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1.
Pharmacol Biochem Behav ; 178: 42-50, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-29289701

RESUMO

Efforts to replicate results from both basic and clinical models have highlighted problems with reproducibility in science. In psychiatry, reproducibility issues are compounded because the complex behavioral syndromes make many disorders challenging to model. We develop translatable tasks that quantitatively measure psychiatry-relevant behaviors across species. The behavioral pattern monitor (BPM) was designed to analyze exploratory behaviors, which are altered in patients with bipolar disorder (BD), especially during mania episodes. We have repeatedly assessed the behavioral effects of reduced dopamine transporter (DAT) expression in the BPM using a DAT knockdown (KD) mouse line (~10% normal expression). DAT KD mice exhibit a profile in the BPM consistent with acutely manic BD patients in the human version of the task-hyperactivity, increased exploratory behavior, and reduced spatial d (Perry et al., 2009). We collected data from multiple DAT KD BPM experiments in our laboratory to assess the reproducibility of behavioral outcomes across experiments. The four outcomes analyzed were: 1) transitions (amount of locomotor activity); 2) rearings (exploratory activity); 3) holepokes (exploratory activity); and 4) spatial d (geometrical pattern of locomotor activity). By comparing DAT KD mice to wildtype (WT) littermates in every experiment, we calculated effect sizes for each of the four outcomes and then calculated a mean effect size using a random effects model. DAT KD mice exhibited robust, reproducible changes in each of the four outcomes, including increased transitions, rearings, and holepokes, and reduced spatial d, vs. WT littermates. Our results demonstrate that the DAT KD mouse line in the BPM is a consistent, reproducible model of mania-relevant behaviors. More work must be done to assess reproducibility of behavioral outcomes across experiments in order to advance the field of psychiatry and develop more effective therapeutics for patients.


Assuntos
Comportamento Animal/fisiologia , Transtorno Bipolar/fisiopatologia , Modelos Animais de Doenças , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Técnicas de Silenciamento de Genes , Animais , Antimaníacos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/psicologia , Estudos de Coortes , Agonistas de Dopamina/uso terapêutico , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Quinolonas/uso terapêutico , Reprodutibilidade dos Testes , Tiofenos/uso terapêutico , Tirosina 3-Mono-Oxigenase/antagonistas & inibidores , Ácido Valproico/uso terapêutico , alfa-Metiltirosina/farmacologia , alfa-Metiltirosina/uso terapêutico
2.
Mol Neurobiol ; 56(4): 2728-2740, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30056575

RESUMO

Reduced movement frequency or physical activity (bradykinesia) occurs with high prevalence in the elderly. However, loss of striatal tyrosine hydroxylase (TH) in aging humans, non-human primates, or rodents does not reach the ~ 80% loss threshold associated with bradykinesia onset in Parkinson's disease. Moderate striatal dopamine (DA) loss, either following TH inhibition or decreased TH expression, may not affect movement frequency. In contrast, moderate DA or TH loss in the substantia nigra (SN), as occurs in aging, is of similar magnitude (~ 40%) to nigral TH loss at bradykinesia onset in Parkinson's disease. In aged rats, increased TH expression and DA in SN alone increases movement frequency, suggesting aging-related TH and DA loss in the SN contributes to aging-related bradykinesia or decreased physical activity. To test this hypothesis, the SN was targeted with bilateral guide cannula in young (6 months old) rats, in a within-subjects design, to evaluate the impact of nigral TH inhibition on movement frequency and speed. The TH inhibitor, α-methyl-p-tyrosine (AMPT) reduced nigral DA (~ 40%) 45-150 min following infusion, without affecting DA in striatum, nucleus accumbens, or adjacent ventral tegmental area. Locomotor activity in the open-field was recorded up to 3 h following nigral saline or AMPT infusion in each test subject. During the period of nigra-specific DA reduction, movement frequency, but not movement speed, was significantly decreased. These results indicate that DA or TH loss in the SN, as observed in aging, contributes as a central mechanism of reduced movement frequency.


Assuntos
Movimento , Substância Negra/enzimologia , Tirosina 3-Mono-Oxigenase/antagonistas & inibidores , Animais , Cateteres , Dopamina/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Movimento/efeitos dos fármacos , Ratos Endogâmicos BN , Reprodutibilidade dos Testes , Tirosina 3-Mono-Oxigenase/metabolismo , alfa-Metiltirosina/farmacologia
3.
Nature ; 564(7735): 273-277, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30542164

RESUMO

Cytokine release syndrome (CRS) is a life-threatening complication of several new immunotherapies used to treat cancers and autoimmune diseases1-5. Here we report that atrial natriuretic peptide can protect mice from CRS induced by such agents by reducing the levels of circulating catecholamines. Catecholamines were found to orchestrate an immunodysregulation resulting from oncolytic bacteria and lipopolysaccharide through a self-amplifying loop in macrophages. Myeloid-specific deletion of tyrosine hydroxylase inhibited this circuit. Cytokine release induced by T-cell-activating therapeutic agents was also accompanied by a catecholamine surge and inhibition of catecholamine synthesis reduced cytokine release in vitro and in mice. Pharmacologic catecholamine blockade with metyrosine protected mice from lethal complications of CRS resulting from infections and various biotherapeutic agents including oncolytic bacteria, T-cell-targeting antibodies and CAR-T cells. Our study identifies catecholamines as an essential component of the cytokine release that can be modulated by specific blockers without impairing the therapeutic response.


Assuntos
Catecolaminas/antagonistas & inibidores , Catecolaminas/metabolismo , Citocinas/efeitos adversos , Síndrome , Animais , Fator Natriurético Atrial/farmacologia , Complexo CD3/antagonistas & inibidores , Catecolaminas/biossíntese , Citocinas/imunologia , Epinefrina/metabolismo , Feminino , Humanos , Imunoterapia Adotiva , Técnicas In Vitro , Estimativa de Kaplan-Meier , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Células Mieloides/efeitos dos fármacos , Células Mieloides/metabolismo , Norepinefrina/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T/uso terapêutico , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , alfa-Metiltirosina/farmacologia
4.
Neuropharmacology ; 134(Pt A): 13-21, 2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-28887185

RESUMO

3,4-Methylenedioxypyrovalerone (MDPV) is a common constituent of illicit bath salts products, and in vitro studies implicate monoamine transporters as mediators of its pharmacological effects. Locomotor and thermoregulatory effects of MDPV depend on ambient temperature, so the current studies aimed to gauge the involvement of dopamine (DA), norepinephrine (NE), and serotonin (5-HT) in MDPV-induced locomotor stimulation and hyperthermia in the mouse at different ambient temperatures. Mice were pretreated with the selective 5-HT-reuptake inhibitor fluoxetine (3 mg/kg), the NE-reuptake inhibitor desipramine (3 mg/kg), the DA-reuptake inhibitor bupropion (10 mg/kg), or saline, followed by 10 mg/kg MDPV while thermoregulation and locomotor activity were monitored via radiotelemetry. In other studies, mice were pretreated for three days with saline, 100 mg/kg of the tryptophan hydroxylase inhibitor para-chlorophenylalanine (p-CPA), or 100 mg/kg of the tyrosine hydroxylase inhibitor α-methyl-para-tyrosine (α-MPT) before receiving 10 mg/kg MDPV on the fourth day. All manipulations were conducted at both 20 °C and 28 °C ambient temperatures. MDPV increased locomotor activity under both ambient conditions and modestly increased core body temperature at 20 °C; however, neither pretreatment with monoamine reuptake inhibitors nor monoamine synthesis inhibitors significantly altered these effects. At 28 °C, MDPV induced a more pronounced hyperthermic effect which was attenuated by bupropion, desipramine, or fluoxetine pretreatment, but not by the monoamine synthesis inhibitors. These results suggest that MDPV may have a more complex pharmacological profile than suggested by in vitro studies, perhaps extending beyond interactions with monoamine transporters. A more thorough binding profile of MDPV at various brain recognition sites should be developed. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.'


Assuntos
Benzodioxóis/toxicidade , Monoaminas Biogênicas/metabolismo , Febre/induzido quimicamente , Locomoção/efeitos dos fármacos , Inibidores da Captação de Neurotransmissores/farmacologia , Pirrolidinas/toxicidade , Temperatura , Análise de Variância , Animais , Temperatura Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Fenclonina/farmacologia , Febre/fisiopatologia , Fluoxetina/farmacologia , Masculino , Camundongos , Telemetria , alfa-Metiltirosina/farmacologia
5.
Neuropsychopharmacology ; 43(4): 868-876, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29105662

RESUMO

The integration of reward magnitudes and effort costs is required for an effective behavioral guidance. This reward-effort integration was reported to be dependent on dopaminergic neurotransmission. As bulimia nervosa has been associated with a dysregulated dopamine system and catecholamine depletion led to reward-processing deficits in remitted bulimia nervosa, the purpose of this study was to identify the role of catecholamine dysfunction and its relation to behavioral and neural reward-effort integration in bulimia nervosa. To investigate the interaction between catecholamine functioning and behavioral, and neural responses directly, 17 remitted bulimic (rBN) and 21 healthy individuals (HC) received alpha-methyl-paratyrosine (AMPT) over 24 h to achieve catecholamine depletion in a randomized, crossover study design. We used functional magnetic resonance imaging (fMRI) and the monetary incentive delay (MID) task to assess reward-effort integration in relation to catecholaminergic neurotransmission at the behavioral and neural level. AMPT reduced the ability to integrate rewards and efforts effectively in HC participants. In contrast, in rBN participants, the reduced reward-effort integration was associated with illness duration in the sham condition and unrelated to catecholamine depletion. Regarding neural activation, AMPT decreased the reward anticipation-related neural activation in the anteroventral striatum. This decrease was associated with the AMPT-induced reduction of monetary earning in HC in contrast to rBN participants. Our findings contributed to the theory of a desensitized dopaminergic system in bulimia nervosa. A disrupted processing of reward magnitudes and effort costs might increase the probability of maintenance of bulimic symptoms.


Assuntos
Encéfalo/diagnóstico por imagem , Bulimia Nervosa/diagnóstico por imagem , Bulimia Nervosa/psicologia , Imagem por Ressonância Magnética/métodos , Recompensa , Adulto , Encéfalo/efeitos dos fármacos , Bulimia Nervosa/sangue , Inibidores Enzimáticos/farmacologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estimulação Luminosa/métodos , Prolactina/sangue , Desempenho Psicomotor/efeitos dos fármacos , Desempenho Psicomotor/fisiologia , Indução de Remissão , Adulto Jovem , alfa-Metiltirosina/farmacologia
6.
Gen Comp Endocrinol ; 252: 236-238, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28716505

RESUMO

In this article, we show that the tyrosine hydroxylase inhibitor α-Methyl-l-tyrosine (AMPT) decreased the responsiveness of the zebrafish stress axis to an acute stressful challenge. These effects were specific for responses to stimulation, since unstimulated (basal) cortisol levels were not altered by AMPT. Moreover, AMPT decreased the stress response 15min after stimulation, but not after that time period. To our knowledge, this is the first report about the effects of AMPT on the neuroendocrine axis of adult zebrafish in acute stress responses. Overall, these results suggest a mechanism of catecholamine-glucocorticoid interplay in neuroendocrine responses of fish, pointing an interesting avenue for physiological research, as well as an important endpoint that can be disrupted by environmental contamination. Further experiments will unravel the mechanisms by which AMPT blocked the cortisol response.


Assuntos
Inibidores Enzimáticos/farmacologia , Estresse Fisiológico/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/antagonistas & inibidores , Peixe-Zebra/fisiologia , alfa-Metiltirosina/farmacologia , Animais , Feminino , Hidrocortisona/sangue , Masculino , Tirosina 3-Mono-Oxigenase/metabolismo , Peixe-Zebra/sangue
7.
Prog Neuropsychopharmacol Biol Psychiatry ; 79(Pt B): 155-161, 2017 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-28647535

RESUMO

Some clinical studies indicate that scopolamine may induce a rapid antidepressant effect. Although scopolamine is a muscarinic antagonist, it seems that not only cholinergic but also glutamatergic and GABAergic systems might be involved in the mechanism of its antidepressant activity in animal models of depression. Here, we present a set of behavioral data aimed at investigating the role of monoaminergic system activity in the mechanism of the antidepressant-like action of scopolamine in an animal model based on behavioral despair, namely, the tail suspension test (TST). It was found that AMPT induced a partial reduction in the antidepressant-like effect of scopolamine (0.3mg/kg) in the TST in C57BL/6 mice and that the effect of scopolamine was comparable to the effect of reboxetine (10mg/kg), which was used in this study as a reference drug. The attenuated antidepressant-like effect of scopolamine in AMPT-treated mice was observed in both its immediate (30min after administration) and prolonged (24h after administration) action in the TST. On the other hand, serotonin depletion by PCPA-pretreatment had no effect on the antidepressant effect of scopolamine (0.3mg/kg) either 30min or 24h after administration. Furthermore, a dose-dependent decrease in the immobility time of mice treated with a non-active dose of reboxetine (2mg/kg) together with non-active doses of scopolamine (0.03 and 0.1mg/kg) was found, suggesting a synergistic interaction between reboxetine and scopolamine in the TST. In contrast, a subeffective dose of the SSRI citalopram co-administered with subeffective doses of scopolamine did not induce significant changes in the behavior of mice in this test. Altogether, these data suggest that activation of the noradrenergic system might be involved in the antidepressant-like effect of scopolamine in the TST.


Assuntos
Antidepressivos/farmacologia , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/metabolismo , Moduladores de Transporte de Membrana/farmacologia , Norepinefrina/metabolismo , Escopolamina/farmacologia , Animais , Citalopram/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Masculino , Camundongos Endogâmicos C57BL , Morfolinas/farmacologia , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Reboxetina , Serotonina/metabolismo , alfa-Metiltirosina/farmacologia
8.
ACS Chem Neurosci ; 8(2): 411-419, 2017 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-28044445

RESUMO

Background-subtracted fast-scan cyclic voltammetry (FSCV) has emerged as a powerful analytical technique for monitoring subsecond molecular fluctuations in live brain tissue. Despite increasing utilization of FSCV, efforts to improve the accuracy of quantification have been limited due to the complexity of the technique and the dynamic recording environment. It is clear that variable electrode performance renders calibration necessary for accurate quantification; however, the nature of in vivo measurements can make conventional postcalibration difficult, or even impossible. Analyte-specific voltammograms and scaling factors that are critical for quantification can shift or fluctuate in vivo. This is largely due to impedance changes, and the effects of impedance on these measurements have not been characterized. We have previously reported that the background current can be used to predict electrode-specific scaling factors in situ. In this work, we employ model circuits to investigate the impact of impedance on FSCV measurements. Additionally, we take another step toward in situ electrode calibration by using the oxidation potential of quinones on the electrode surface to accurately predict the oxidation potential for dopamine at any point in an electrochemical experiment, as both are dependent on impedance. The model, validated both in adrenal slice and live brain tissue, enables information encoded in the shape of the background voltammogram to determine electrochemical parameters that are critical for accurate quantification. This improves data interpretation and provides a significant next step toward more automated methods for in vivo data analysis.


Assuntos
Encéfalo/metabolismo , Dopamina/metabolismo , Técnicas Eletroquímicas , Análise de Variância , Animais , Antipsicóticos/farmacologia , Biofísica , Encéfalo/efeitos dos fármacos , Estimulação Elétrica , Eletrodos , Inibidores Enzimáticos/farmacologia , Masculino , Vias Neurais/efeitos dos fármacos , Vias Neurais/metabolismo , Oxirredução , Ratos , Ratos Sprague-Dawley , Reserpina/farmacologia , alfa-Metiltirosina/farmacologia
9.
Mol Neurobiol ; 54(5): 3618-3632, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-27194433

RESUMO

A crucial event in the pathogenesis of Parkinson's disease is the death of dopaminergic neurons of the nigrostriatal system, which are responsible for the regulation of motor function. Motor symptoms first appear in patients 20-30 years after the onset of the neurodegeneration, when there has been a loss of an essential number of neurons and depletion of compensatory reserves of the brain, which explains the low efficiency of treatment. Therefore, the development of a technology for the diagnosing of Parkinson's disease at the preclinical stage is of a high priority in neurology. In this study, we have developed at an experimental model a fundamentally novel for neurology approach for diagnosis of Parkinson's disease at the preclinical stage. This methodology, widely used for the diagnosis of chronic diseases in the internal medicine, is based on the application of a challenge test that temporarily increases the latent failure of a specific functional system, thereby inducing the short-term appearance of clinical symptoms. The provocation test was developed by a systemic administration of α-methyl-p-tyrosine (αMpT), a reversible inhibitor of tyrosine hydroxylase to MPTP-treated mice at the presymptomatic stage of parkinsonism. For this, we first selected a minimum dose of αMpT, which caused a decrease of the dopamine level in the striatum of normal mice below the threshold at which motor dysfunctions appear. Then, we found the maximum dose of αMpT at which a loss of dopamine in the striatum of normal mice did not reach the threshold level, and motor behavior was not impaired. We showed that αMpT at this dose induced a decrease of the dopamine concentration in the striatum of MPTP-treated mice at the presymptomatic stage of parkinsonism below a threshold level that results in the impairment of motor behavior. Finally, we proved that αMpT exerts a temporal and reversible influence on the nigrostriatal dopaminergic system of MPTP-treated mice with no long-term side effects on other catecholaminergic systems. Thus, the above experimental data strongly suggest that αMpT-based challenge test might be considered as the provocation test for Parkinson's disease diagnosis at the preclinical stage in the future clinical trials.


Assuntos
Diagnóstico Precoce , Atividade Motora , Doença de Parkinson/diagnóstico , Doença de Parkinson/fisiopatologia , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Catecolaminas/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Modelos Biológicos , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Fibras Nervosas/efeitos dos fármacos , Fibras Nervosas/metabolismo , Doença de Parkinson/tratamento farmacológico , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , alfa-Metiltirosina/administração & dosagem , alfa-Metiltirosina/farmacologia , alfa-Metiltirosina/uso terapêutico
10.
J Pharmacol Exp Ther ; 358(3): 528-36, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27405316

RESUMO

Our objective was to study hypertension induced by chronic administration of synthetic glucocorticoid, dexamethasone (DEX), under nonstressful conditions and examine the role of catecholamine biosynthesis. To achieve this, we did the following: 1) used radiotelemetry to record mean arterial pressure (MAP) and heart rate (HR) in freely moving rats, and 2) administered different doses of DEX in drinking water. To evaluate the involvement of tyrosine hydroxylase (TH), the rate-limiting step in catecholamine biosynthesis, we treated rats with the TH inhibitor, α-methyl-para-tyrosine (α-MPT), for 3 days prior to administration of DEX and assessed TH mRNA and protein expression by quantitative real-time polymerase chain reaction and Western blot in the adrenal medulla. We observed a dose-dependent elevation in blood pressure with a DEX dose of 0.3 mg/kg administered for 10 days, significantly increasing MAP by +15.0 ± 1.1 mm Hg, while concomitantly reducing HR. Although this DEX treatment also significantly decreased body weight, pair-fed animals that showed similar decreases in body weight due to lowered food intake were not hypertensive, suggesting that body weight changes may not account for DEX-induced hypertension. Chronic DEX treatment significantly increased the TH mRNA and protein levels in the adrenal medulla, and α-MPT administration not only reduced DEX pressor effects, but also inhibited TH (serine(40)) phosphorylation. Our study thus validates a novel model to study hypertension induced by chronic intake of DEX in freely moving rats not subject to the confounding factors of previous models and establishes its dependence on concomitant activation of peripheral catecholamine biosynthesis.


Assuntos
Dexametasona/farmacologia , Modelos Animais de Doenças , Hipertensão/induzido quimicamente , Hipertensão/enzimologia , Tirosina 3-Mono-Oxigenase/metabolismo , Medula Suprarrenal/efeitos dos fármacos , Medula Suprarrenal/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Fosforilação/efeitos dos fármacos , Ratos , Serina/metabolismo , Tirosina 3-Mono-Oxigenase/antagonistas & inibidores , Tirosina 3-Mono-Oxigenase/química , Tirosina 3-Mono-Oxigenase/genética , alfa-Metiltirosina/farmacologia
11.
Pain ; 156(12): 2595-2606, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26447701

RESUMO

Physical exercise is a low-cost, safe, and efficient intervention for the reduction of neuropathic chronic pain in humans. However, the underlying mechanisms for how exercise reduces neuropathic pain are not yet well understood. Central monoaminergic systems play a critical role in endogenous analgesia leading us to hypothesize that the analgesic effect of low-intensity exercise occurs through activation of monoaminergic neurotransmission in descending inhibitory systems. To test this hypothesis, we induced peripheral nerve injury (PNI) by crushing the sciatic nerve. The exercise intervention consisted of low-intensity treadmill running for 2 weeks immediately after injury. Animals with PNI showed an increase in pain-like behaviors that were reduced by treadmill running. Reduction of serotonin (5-hydroxytryptamine) synthesis using the tryptophan hydroxylase inhibitor para-chlorophenylalanine methyl ester prevented the analgesic effect of exercise. However, blockade catecholamine synthesis with the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine had no effect. In parallel, 2 weeks of exercise increased brainstem levels of the 5-HT and its metabolites (5-hydroxyindoleacetic acid), decreased expression of the serotonin transporter, and increased expression of 5-HT receptors (5HT-1B, 2A, 2C). Finally, PNI-induced increase in inflammatory cytokines, tumor necrosis factor-alpha, and interleukin-1 beta, in the brainstem, was reversed by 2 weeks of exercise. These findings provide new evidence indicating that low-intensity aerobic treadmill exercise suppresses pain-like behaviors in animals with neuropathic pain by enhancing brainstem 5-HT neurotransmission. These data provide a rationale for the analgesia produced by exercise to provide an alternative approach to the treatment of chronic neuropathic pain.


Assuntos
Comportamento Animal/fisiologia , Tronco Encefálico/metabolismo , Ácido Hidroxi-Indolacético/metabolismo , Neuralgia/metabolismo , Traumatismos dos Nervos Periféricos/metabolismo , Condicionamento Físico Animal , Receptores de Serotonina/metabolismo , Nervo Isquiático/lesões , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Serotonina/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Fenclonina/análogos & derivados , Fenclonina/farmacologia , Interleucina-1beta/metabolismo , Camundongos , Triptofano Hidroxilase/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo , Tirosina 3-Mono-Oxigenase/antagonistas & inibidores , alfa-Metiltirosina/farmacologia
12.
J Ethnopharmacol ; 175: 30-8, 2015 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-26344850

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Cedrus atlantica essential oil (CaEO) presents analgesic and anti-inflammatory sedative properties. However, it remains unknown whether CaEO alleviates acute postoperative pain. MATERIALS AND METHODS: Here, we investigated the effect of CaEO on postoperative pain and its mechanisms related to the descending pain control in Swiss males mice induced by a plantar incision surgery (PIS) in the hindpaw. RESULTS: Inhalation of CaEO (5', 30' or 60') markedly reduced mechanical hypersensitivity. This effect was prevented by pre-treatment with naloxone or p-chlorophenylalanine methyl ester (PCPA, 100mg/kg, i.p.)-induced depletion of serotonin. In addition, p-alpha-methyl-para-tyrosin (AMPT, 100mg/kg, i.p.)-induced depletion of norepinephrine, intraperitoneal injection of the α2-adrenergic receptor antagonist yohimbine (0.15 mg/kg, i.p.) or haloperidol (1mg/kg, i.p.) an antagonist of dopaminergic (D1 and D2) receptors prevented the effect of CaEO on hypersensitivity. CONCLUSIONS: These findings suggest that CaEO alleviates postoperative pain by activating the descending pain modulation pathways on the opioidergic, serotonergic, noradrenergic (α2-adrenergic) and dopaminergic (dopamine D1 and D2 receptors) systems.


Assuntos
Analgésicos/uso terapêutico , Cedrus , Hiperalgesia/tratamento farmacológico , Óleos Voláteis/uso terapêutico , Dor Pós-Operatória/tratamento farmacológico , Administração por Inalação , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Analgésicos/administração & dosagem , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Antagonistas de Dopamina/farmacologia , Fenclonina/análogos & derivados , Fenclonina/farmacologia , Pé/cirurgia , Haloperidol/farmacologia , Hiperalgesia/metabolismo , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Óleos Voláteis/administração & dosagem , Dor Pós-Operatória/metabolismo , Fitoterapia , Antagonistas da Serotonina/farmacologia , Ioimbina/farmacologia , alfa-Metiltirosina/farmacologia
13.
Brain Res Bull ; 115: 23-9, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25917396

RESUMO

Zinc can regulate neural function in the brain via the GPR39 receptor. In the present study we investigated whether inhibition of serotonin, noradrenaline and dopamine synthesis and potentialization of glutamate, via administration of p-chlorophenylalanine (pCPA), α-methyl-p-tyrosine (αMT) and N-methyl-D-aspartatic acid (NMDA), respectively, would cause changes in GPR39 levels. Western blot analysis showed GPR39 up-regulation following 3-day administration of αMT and NMDA in the frontal cortex, and GPR39 down-regulation following 10-day administration of pCPA, αMT, and NMDA in the hippocampus of CD-1 mice. There were no changes in serum zinc levels. Additionally, we investigated tryptophan, tyrosine and glutamate concentrations in the hippocampus and frontal cortex of GPR39 knockout (GPR39 KO) mice. Liquid chromatography-mass spectrometry (LC-MS) showed a significant decrease in tryptophan and tyrosine, but not in glutamate concentrations in the hippocampus of GPR39 KO mice. There were no changes in the frontal cortex between GPR39 KO and wild type. These results indicate a possible role of the GPR39 receptor in monoaminergic and glutamatergic neurotransmission, which plays an important role in the pathophysiology of depression.


Assuntos
Lobo Frontal/metabolismo , Hipocampo/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Transmissão Sináptica/fisiologia , Animais , Dopamina/metabolismo , Fenclonina/farmacologia , Lobo Frontal/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Hipocampo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , N-Metilaspartato/farmacologia , Neurotransmissores/farmacologia , Norepinefrina/metabolismo , Receptores Acoplados a Proteínas-G/genética , Serotonina/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Triptofano/metabolismo , Tirosina/metabolismo , Zinco/sangue , alfa-Metiltirosina/farmacologia
15.
Neuropharmacology ; 93: 124-33, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25666033

RESUMO

Methylenedioxymethamphetamine (MDMA) causes a persistent loss of dopaminergic cell bodies in the substantia nigra of mice. Current evidence indicates that MDMA-induced neurotoxicity is mediated by oxidative stress probably due to the inhibition of mitochondrial complex I activity. In this study we investigated the contribution of dopamine (DA) to such effects. For this, we modulated the dopaminergic system of mice at the synthesis, uptake or metabolism levels. Striatal mitochondrial complex I activity was decreased 1 h after MDMA; an effect not observed in the striatum of DA depleted mice or in the hippocampus, a dopamine spare region. The DA precursor, L-dopa, caused a significant reduction of mitochondrial complex I activity by itself and exacerbated the dopaminergic deficits when combined with systemic MDMA. By contrast, no damage was observed when L-dopa was combined with intrastriatal injections of MDMA. On the other hand, dopamine uptake blockade using GBR 12909, inhibited both, the acute inhibition of complex I activity and the long-term dopaminergic toxicity caused by MDMA. Moreover, the inhibition of DA metabolism with the monoamine oxidase (MAO) inhibitor, pargyline, afforded a significant protection against MDMA-induced complex I inhibition and neurotoxicity. Taken together, these findings point to the formation of hydrogen peroxide subsequent to DA metabolism by MAO, rather than a direct DA-mediated mitochondrial complex I inhibition, and the contribution of a peripheral metabolite of MDMA, as the key steps in the chain of biochemical events leading to DA neurotoxicity caused by MDMA in mice.


Assuntos
Dopamina/deficiência , Complexo I de Transporte de Elétrons/metabolismo , Alucinógenos/farmacologia , N-Metil-3,4-Metilenodioxianfetamina/farmacologia , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Aconitato Hidratase/metabolismo , Animais , Temperatura Corporal/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Dopaminérgicos/farmacologia , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Homovanílico/metabolismo , Levodopa/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Piperazinas/farmacologia , Tirosina 3-Mono-Oxigenase/metabolismo , alfa-Metiltirosina/farmacologia
16.
Cardiovasc Toxicol ; 15(4): 336-44, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25503950

RESUMO

This study investigated the effect of metyrosine against ketamine-induced cardiotoxicity in rats and compared the results with the effect of metoprolol. In this study, rats were divided into groups A, B and C. In group A, we investigated the effects of a single dose of metyrosine (150 mg/kg) and metoprolol (20 mg/kg) on single dose ketamine (60 mg/kg)-induced cardiotoxicity. In group B, we investigated the effect of metyrosine and metoprolol, which were given together with ketamine for 30 days. In group C, we investigated the effect of metyrosine and metoprolol given 15 days before ketamine and 30 days together with ketamine on ketamine cardiotoxicity. By the end of this process, we evaluated the effects of the levels of oxidant-antioxidant parameters such as MDA, MPO, 8-OHGua, tGSH, and SOD in addition to CK-MB and TP I on cardiotoxicity in rat heart tissue. The experimental results show that metyrosine prevented ketamine cardiotoxicity in groups A, B and C and metoprolol prevented it in only group C.


Assuntos
Antioxidantes/farmacologia , Cardiopatias/prevenção & controle , Ketamina , Metoprolol/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , alfa-Metiltirosina/farmacologia , Animais , Biomarcadores/metabolismo , Citoproteção , Dano ao DNA/efeitos dos fármacos , Modelos Animais de Doenças , Quimioterapia Combinada , Cardiopatias/induzido quimicamente , Cardiopatias/metabolismo , Masculino , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Fatores de Tempo
17.
Addict Biol ; 20(1): 182-93, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24103023

RESUMO

Ethanol excites dopamine (DA) neurons in the posterior ventral tegmental area (pVTA). This effect is responsible for ethanol's motivational properties and may contribute to alcoholism. Evidence indicates that catalase-mediated conversion of ethanol into acetaldehyde in pVTA plays a critical role in this effect. Acetaldehyde, in the presence of DA, condensates with it to generate salsolinol. Salsolinol, when administered in pVTA, excites pVTA DA cells, elicits DA transmission in nucleus accumbens and sustains its self-administration in pVTA. Here we show, by using ex vivo electrophysiology, that ethanol and acetaldehyde, but not salsolinol, failed to stimulate pVTA DA cell activity in mice administered α-methyl-p-tyrosine, a DA biosynthesis inhibitor that reduces somatodendritic DA release. This effect was specific for ethanol and acetaldehyde since morphine, similarly to salsolinol, was able to excite pVTA DA cells in α-methyl-p-tyrosine-treated mice. However, when DA was bath applied in slices from α-methyl-p-tyrosine-treated mice, ethanol-induced excitation of pVTA DA neurons was restored. This effect requires ethanol oxidation into acetaldehyde given that, when H2 O2 -catalase system was impaired by either 3-amino-1,2,4-triazole or in vivo administration of α-lipoic acid, ethanol did not enhance DA cell activity. Finally, high performance liquid chromatography-tandem mass spectrometry analysis of bath medium detected salsolinol only after co-application of ethanol and DA in α-methyl-p-tyrosine-treated mice. These results demonstrate the relationship between ethanol and salsolinol effects on pVTA DA neurons, help to untangle the mechanism(s) of action of ethanol in this area and contribute to an exciting research avenue prosperous of theoretical and practical consequences.


Assuntos
Acetaldeído/farmacologia , Depressores do Sistema Nervoso Central/farmacologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Etanol/farmacologia , Isoquinolinas/farmacologia , Área Tegmentar Ventral/efeitos dos fármacos , Amitrol (Herbicida)/farmacologia , Animais , Antioxidantes/farmacologia , Catalase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Camundongos , Núcleo Accumbens/efeitos dos fármacos , Ácido Tióctico/farmacologia , alfa-Metiltirosina/farmacologia
18.
Biol Psychiatry ; 77(7): 661-7, 2015 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-24209774

RESUMO

BACKGROUND: Bulimia nervosa (BN) has been associated with dysregulation of the central catecholaminergic system. An instructive way to investigate the relationship between catecholaminergic function and psychiatric disorder has involved behavioral responses to experimental catecholamine depletion (CD). The purpose of this study was to examine a possible catecholaminergic dysfunction in the pathogenesis of bulimia nervosa. METHODS: CD was achieved by oral administration of alpha-methyl-para-tyrosine (AMPT) in 18 remitted female subjects with BN (rBN) and 31 healthy female control subjects. The study design consisted of a randomized, double blind, placebo-controlled crossover, single-site experimental trial. The main outcome measures were bulimic symptoms assessed by the Eating Disorder Examination-Questionnaire. Measures were assessed before and 26, 30, 54, 78, 102 hours after the first AMPT or placebo administration. RESULTS: In the experimental environment (controlled environment with a low level of food cues) rBN subjects had a greater increase in eating disorder symptoms during CD compared with healthy control subjects (condition × diagnosis interaction, p < .05). In the experimental environment, rBN subjects experienced fewer bulimic symptoms than in the natural environment (uncontrolled environment concerning food cues) 36 hours after the first AMPT intake (environment × diagnosis interaction, p < .05). Serum prolactin levels increased significantly, and to a comparable degree across groups, after AMPT administration. CONCLUSIONS: This study suggests that rBN is associated with vulnerability for developing eating disorder symptoms in response to reduced catecholamine neurotransmission after CD. The findings support the notion of catecholaminergic dysfunction as a possible trait abnormality in BN.


Assuntos
Bulimia Nervosa/metabolismo , Bulimia Nervosa/psicologia , Catecolaminas/deficiência , Adulto , Fármacos do Sistema Nervoso Central/farmacologia , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Prolactina/sangue , Escalas de Graduação Psiquiátrica , Inquéritos e Questionários , Fatores de Tempo , Adulto Jovem , alfa-Metiltirosina/farmacologia
19.
J Psychopharmacol ; 28(10): 923-34, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24920136

RESUMO

Our study sought to evaluate the anxiolytic and antidepressant activities of oleanolic acid as well as the neural mechanisms involved. Animal models such as barbiturate sleep-induction, light-dark box, elevated plus maze, forced swimming test, tail suspension test and open field test were conducted. Male Albino Swiss mice were treated orally with vehicle 10 mL/kg, fluoxetine 20 mg/kg, imipramine 15 mg/kg, diazepam 1 mg/kg or oleanolic acid 5-40 mg/kg. Pretreatment (intraperitoneal) of animals with pentylenetetrazole (PTZ) 20 mg/kg, 1-(2-methoxyphenyl)-4-[4- (2-phthalimido) butyl]piperazine hydrobromide (NAN-190) 0.5 mg/kg, p-chlorophenylalanine methyl ester (PCPA) 100 mg/kg or α-methyl-p-tyrosine (AMPT) 100 mg/kg, WAY100635 (WAY) 0.3 mg/kg, prazosin (PRAZ) 1 mg/kg, yohimbine 2 mg/kg as well as monoamine oxidase assay and hippocampal brain-derived neurotrophic factor (BDNF) quantification were carried out. Oleanolic acid potentiated the hypnotic effect of barbiturate and demonstrated an anxiolytic effect in both the light-dark box and elevated plus maze. This effect was not reversed by PTZ. Acute and/or chronic oral treatment of mice with oleanolic acid (5-20 mg/kg) elicited an antidepressant effect in the forced swimming test and the tail suspension test without interfering with the locomotor activity. The antidepressant effect of oleanolic acid was attenuated by NAN-190, AMPT, PCPA, WAY and PRAZ. Although monoamine oxidase activity remained unaltered by oleanolic acid, chronic administration of oleanolic acid augmented hippocampal BDNF level. These findings demonstrate multiple mechanisms of the anxiolytic and antidepressant effect of oleanolic acid.


Assuntos
Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Ácido Oleanólico/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Diazepam/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Fenclonina/análogos & derivados , Fenclonina/farmacologia , Fluoxetina/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Imipramina/farmacologia , Masculino , Camundongos , Monoaminoxidase/metabolismo , Atividade Motora/efeitos dos fármacos , Ácido Oleanólico/antagonistas & inibidores , Pentilenotetrazol/farmacologia , Piperazinas/farmacologia , Piridinas/farmacologia , alfa-Metiltirosina/farmacologia
20.
J Neuroimmunol ; 272(1-2): 16-28, 2014 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-24837703

RESUMO

The present study, through quantification of tyrosine hydroxylase (TH) expression and catecholamine (CA) content in the presence and in the absence of α-methyl-p-tyrosine (AMPT), a TH inhibitor, in adult thymic organ (ATOC) and thymocyte culture, demonstrated that thymic cells produce CAs. In addition, in ATOC an increase in ß2-adrenoceptor (AR) mRNA expression and ß2-AR thymocyte surface density was registered. Furthermore, AMPT (10(-4)M), as propranolol (10(-4)M), augmented thymocyte apoptosis and diminished thymocyte proliferation in ATOC. Propranolol exerted these effects acting on CD3(high) thymocytes. However, in thymocyte cultures, propranolol (10(-6)M) acting on the same thymocyte subset exerted the opposing effect on thymocyte apoptosis and ConA-stimulated proliferation. This suggested that, depending on thymocyte microenvironment, differential effects can be induced through the same type of AR. Additionally, arterenol (10(-8) to 10(-6)M), similar to propranolol, diminished apoptosis, but increased ConA-stimulated thymocyte proliferation in thymocyte culture. However, differently from propranolol, arterenol affected manly CD3- thymocyte subset, which harbors majority of α1-AR+thymocytes. Additionally, arterenol showed a dose-dependent decrease in efficiency of thymocyte apoptosis and proliferation modulation with the rise in its concentration. Considering greater affinity of arterenol for α1-ARs than for ß2-ARs, the previous findings could be attributable to increased engagement of ß2-ARs with the rise of arterenol concentration. Consistently, in the presence of propranolol (10(-6)M), a ß-AR blocker, the arterenol (10(-8)M) effects on thymocytes were augmented. In conclusion, thymic endogenous CAs, acting through distinct AR types and, possible, the same AR type (but in different cell microenvironment) may exert the opposing effects on thymocyte apoptosis/proliferation.


Assuntos
Apoptose/fisiologia , Catecolaminas/metabolismo , Timócitos/metabolismo , Timo/citologia , Agonistas alfa-Adrenérgicos/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Apoptose/efeitos dos fármacos , Catecolaminas/genética , Catecolaminas/farmacologia , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Inibidores Enzimáticos/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Norepinefrina/farmacologia , Técnicas de Cultura de Órgãos , Propranolol/farmacologia , Ratos , Timócitos/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo , alfa-Metiltirosina/farmacologia
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