently prevented scopolamine disruption of social recognition in adult rats. Over similar dose ranges, they also prevented a delay-induced impairment of novel object recognition (NOR). Glycine reuptake inhibitors specifically elevated glycine but not D-serine levels in rat prefrontal cortical (PFC) microdialysates, while glycine and D-serine markedly increased levels of glycine and D-serine, respectively. D-Cycloserine slightly elevated D-serine levels. Conversely, S18841 exerted no influence on glycine, D-serine, other amino acids, monamines, or acetylcholine. Reversal of NOR deficits by systemic S18841 was prevented by the NMDA receptor antagonist, CPP (20 mg/kg), and the glycine modulatory site antagonist, L701,324 (10 mg/kg). S18841 blocked deficits in NOR following microinjection into the PFC (2.5-10 µg/side) but not the striatum. Finally, in rats socially isolated from weaning (a neurodevelopmental model of schizophrenia), S18841 (2.5 and 10 mg/kg s.c.) reversed impairment of NOR and contextual fear-motivated learning without altering isolation-induced hyperactivity. In conclusion, despite contrasting neurochemical profiles, partial glycine site agonists and glycine reuptake inhibitors exhibit comparable pro-cognitive effects in rats of potential relevance to treatment of schizophrenia and other brain disorders where cognitive performance is impaired.


Assuntos
Transtornos Cognitivos/tratamento farmacológico , Cognição/efeitos dos fármacos , Glicinérgicos/farmacologia , Glicina/metabolismo , Memória de Curto Prazo/efeitos dos fármacos , Inibidores da Captação de Neurotransmissores/farmacologia , Nootrópicos/farmacologia , Aminoácidos/análise , Animais , Transtorno do Espectro Autista/tratamento farmacológico , Ciclosserina/farmacologia , Relação Dose-Resposta a Droga , Reação de Congelamento Cataléptica/efeitos dos fármacos , Glicina/agonistas , Glicina/análogos & derivados , Glicina/farmacologia , Masculino , Atividade Motora/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores de Glicina/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/fisiologia , Reconhecimento Psicológico/efeitos dos fármacos , Sarcosina/farmacologia , Esquizofrenia/tratamento farmacológico , Escopolamina/antagonistas & inibidores , Serina/farmacologia , Comportamento Social
7.
Behav Brain Res ; 379: 112267, 2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-31593789

RESUMO

Ketamine significantly increases the locomotor activity of rodents, however this effect varies according to the sex and age of the animal being tested. To determine the role monoamine systems play in ketamine's locomotor activating effects: (a) male and female preweanling, adolescent, and adult rats were pretreated with vehicle or the monoamine depleting agent reserpine (1 or 5 mg/kg), and (b) the behavioral actions of ketamine (20 or 40 mg/kg) were then compared to d-amphetamine (2 mg/kg) and cocaine (10 or 15 mg/kg). The ability of reserpine to deplete dorsal striatal dopamine (DA) and serotonin (5-HT) in male and female rats was determined using HPLC. Ketamine caused substantial increases in the locomotion of preweanling rats and older female rats (adolescents and adults), but had only small stimulatory effects on adolescent and adult male rats. When compared to cocaine and d-amphetamine, ketamine was especially sensitive to the locomotor-inhibiting effects of monoamine depletion. Ketamine-induced locomotion is at least partially mediated by monoamine systems, since depleting DA and 5-HT levels by 87-96% significantly attenuated the locomotor activating effects of ketamine in male and female rats from all three age groups. When administered to reserpine-pretreated rats, ketamine produced a different pattern of behavioral effects than either psychostimulant, suggesting that ketamine does not stimulate locomotor activity via actions at the presynaptic terminal. Instead, our results are consistent with the hypothesis that ketamine increases locomotor activity through a down-stream mechanism, possibly involving ascending DA and/or 5-HT projection neurons.


Assuntos
Comportamento Animal/efeitos dos fármacos , Monoaminas Biogênicas/metabolismo , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ketamina/farmacologia , Locomoção/efeitos dos fármacos , Inibidores da Captação de Neurotransmissores/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Transmissão Sináptica/efeitos dos fármacos , Inibidores da Captação Adrenérgica/farmacologia , Fatores Etários , Animais , Cocaína/farmacologia , Dextroanfetamina/metabolismo , Inibidores da Captação de Dopamina/farmacologia , Interações Medicamentosas , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Feminino , Ketamina/administração & dosagem , Masculino , Inibidores da Captação de Neurotransmissores/administração & dosagem , Ratos , Ratos Sprague-Dawley , Reserpina/farmacologia , Caracteres Sexuais
8.
Behav Brain Res ; 378: 112266, 2020 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-31580915

RESUMO

Psychostimulants are highly effective cognitive-enhancing therapeutics yet have a significant potential for abuse and addiction. While psychostimulants likely exert their rewarding and addictive properties through dopamine transporter (DAT) inhibition, the mechanisms of their procognitive effects are less certain. By one prevalent view, psychostimulants exert their procognitive effects exclusively through norepinephrine transporter (NET) inhibition, however increasing evidence suggests that DAT also plays a critical role in their cognitive-enhancing properties, including long-term memory enhancement. The present experiments test the hypothesis that combined strong NET and weak DAT inhibition will mimic the fear memory-enhancing but not the addiction-related effects of psychostimulants in mice. We examined the effects of the high affinity NET inhibitors atomoxetine or nisoxetine and the low affinity DAT inhibitor bupropion, either alone or in combination, on short- and long-term memory of Pavlovian fear conditioning. We also examined the addiction-related effects of combined strong NET and weak DAT inhibition using conditioned place preference and a locomotor activity test. While atomoxetine or nisoxetine alone enhanced short-term fear memory, the addition of bupropion was required to significantly enhance long-term fear memory. Additionally, combined atomoxetine and bupropion did not produce substantial motor stimulation or place preference. These findings suggest that combining strong NET and weak DAT inhibition could lead to the development of a highly effective cognitive enhancer that lacks the potential for addiction.


Assuntos
Cloridrato de Atomoxetina/farmacologia , Comportamento Animal/efeitos dos fármacos , Bupropiona/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Condicionamento Clássico/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Medo/efeitos dos fármacos , Fluoxetina/análogos & derivados , Memória de Longo Prazo/efeitos dos fármacos , Inibidores da Captação de Neurotransmissores/farmacologia , Nootrópicos/farmacologia , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Animais , Cloridrato de Atomoxetina/administração & dosagem , Bupropiona/administração & dosagem , Estimulantes do Sistema Nervoso Central/administração & dosagem , Quimioterapia Combinada , Feminino , Fluoxetina/administração & dosagem , Fluoxetina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Inibidores da Captação de Neurotransmissores/administração & dosagem , Nootrópicos/administração & dosagem
9.
Int J Neuropsychopharmacol ; 23(1): 12-19, 2020 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-31701133

RESUMO

BACKGROUND: Catecholamines are important for cognitive control and the ability to adapt behavior (e.g., after response errors). A prominent drug that modulates the catecholaminergic system is methylphenidate. On the basis of theoretical consideration, we propose that the effects of methylphenidate on behavioral adaptation depend on prior learning experience. METHODS: In a double-blind, randomized, placebo-controlled crossover study design, we examined the effect of methylphenidate (0.25 mg/kg) on post error behavioral adaptation processes in a group of n = 43 healthy young adults. Behavioral adaptation processes were examined in a working memory, modulated response selection task. The focus of the analysis was on order effects within the crossover study design to evaluate effects of prior learning/task experience. RESULTS: The effect of methylphenidate/placebo on post-error behavioral adaptation processes reverses depending on prior task experience. When there was no prior experience with the task, methylphenidate increased post-error slowing and thus intensified behavioral adaptation processes. However, when there was prior task experience, (i.e., when the placebo session was conducted first in the crossover design), methylphenidate even decreased post-error slowing and behavioral adaptation. Effect sizes were large and the power of the observed effects was higher than 95%. CONCLUSIONS: The data suggest that catecholaminergic effects on cognitive control functions vary as a function of prior learning/task experience. The data establish a close link between learning/task familiarization and catecholaminergic effects for executive functions, which has not yet been studied, to our knowledge, but is of considerable clinical relevance. Theoretical implications are discussed.


Assuntos
Adaptação Psicológica/efeitos dos fármacos , Função Executiva/efeitos dos fármacos , Metilfenidato/farmacologia , Inibidores da Captação de Neurotransmissores/farmacologia , Prática Psicológica , Desempenho Psicomotor/efeitos dos fármacos , Reconhecimento Psicológico , Adulto , Estudos Cross-Over , Dopamina/fisiologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Norepinefrina/fisiologia , Adulto Jovem
11.
Molecules ; 24(23)2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31757051

RESUMO

SMe1EC2M3 is a pyridoindole derivative related to the neuroleptic drug carbidine. Based on the structural similarities of SMe1EC2M3 and known serotonin (5-HT), norepinephrine, and dopamine reuptake inhibitors, we hypothesized that this compound may also have triple reuptake inhibition efficacy and an antidepressant-like effect. PreADMET and Dragon software was used for in silico prediction of pharmacokinetics and pharmacodynamics of SMe1EC2M3. Forced swim test was used to evaluate its antidepressant-like effects. Extracellular in vivo electrophysiology was used to assess 5-HT, norepinephrine, and dopamine reuptake inhibition efficacy of SMe1EC2M3. PreADMET predicted reasonable intestinal absorption, plasma protein binding, and blood-brain permeability for SMe1EC2M3. Dragon forecasted its efficiency as an antidepressant. Using behavioral measurements, it was found that SMe1EC2M3 decreased immobility time and increase swimming time during the forced swim test (FST). Electrophysiological investigations showed that SMe1EC2M3 dose-dependently suppressed the excitability of 5-HT neurons of the dorsal raphe nucleus (DRN), norepinephrine neurons of the locus coeruleus (LC), and dopamine neurons of the ventral tegmental area (VTA). The SMe1EC2M3-induced suppression of 5-HT, norepinephrine, and dopamine neurons was reversed by the antagonists of serotonin-1A (5-HT1A; WAY100135), α-2 adrenergic (α2, yohimbine), and dopamine-2 receptors (D2, haloperidol), respectively. We conclude that SMe1EC2M3 is prospective triple 5-HT, norepinephrine, and dopamine reuptake inhibitor with antidepressant-like properties, however future studies should be performed to complete the pharmacological profiling of this compound.


Assuntos
Antidepressivos , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Neurônios/metabolismo , Inibidores da Captação de Neurotransmissores , Transmissão Sináptica/efeitos dos fármacos , Animais , Antidepressivos/química , Antidepressivos/farmacocinética , Antidepressivos/farmacologia , Masculino , Inibidores da Captação de Neurotransmissores/química , Inibidores da Captação de Neurotransmissores/farmacocinética , Inibidores da Captação de Neurotransmissores/farmacologia , Ratos , Ratos Wistar
12.
Neurochem Int ; 131: 104551, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31542295

RESUMO

In Parkinson's disease, degeneration of substantia nigra dopaminergic neurons is accompanied by damage on other neuronal systems. A severe denervation is for example seen in the locus coerulean noradrenergic system. Little is known about the relation between noradrenergic and dopaminergic degeneration, and the effects of noradrenergic denervation on the function of the dopaminergic neurons of substantia nigra are not fully understood. In this study, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) was injected in rats, whereafter behavior, striatal KCl-evoked dopamine and glutamate releases, and immunohistochemistry were monitored at 3 days, 3 months, and 6 months. Quantification of dopamine-beta-hydroxylase-immunoreactive nerve fiber density in the cortex revealed a tendency towards nerve fiber regeneration at 6 months. To sustain a stable noradrenergic denervation throughout the experimental timeline, the animals in the 6-month time point received an additional DSP4 injection (2 months after the first injection). Behavioral examinations utilizing rotarod revealed that DSP4 reduced the time spent on the rotarod at 3 but not at 6 months. KCl-evoked dopamine release was significantly increased at 3 days and 3 months, while the concentrations were normalized at 6 months. DSP4 treatment prolonged both time for onset and reuptake of dopamine release over time. The dopamine degeneration was confirmed by unbiased stereology, demonstrating significant loss of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra. Furthermore, striatal glutamate release was decreased after DSP4. In regards of neuroinflammation, reactive microglia were found over the substantia nigra after DSP4 treatment. In conclusion, long-term noradrenergic denervation reduces the number of dopaminergic neurons in the substantia nigra and affects the functionality of the nigrostriatal system. Thus, locus coeruleus is important for maintenance of nigral dopaminergic neurons.


Assuntos
Neurônios Dopaminérgicos/fisiologia , Norepinefrina/fisiologia , Substância Negra/citologia , Substância Negra/fisiologia , Animais , Benzilaminas , Proteínas de Ligação ao Cálcio/metabolismo , Denervação , Dopamina/metabolismo , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Feminino , Ácido Glutâmico/metabolismo , Locus Cerúleo/efeitos dos fármacos , Locus Cerúleo/metabolismo , Proteínas dos Microfilamentos/metabolismo , Microglia/efeitos dos fármacos , Microglia/metabolismo , Fibras Nervosas/metabolismo , Neurônios/fisiologia , Inibidores da Captação de Neurotransmissores , Ratos , Ratos Sprague-Dawley
13.
Eur J Pharmacol ; 862: 172632, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31473161

RESUMO

Significant unmet needs exist for development of better pharmacotherapeutic agents for major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) as the current drugs are inadequate. Our goal in this study is to investigate behavioral pharmacological characterization of a novel triple reuptake inhibitor (TRI) D-578 which exhibits nanomolar potency at all three monoamine transporters (Ki; 16.2. 16.2, 3.23 nM, and 29.6, 20.6, 6.10 nM for the rat brain and cloned human dopamine, serotonin and norepinephrine transporters, respectively) and exhibited little to no affinity for other off-target CNS receptors. In a rat forced swim test, compound D-578 upon oral administration displayed high efficacy and not stimulating in locomotor behavior. The effects of D-578 and paroxetine were next evaluated in a rat model for traumatic stress exposure - the single prolonged stress (SPS) model - which has been shown to have construct, predictive, and behavioral validity in modeling aspects of PTSD. Our results show that SPS had no effect on the acquisition of conditioned fear, but impaired extinction learning and extinction retention of fear behavior compared to sham treatment. D-578, but not paroxetine, attenuated the extinction and extinction-retention deficit induced by SPS. These findings suggest that D-578 has greater efficacy in normalizing traumatic stress-induced extinction-retention learning in a model for PTSD compared to paroxetine. Overall these results suggest that D-578, in addition to producing a robust and efficacious antidepressant effect, may attenuate maladaptive retention of fearful memories and support further testing of this agent for the pharmacotherapy of depression and PTSD.


Assuntos
Antidepressivos/farmacologia , Transtorno Depressivo Maior/tratamento farmacológico , Inibidores da Captação de Neurotransmissores/farmacologia , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Estresse Psicológico/complicações , Administração Oral , Animais , Antidepressivos/uso terapêutico , Técnicas de Observação do Comportamento , Comportamento Animal/efeitos dos fármacos , Transtorno Depressivo Maior/etiologia , Transtorno Depressivo Maior/psicologia , Modelos Animais de Doenças , Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Avaliação Pré-Clínica de Medicamentos , Humanos , Masculino , Inibidores da Captação de Neurotransmissores/uso terapêutico , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Ratos , Retenção Psicológica/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Transtornos de Estresse Pós-Traumáticos/etiologia , Transtornos de Estresse Pós-Traumáticos/psicologia , Estresse Psicológico/psicologia
14.
Drugs ; 79(7): 785-790, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31062265

RESUMO

Solriamfetol (Sunosi™) is an orally active, selective dopamine and norepinephrine reuptake inhibitor that was recently approved in the USA as a treatment for excessive daytime sleepiness (hypersomnia) associated with narcolepsy and obstructive sleep apnoea (OSA). Norepinephrine and dopamine influence various physiologic functions, including sleep-wake regulation, and excessive sleepiness has been linked with dysregulation of dopaminergic and norepinephrine systems. This article summarizes the milestones in the development of solriamfetol leading to this first approval as a treatment for excessive daytime sleepiness associated with narcolepsy and OSA.


Assuntos
Distúrbios do Sono por Sonolência Excessiva/tratamento farmacológico , Inibidores da Captação de Dopamina/farmacocinética , Inibidores da Captação de Dopamina/administração & dosagem , Inibidores da Captação de Dopamina/efeitos adversos , Inibidores da Captação de Dopamina/uso terapêutico , Relação Dose-Resposta a Droga , Aprovação de Drogas , Humanos , Narcolepsia/tratamento farmacológico , Inibidores da Captação de Neurotransmissores/administração & dosagem , Inibidores da Captação de Neurotransmissores/efeitos adversos , Inibidores da Captação de Neurotransmissores/farmacocinética , Inibidores da Captação de Neurotransmissores/uso terapêutico , Norepinefrina/metabolismo , Transtornos do Sono-Vigília/tratamento farmacológico , Resultado do Tratamento , Estados Unidos , United States Food and Drug Administration
16.
J Clin Pharmacol ; 59(8): 1120-1129, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30865315

RESUMO

Solriamfetol (JZP-110), a selective dopamine and norepinephrine reuptake inhibitor with wake-promoting effects, is renally excreted ∼90% unchanged within 48 hours. Effects of renal impairment and hemodialysis on the pharmacokinetics and safety of 75-mg single-dose solriamfetol were evaluated in adults with normal renal function (n = 6); mild (n = 6), moderate (n = 6), or severe (n = 6) renal impairment; and end-stage renal disease (ESRD) with and without hemodialysis (n = 7). Relative to normal renal function, geometric mean area under the plasma concentration-time curve from time zero to infinity increased 53%, 129%, and 339%, and mean half-life was 1.2-, 1.9-, and 3.9-fold higher with mild, moderate, and severe renal impairment, respectively. Renal excretion of unchanged solriamfetol over 48 hours was 85.8%, 80.0%, 66.4%, and 57.1% in normal, mild, moderate, and severe renal impairment groups, respectively; mean maximum concentration and time to maximum concentration did not vary substantially. Decreases in solriamfetol clearance were proportional to decreases in estimated glomerular filtration rate. Geometric mean area under the plasma concentration-time curve from time zero to time of last quantifiable concentration increased 357% and 518% vs normal in ESRD with and without hemodialysis, respectively, with half-life >100 hours in both groups. Over the 4-hour hemodialysis period, ∼21% of solriamfetol dose was removed. Adverse events included headache (n = 1) and nausea (n = 1). Six days after dosing, 1 participant had increased alanine and aspartate aminotransferase, leading to study discontinuation. While these adverse events were deemed study-drug related, they were mild and resolved. Results from this study combined with population pharmacokinetic modeling/simulation suggest that solriamfetol dosage adjustments are necessary in patients with moderate or severe but not with mild renal impairment. Due to significant exposure increase/prolonged half-life, dosing is not recommended in patients with ESRD.


Assuntos
Carbamatos/farmacocinética , Falência Renal Crônica/metabolismo , Inibidores da Captação de Neurotransmissores/farmacocinética , Fenilalanina/análogos & derivados , Insuficiência Renal/metabolismo , Adulto , Idoso , Carbamatos/efeitos adversos , Carbamatos/sangue , Carbamatos/urina , Feminino , Humanos , Rim/metabolismo , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Inibidores da Captação de Neurotransmissores/efeitos adversos , Inibidores da Captação de Neurotransmissores/sangue , Inibidores da Captação de Neurotransmissores/urina , Fenilalanina/efeitos adversos , Fenilalanina/sangue , Fenilalanina/farmacocinética , Fenilalanina/urina , Diálise Renal
17.
Expert Rev Neurother ; 19(4): 311-315, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30871381

RESUMO

INTRODUCTION: A 'holy grail' of treatment options for attention-deficit hyperactivity disorder (ADHD) has been an agent with low abuse potential and peak-trough clinical effects, providing sustained therapeutic benefits throughout the day. One such agent, dasotraline, a dopamine and norepinephrine reuptake inhibitor agent, was recently reviewed by the FDA. Areas covered: The authors completed a timely drug review using a PubMed literature search using words 'Dasotraline, ADHD' 'stimulant, abuse' 'atomoxetine, ADHD.' FDA fact sheets of available medications were reviewed for comparison of safety and tolerability data. The authors reviewed preclinical, efficacy, and safety trials of dasotraline in ADHD: two phase 1, one phase 2, and several phase 3 trials have established efficacy in reducing ADHD symptoms. Expert opinion: Due to its stable plasma concentrations with once-daily dosing, dasotraline could have sustained treatment benefits for ADHD, with low abuse potential and a stable therapeutic response over a 24-h period.


Assuntos
1-Naftilamina/análogos & derivados , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Inibidores da Captação de Neurotransmissores/farmacologia , 1-Naftilamina/farmacocinética , 1-Naftilamina/farmacologia , Humanos , Inibidores da Captação de Neurotransmissores/farmacocinética
18.
J Clin Psychiatry ; 80(1)2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30753760

RESUMO

OBJECTIVE: To evaluate the efficacy and tolerability of pharmacotherapy in pediatric anxiety disorders using network meta-analysis. DATA SOURCES: PubMed, Cochrane Database, Web of Science, PsycNET, and ClinicalTrials.gov were searched for double-blind, controlled pharmacotherapy trials in youth with anxiety disorders from 1966 to September 2017. DATA SELECTION: All double-blind, placebo-controlled trials of pharmacotherapy in the treatment of pediatric patients with generalized, social, and/or separation anxiety disorders were included. DATA EXTRACTION: We extracted demographic, symptom severity, global improvement, discontinuation, and suicidality data. Risk of bias was assessed with the Cochrane risk-of-bias tool, and a network meta-analysis comparing the efficacy and tolerability of medications and medication classes was performed using the gemtc package (R). RESULTS: We identified 20 citations (22 RCTs, 24 treatment arms) with 2,623 patients. Selective serotonin reuptake inhibitors (SSRIs) were the only class that was superior in reducing anxiety (standardized mean difference: 5.2; credible interval [CrI]: [2.8 to 8.8]) and in likelihood of treatment response compared to placebo (odds ratio [OR]: 4.6; CrI: [3.1 to 7.5]). Serotonin-norepinephrine reuptake inhibitor (SNRI) and α2 agonist treatment were associated with more frequent treatment response compared to placebo. The likelihood of treatment response was greater for SSRIs compared to SNRIs (OR: 1.9; CrI: [1.1 to 3.5]). All-cause discontinuation and treatment-emergent suicidality significantly differed among medications but not medication class. CONCLUSIONS: Although multiple medications reduce anxiety in children and adolescents, treatment response, tolerability, and treatment-emergent suicidality differ among these medications and medication classes. Determining whether efficacy and tolerability differences represent true differences (or reflect differences in trial design) requires additional head-to-head medication trials and-to exclude the impact of missing treatment interventions-requires trials of medications that successfully treat anxiety in adults but that have not been evaluated in youth.


Assuntos
Transtornos de Ansiedade/tratamento farmacológico , Inibidores da Captação de Neurotransmissores/farmacologia , Criança , Humanos , Metanálise em Rede , Resultado do Tratamento
19.
J Alzheimers Dis ; 68(1): 115-126, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30689563

RESUMO

The degeneration in the locus coeruleus associated with Alzheimer's disease suggests an involvement of the noradrenergic system in the disease pathogenesis. The role of depleted norepinephrine was tested in adult and aged rhesus macaques to develop a potential model for testing Alzheimer's disease interventions. Monkeys were injected with the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) or vehicle at 0, 3, and 6 months; brains were harvested at 9 months. Reduced norepinephrine in the locus coeruleus was accompanied by decreased dopamine ß-hydroxylase staining and increased amyloid-ß load in the aged group, and the proportion of potentially toxic amyloid-ß42 peptide was increased. Immunohistochemistry revealed no effects on microglia or astrocytes. DSP4 treatment altered amyloid processing, but these changes were not associated with the induction of chronic neuroinflammation. These findings suggest norepinephrine deregulation is an essential component of a nonhuman primate model of Alzheimer's disease, but further refinement is necessary.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Benzilaminas/farmacologia , Locus Cerúleo/metabolismo , Inibidores da Captação de Neurotransmissores/farmacologia , Norepinefrina/metabolismo , Fragmentos de Peptídeos/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Precursor de Proteína beta-Amiloide/antagonistas & inibidores , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Feminino , Locus Cerúleo/efeitos dos fármacos , Macaca mulatta , Norepinefrina/antagonistas & inibidores , Fragmentos de Peptídeos/antagonistas & inibidores , Distribuição Aleatória
20.
Behav Brain Res ; 357-358: 39-47, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-28662893

RESUMO

Acute exposure to stress induces significant behavioural changes, while repeated exposure to the same stressor leads to the development of tolerance to stress. The development of tolerance appears to involve the serotonergic projections from the Median Raphe Nucleus (MnRN) to the dorsal Hippocampus (dH), since rats with lesions of this pathway does not develop tolerance to stress. Previous data from our laboratory showed that treatment with imipramine, a serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor, lead to the development of tolerance. However, it remains to be elucidated whether such tolerance involves the participation of the noradrenergic system, apart from the serotonergic projections. Therefore, the aim of this work was to investigate the behavioural and neurochemical effects of chronic treatment with desipramine (NA reuptake inhibitor) or fluoxetine (5-HT reuptake inhibitor) in chronically stressed rats with lesions of the serotonergic neurons of the MnRN. Male Wistar rats with or without lesion in the MnRN were submitted or not to acute (2 h) or chronic restraint (2 h/seven days) stress and tested in the elevated pus maze (EPM). Treatment with fluoxetine, desipramine (10 mg/kg) or saline was performed twice daily (12-12 h interval), for 7 consecutive days. EPM test was conducted 24 h after the treatment. Fluoxetine attenuated the anxiogenic-induced effect of lesion in chronically restrained rats, without changing serotonin and noradrenaline levels in the hippocampus of lesioned rats. A similar profile was also observed after treatment with desipramine. These results suggest that both the serotonergic and the noradrenergic systems are involved in the development of tolerance to chronic stress. Additionally, the integrity of the serotonergic pathway of the MnRN-dH is not essential for the anxiolytic-like effects of these drugs.


Assuntos
Núcleo Dorsal da Rafe/citologia , Núcleo Dorsal da Rafe/lesões , Norepinefrina/metabolismo , Neurônios Serotoninérgicos/fisiologia , Serotonina/metabolismo , Estresse Psicológico , 5,7-Di-Hidroxitriptamina/farmacologia , Análise de Variância , Animais , Desipramina/farmacologia , Modelos Animais de Doenças , Tolerância a Medicamentos , Fluoxetina/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Inibidores da Captação de Neurotransmissores/farmacologia , Ratos , Ratos Wistar , Serotoninérgicos/farmacologia , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Estresse Psicológico/patologia
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