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1.
Fundam Clin Pharmacol ; 30(6): 549-567, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27421789

RESUMO

In this study, we investigated the effects of subacute agomelatine (40 and 80 mg/kg) administration on chronic hyperglycemia, metabolic parameters, and pain perception in streptozotocin-induced diabetic rats. Fasting blood glucose measurements and oral glucose tolerance tests were performed to evaluate the effect of agomelatine on glycemia, while metabolic parameters were monitored using metabolic cages. Potential effect of agomelatine on diabetes-induced mechanical and thermal allodynia was evaluated using dynamic plantar aesthesiometer and warm plate (38 °C) tests, respectively. Additionally, influence of agomelatine on hyperalgesia occurring in connection with diabetic neuropathy was examined using the Randall-Selitto (mechanical nociceptive stimulus), Hargreaves (thermal nociceptive stimulus), and cold plate (4 °C, thermal nociceptive stimulus) tests. Obtained data indicated that, in diabetic rats, agomelatine significantly improved hyperalgesia and allodynia responses, without no effect on hyperglycemia or the associated polydipsia, polyuria, and hyperphagia. Therapeutic potential of agomelatine on neuropathic pain was suppressed with α-methyl-para-tyrosine methyl ester (an inhibitor of catecholamine synthesis), phentolamine (a nonselective α-adrenoceptor antagonist), and propranolol (a nonselective ß-adrenoceptor antagonist) administrations. However, p-chlorophenylalanine methyl ester (an inhibitor of serotonin synthesis) pretreatment could not be achieved to reverse these antihyperalgesic and antiallodynic effects. These results suggest that the curative effect of agomelatine on neuropathic pain is mediated through rising synaptic catecholamine levels as well as through interactions with both α- and ß-adrenoceptors. To our knowledge, this is the first study to show findings that indicate catecholaminergic system mediated antihyperalgesic and antiallodynic effects of agomelatine.


Assuntos
Acetamidas/farmacologia , Catecolaminas/metabolismo , Neuropatias Diabéticas/tratamento farmacológico , Neuralgia/tratamento farmacológico , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Neuropatias Diabéticas/etiologia , Neuropatias Diabéticas/metabolismo , Fenclonina/análogos & derivados , Fenclonina/farmacologia , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Metiltirosinas/farmacologia , Neuralgia/metabolismo , Fentolamina/farmacologia , Propranolol/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos alfa/metabolismo , Receptores Adrenérgicos beta/metabolismo , Estreptozocina/farmacologia
2.
Free Radic Biol Med ; 71: 231-9, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24681257

RESUMO

Free radicals are essential for the vasopressin (AVP) response to plasmatic hyperosmolarity. Noradrenergic afferents are the major projections on the supraoptic nucleus (SON) of the hypothalamus and stimulate the expression of AVP via a nitric oxide (NO) pathway. In this study, we investigated the mechanisms linking free radicals and noradrenaline (NA)-induced regulation of AVP. Analysis of Tg8 transgenic mice, invalidated for the monoamine oxidase-A gene and with consequently high levels of brain monoamines and AVP in the SON, showed that free radicals are more abundant in their SON than in that of wild-type mice (WT). Antioxidant superoxide dismutase 1 and 2 and catalase enzyme activities were also higher in these mice than in WT. This may explain the observed absence of cytotoxicity that would otherwise be associated with such high level of free radicals. Treatment of Tg8 mice with α-MPT, a blocking agent for NA synthesis, decreased both the production of free radicals and the AVP levels in the SON. Furthermore, incubation of ex vivo slices including the SON with NA increased the production of free radicals and AVP levels in wild-type mice. When NA was associated with α-lipoic acid, an antioxidant blocking the production of free radicals, AVP remained at its control level, indicating that free radicals are required for the effect of NA on the expression of AVP. In slices incubated with SNP, a producer of NO, free radicals and AVP levels increased. When NA was associated with L-NAME (a NO synthase blocker), the levels of free radicals and AVP were the same as in controls. Thus, the noradrenaline-NO pathway, which stimulates the expression of vasopressin, involves free radicals. This study provides further evidence of the physiological importance of free radicals, which should no longer be considered solely as cytotoxic factors.


Assuntos
Óxido Nítrico/metabolismo , Norepinefrina/metabolismo , Núcleo Supraóptico/metabolismo , Vasopressinas/metabolismo , Animais , Catalase/metabolismo , Radicais Livres/agonistas , Radicais Livres/antagonistas & inibidores , Radicais Livres/metabolismo , Expressão Gênica , Masculino , Metiltirosinas/farmacologia , Camundongos , Camundongos Endogâmicos C3H , Camundongos Transgênicos , NG-Nitroarginina Metil Éster/farmacologia , Nitroprussiato/farmacologia , Norepinefrina/agonistas , Norepinefrina/antagonistas & inibidores , Transdução de Sinais , Superóxido Dismutase/metabolismo , Superóxido Dismutase-1 , Núcleo Supraóptico/efeitos dos fármacos , Ácido Tióctico/farmacologia , Técnicas de Cultura de Tecidos , Vasopressinas/agonistas , Vasopressinas/antagonistas & inibidores , Vasopressinas/genética
3.
Naunyn Schmiedebergs Arch Pharmacol ; 384(1): 39-45, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21533991

RESUMO

Dopaminergic stabilizers may be conceptualized as drugs with normalizing effects on dopamine-mediated behaviours and neurochemical events. (S)-(-)-OSU6162 (OSU6162) and ACR16 are two structurally related compounds ascribed such properties, principally because of their stabilizing effects on motor activity in rodents. Reports in the literature indicate possible partial D2 receptor agonist effects using various in vitro systems. This study aimed to measure D2 receptor antagonist and agonist effects of OSU6162 and ACR16 in vivo. To address this, we have studied the effects of both compounds on prolactin secretion in drug-naive and dopamine-depleted rats; dopamine depletion was induced by pretreatment with reserpine plus α-methyl-DL: -p-tyrosine. We find that OSU6162 and ACR16 both stimulate prolactin secretion in drug-naive rats with OSU6162 being considerably more potent and efficacious. Both compounds show a non-significant trend towards reversal of the increased secretion caused by dopamine depletion, whereas the D2 receptor antagonist haloperidol further increased prolactin secretion. Thus, this study suggests that OSU6162 and ACR16 act as D2 receptor antagonists under normal conditions in vivo, possibly with minor agonist effects in a state of dopamine depletion.


Assuntos
Antagonistas dos Receptores de Dopamina D2 , Dopamina/deficiência , Lactotrofos/efeitos dos fármacos , Piperidinas/farmacologia , Prolactina/sangue , Receptores de Dopamina D2/agonistas , Animais , Aripiprazol , Agonistas de Dopamina/administração & dosagem , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/administração & dosagem , Antagonistas de Dopamina/farmacologia , Haloperidol/administração & dosagem , Haloperidol/farmacologia , Hiperprolactinemia/sangue , Hiperprolactinemia/induzido quimicamente , Lactotrofos/metabolismo , Masculino , Metiltirosinas/administração & dosagem , Metiltirosinas/farmacologia , Piperazinas/administração & dosagem , Piperazinas/farmacologia , Piperidinas/administração & dosagem , Prolactina/metabolismo , Quinolonas/administração & dosagem , Quinolonas/farmacologia , Ratos , Ratos Sprague-Dawley , Reserpina/administração & dosagem , Reserpina/farmacologia
4.
Toxicol Appl Pharmacol ; 241(1): 23-35, 2009 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-19647008

RESUMO

LUHMES cells are conditionally-immortalized non-transformed human fetal cells that can be differentiated to acquire a dopaminergic neuron-like phenotype under appropriate growth conditions. After differentiation by GDNF and cyclic adenosine monophosphate, LUHMES were sensitive to 1-methyl-4-phenylpyridinium (MPP(+)) toxicity at < or =5 microM, but resistant to the parental compound 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The high homogeneity and purity of the cultures allowed the detection of metabolic changes during the degeneration. Cellular ATP dropped in two phases after 24 and 48 h; cellular glutathione (GSH) decreased continuously, paralleled by an increase in lipid peroxidation. These events were accompanied by a time-dependent degeneration of neurites. Block of the dopamine transporter by GBR 12909 or mazindol completely abrogated MPP(+) toxicity. Inhibition of de novo dopamine synthesis by alpha-methyl-l-tyrosine or 3-iodo-l-tyrosine attenuated toxicity, but did not reduce the initial drop in ATP. Inhibition of mixed lineage kinases by CEP1347 completely prevented the MPP(+)-induced loss of viability and intracellular GSH, but failed to attenuate the initial drop of ATP. For the quantitative assessment of neurite degeneration, an automated imaging-based high content screening approach was applied and confirmed the findings made by pharmacological interventions in this study. Our data indicate that inhibition of mitochondrial ATP synthesis is not sufficient to trigger cell death in MPP(+)-treated LUHMES.


Assuntos
1-Metil-4-fenilpiridínio/toxicidade , Trifosfato de Adenosina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/efeitos dos fármacos , Intoxicação por MPTP , Neurônios/efeitos dos fármacos , 1-Metil-4-fenilpiridínio/administração & dosagem , Trifosfato de Adenosina/biossíntese , Morte Celular/efeitos dos fármacos , Células Cultivadas , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Relação Dose-Resposta a Droga , Glutationa/efeitos dos fármacos , Glutationa/metabolismo , Humanos , Peroxidação de Lipídeos , Mesencéfalo/citologia , Mesencéfalo/efeitos dos fármacos , Mesencéfalo/metabolismo , Metiltirosinas/farmacologia , Mitocôndrias/metabolismo , Monoiodotirosina/farmacologia , Neuritos/efeitos dos fármacos , Neuritos/metabolismo , Neurônios/metabolismo , Fatores de Tempo
5.
Neuropharmacology ; 56(6-7): 1068-73, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19298831

RESUMO

So far, the mechanisms underlying the action of selective serotonin reuptake inhibitors, such as fluoxetine, are not completely understood. Thus, to clarify if fluoxetine has any effect on noradrenergic transmission, we measured the spontaneous firing rate of noradrenergic neurons in the locus coeruleus both in vivo and in vitro using single-unit extracellular recordings. In anesthetized rats, fluoxetine (2.5-20 mg/kg, i.v.) reduced the firing rate in a dose-dependent manner, reaching a maximal inhibition of 55 +/- 5% with respect to the basal value. This effect was not only completely reversed by the alpha(2)-adrenoceptor antagonist, RX 821002 (0.2 mg/kg, i.v.), but also prevented by previous application of both idazoxan (0.05 and 0.1 mg/kg, i.v.) and RX 821002 (6.25 microg/kg, i.v). Furthermore, when noradrenaline was depleted from axon terminals by means of the injection of alpha-methyl-DL-tyrosine (250 mg/kg, i.p.) 24 h prior to the experiment, fluoxetine failed to inhibit locus coeruleus activity. In rat brain slices, perfusion with fluoxetine (100 microM for 5 min) did not modify the firing rate of locus coeruleus neurons (n = 7). We conclude that fluoxetine inhibits locus coeruleus neurons in vivo through a mechanism involving noradrenaline interacting with alpha(2)-adrenoceptors. However, the lack of effect on brain slices would seem to indicate that afferents to the nucleus may be involved in the observed inhibitory effect.


Assuntos
Fluoxetina/farmacologia , Locus Cerúleo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Receptores Adrenérgicos alfa 2/fisiologia , Inibidores de Captação de Serotonina/farmacologia , Potenciais de Ação/efeitos dos fármacos , Antagonistas de Receptores Adrenérgicos alfa 2 , Animais , Técnicas In Vitro , Locus Cerúleo/citologia , Locus Cerúleo/fisiologia , Masculino , Metiltirosinas/farmacologia , Neurônios/fisiologia , Norepinefrina/fisiologia , Ratos , Ratos Sprague-Dawley
6.
Eur J Neurosci ; 25(9): 2755-65, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17561841

RESUMO

The influence of nigrostriatal cell firing on the dopamine transporter (DAT) activity of the rat striatum was studied in vivo with amperometric methods. Data were obtained after preventing dopamine (DA) release with alpha-methyl-L-tyrosine and replenishing extracellular DA with local injections. The DA cell stimulation, which under basal conditions increased extracellular DA, decreased DA after this pre-treatment, suggesting that firing activity facilitates the DA cell uptake of DA under these circumstances (drain response). Cocaine and GBR13069 markedly decreased the drain response, suggesting that it is dependent on DAT activation. Data obtained after haloperidol and apomorphine administration showed that the drain response was facilitated by pre-synaptic DA receptor stimulation but that receptors are not a necessary requirement. Two components in the drain response were observed, one with a short latency and duration that needed high-frequency stimuli, and the other with a long latency and duration that was even induced by low-frequency stimuli. This is the first evidence showing that DAT can be activated by the firing activity in nigrostriatal cells in a direct way and without the participation of pre-synaptic DA receptors.


Assuntos
Potenciais de Ação/fisiologia , Corpo Estriado/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Dopamina/metabolismo , Neurônios/metabolismo , Substância Negra/metabolismo , Potenciais de Ação/efeitos dos fármacos , Animais , Corpo Estriado/efeitos dos fármacos , Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Vias Eferentes/efeitos dos fármacos , Vias Eferentes/metabolismo , Masculino , Metiltirosinas/farmacologia , Neurônios/efeitos dos fármacos , Terminações Pré-Sinápticas/efeitos dos fármacos , Terminações Pré-Sinápticas/metabolismo , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Substância Negra/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia
7.
Neurochem Res ; 30(3): 315-23, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16018575

RESUMO

Wistar rats treated with alpha-methyl-DL-p-tyrosine methylester showed significant level of inhibition in the activity of Na+, K+ -ATPase, Mg2+ -ATPase and Ca2+ -ATPase enzymes in different regions of the brain. The enzyme activity was assayed in cerebral hemispheres, hypothalamus, thalamus, hippocampus, amygdala and septum at proestrous (12 h), estrous (25 h), metestrous (38 h) and diestrous periods (92 h) of the rat. The Na+, K+ -ATPase activity was significantly inhibited in most of the brain regions after treated with alpha-methyl-DL-p-tyrosine methylester (MPT) and this indicated that MPT affected the active transport system and nerve impulse transmission. Mg2+ -ATPase and Ca2+ -ATPase was also significantly (P < 0.001) reduced in different regions of the brain. The results revealed that MPT affected active transport system and nerve impulse transmission by inhibiting Na+, K+ -ATPase and Ca2+ -ATPase. It has induced energy crisis by inhibiting Mg2+ -ATPase and all these cumulative effects of MPT have adversely affected the female Wistar rats. These effects have been manifested in the form of aberrations in the behavior of MPT treated female rats, which have shown their inability to perform their normal sexual activity.


Assuntos
Adenosina Trifosfatases/antagonistas & inibidores , Encéfalo/enzimologia , Inibidores Enzimáticos/farmacologia , Ciclo Estral/efeitos dos fármacos , Adenosina Trifosfatases/metabolismo , Animais , ATPase de Ca(2+) e Mg(2+)/antagonistas & inibidores , ATPase de Ca(2+) e Mg(2+)/metabolismo , ATPases Transportadoras de Cálcio/antagonistas & inibidores , ATPases Transportadoras de Cálcio/metabolismo , Metabolismo Energético/efeitos dos fármacos , Feminino , Metiltirosinas/farmacologia , Proteínas do Tecido Nervoso/metabolismo , Ratos , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , ATPase Trocadora de Sódio-Potássio/metabolismo
8.
Dev Biol ; 282(1): 246-56, 2005 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-15936344

RESUMO

Neurotransmitters play an important role in larval metamorphosis in different groups of marine invertebrates. In this work, the role of dopamine and serotonin during metamorphosis of the ascidian Phallusia mammillata larvae was examined. By immunofluorescence experiments, dopamine was localized in some neurons of the central nervous system and in the adhesive papillae of the larvae. Dopamine and serotonin signaling was inhibited by means of antagonists of these neurotransmitters receptors (R(+)-SCH-23390, a D(1) antagonist; clozapine, a D(4) antagonist; WAY-100635, a 5-HT(1A) antagonist) and by sequestering the neurotransmitters with specific antibodies. Moreover, dopamine synthesis was inhibited by exposing 2-cell embryos to alpha-methyl-l-tyrosine. Dopamine depletion, obtained by these different approaches, caused early metamorphosis, while serotonin depletion delayed the onset of metamorphosis. The opposite effects were obtained using agonists of the neurotransmitters: lisuride, a D(2) agonist, inhibited metamorphosis, while DOI hydrochloride and 8-OH-DPAT HBr, two serotonin agonists, promoted it. So, it is possible to suppose that dopamine signaling delayed metamorphosis while serotonin signaling triggers it. We propose a mechanism by which these neurotransmitters may modulate the timing of metamorphosis in larvae.


Assuntos
Dopamina/metabolismo , Metamorfose Biológica/fisiologia , Serotonina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Urocordados/crescimento & desenvolvimento , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Análise de Variância , Animais , Clozapina/farmacologia , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Imunofluorescência , Técnicas Histológicas , Imuno-Histoquímica , Larva/efeitos dos fármacos , Larva/fisiologia , Lisurida/farmacologia , Metamorfose Biológica/efeitos dos fármacos , Metiltirosinas/farmacologia , Piperazinas/farmacologia , Piridinas/farmacologia , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Urocordados/efeitos dos fármacos
9.
Gen Comp Endocrinol ; 140(3): 176-83, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15639145

RESUMO

It is established that dopamine inhibits while GABA stimulates LH release in goldfish. In this study, we examine dopaminergic regulation of GABAergic activity in the hypothalamus of early recrudescent female goldfish (Carassius auratus). We utilize a unique technique that permits concomitant quantification and correlation of in vivo GAD65 and GAD67 mRNA with GABA synthesis rate in response to decreased dopamine levels. Catecholamine depletion was achieved by treatment with alpha-methyl-para-tyrosine methyl ester (alphaMPT; 240 microg/g body weight), an inhibitor of tyrosine hydroxylase. Endogenous GABA levels were increased by intraperitoneal administration of gamma-vinyl GABA (GVG; 300 microg/g body weight), an inhibitor of the GABA catabolic enzyme GABA transaminase. Dual treatment of GVG+alphaMPT increased serum LH levels 4-fold. However, LH mRNA levels in the pituitary remained stable, suggesting that treatments affected secretion and not synthesis. In the hypothalamus, GABA synthesis rates increased 30% in response to alphaMPT treatment. This was correlated (r=0.61; p<0.05) to increased levels of GAD67 mRNAs but not GAD65 (r=0.14; p>0.05). These observations suggest that catecholamines inhibit GABA synthesis in the goldfish hypothalamus through isoform specific regulation of GAD67.


Assuntos
Dopamina/metabolismo , Glutamato Descarboxilase/biossíntese , Carpa Dourada/metabolismo , Isoenzimas/biossíntese , Hormônio Luteinizante/sangue , RNA Mensageiro/metabolismo , Ácido gama-Aminobutírico/biossíntese , Animais , Northern Blotting/veterinária , Inibidores Enzimáticos/farmacologia , Feminino , Hormônio Foliculoestimulante/sangue , Regulação da Expressão Gênica , Glutamato Descarboxilase/genética , Carpa Dourada/genética , Hipotálamo/metabolismo , Isoenzimas/genética , Hormônio Luteinizante/genética , Metiltirosinas/farmacologia , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/veterinária , Vigabatrina/farmacologia , Ácido gama-Aminobutírico/metabolismo
10.
Neuropharmacology ; 47(3): 414-26, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15275831

RESUMO

The influence of the selective adenosine A(2A) receptor antagonist ZM 241385 on exogenous l-DOPA-derived dopamine (DA) release in intact and dopamine-denervated rats was studied using an in vivo microdialysis in freely moving animals. Local infusion of l-DOPA (2.5 microM) produced a marked increase in striatal extracellular DA level in intact and malonate-lesioned rats. Intrastriatal perfusion of ZM 241385 (50-100 microM) had no effect on basal extracellular DA level, but enhanced dose-dependently the l-DOPA-induced DA release in intact and malonate-lesioned animals. A non-selective adenosine A(2A) receptor antagonist DMPX (100 microM), similarly to ZM 241385, accelerated conversion of l-DOPA in intact and malonate-denervated rats. This effect was not produced by the adenosine A(1) receptor antagonist, CPX (10-50 microM). However, ZM 241385 did not affect the l-DOPA-induced DA release in rats pretreated with reserpine (5 mg/kg i.p.) and alpha-methyl-p-tyrosine (AMPT, 300 mg/kg i.p.). Obtained results indicate that blockade of striatal adenosine A(2A) receptors increases the l-DOPA-derived DA release possibly by indirect mechanism exerted on DA terminals, an effect dependent on striatal tyrosine hydroxylase activity. Selective antagonists of adenosine A(2A) receptors may exert a beneficial effect at early stages of Parkinson's disease by enhancing the therapeutic efficacy of l-DOPA applied exogenously.


Assuntos
Antagonistas do Receptor A2 de Adenosina , Corpo Estriado/efeitos dos fármacos , Dopaminérgicos/farmacologia , Dopamina/metabolismo , Levodopa/farmacologia , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Análise de Variância , Animais , Área Sob a Curva , Química Encefálica/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão/métodos , Corpo Estriado/metabolismo , Denervação/métodos , Relação Dose-Resposta a Droga , Interações Medicamentosas , Espaço Extracelular/metabolismo , Ácido Homovanílico/metabolismo , Ácido Hidroxi-Indolacético/metabolismo , Masculino , Malonatos/farmacologia , Metiltirosinas/farmacologia , Ratos , Ratos Wistar , Receptor A2A de Adenosina/metabolismo , Reserpina/farmacologia , Serotonina/metabolismo , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Fatores de Tempo , Triazinas/farmacologia , Triazóis/farmacologia , Xantinas/farmacologia
11.
J Pharmacol Exp Ther ; 311(2): 576-84, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15254142

RESUMO

5-Hydroxytryptamine (serotonin) (5-HT) and norepinephrine (NE) are implicated in modulating descending inhibitory pain pathways in the central nervous system. Duloxetine is a selective and potent dual 5-HT and NE reuptake inhibitor (SNRI). The ability of duloxetine to antagonize 5-HT depletion in para-chloramphetamine-treated rats was comparable with that of paroxetine, a selective serotonin reuptake inhibitor (SSRI), whereas its ability to antagonize NE depletion in alpha-methyl-m-tyrosine-treated rats was similar to norepinephrine reuptake inhibitors (NRIs), thionisoxetine or desipramine. In this paradigm, duloxetine was also more potent than other SNRIs, including venlafaxine or milnacipran and amitriptyline. Low doses of the SSRI paroxetine or the NRI thionisoxetine alone did not have an effect on late phase paw-licking pain behavior in the formalin model of persistent pain; however, when combined, significantly attenuated this pain behavior. Duloxetine (3-15 mg/kg intraperitoneal) significantly attenuated late phase paw-licking behavior in a dose-dependent manner in the formalin model and was more potent than venlafaxine, milnacipran, and amitriptyline. These effects of duloxetine were evident at doses that did not cause neurologic deficits in the rotorod test. Duloxetine (5-30 mg/kg oral) was also more potent and efficacious than venlafaxine and milnacipran in reversing mechanical allodynia behavior in the L5/L6 spinal nerve ligation model of neuropathic pain. Duloxetine (3-30 mg/kg oral) was minimally efficacious in the tail-flick model of acute nociceptive pain. These data suggest that inhibition of both 5-HT and NE uptake may account for attenuation of persistent pain mechanisms. Thus, duloxetine may have utility in treatment of human persistent and neuropathic pain states.


Assuntos
Fluoxetina/análogos & derivados , Norepinefrina/metabolismo , Dor/tratamento farmacológico , Serotonina/metabolismo , Tiofenos/uso terapêutico , Doença Aguda , Aminas/uso terapêutico , Amitriptilina/uso terapêutico , Animais , Sedação Consciente , Ácidos Cicloexanocarboxílicos/uso terapêutico , Cicloexanóis/uso terapêutico , Ciclopropanos/uso terapêutico , Modelos Animais de Doenças , Quimioterapia Combinada , Cloridrato de Duloxetina , Fluoxetina/uso terapêutico , Formaldeído , Gabapentina , Masculino , Metiltirosinas/farmacologia , Milnaciprano , Junção Neuromuscular/efeitos dos fármacos , Dor/induzido quimicamente , Paroxetina/uso terapêutico , Ratos , Ratos Sprague-Dawley , Cloridrato de Venlafaxina , Ácido gama-Aminobutírico/uso terapêutico , p-Cloroanfetamina/farmacologia
13.
Am J Physiol ; 277(4): E668-77, 1999 10.
Artigo em Inglês | MEDLINE | ID: mdl-10516126

RESUMO

To further investigate neural effects on leptin and uncoupling proteins (UCPs), we studied in vivo perturbations intended to block adrenergic input to peripheral tissues. We examined plasma leptin, leptin mRNA, and adipose and muscle UCP subtype mRNA in rats treated with alpha-methyl-p-tyrosine methyl ester (AMPT-ME), which inhibits catecholamine synthesis and 6-hydroxydopamine (6HDA), which is toxic to catecholinergic nerve terminals but, unlike AMPT-ME, does not enter the central nervous system. Intraperitoneal AMPT-ME, 250 mg/kg, was administered at 1800 and 0700 the following day, and rats were killed at 1200-1400. All rats were fasted with free access to water during this time. Intraperitoneal AMPT-ME increased plasma leptin by 15-fold, increased interscapular brown adipose tissue (IBAT) and epididymal fat leptin mRNA by 2- to 2.5-fold, and also increased plasma insulin and glucose concentrations. Intraperitoneal AMPT-ME decreased IBAT UCP-3 mRNA to 40% of control, while it increased epididymal adipose UCP-3 mRNA approximately twofold. Intravenous AMPT-ME, 250 mg/kg, administered to conscious rats for 5 h decreased lumbar sympathetic nerve activity, increased plasma leptin (5.89 +/- 1.43 compared with 2.75 +/- 0.31 ng/ml in vehicle-treated rats, n = 7, P < 0.05), and decreased cardiac rate with no sustained change in blood pressure. Intraperitoneal 6HDA, 100 mg/kg, as a single dose at 1800, increased plasma leptin approximately twofold after 18-20 h, increased IBAT (but not epididymal fat) leptin mRNA by two- to threefold, and decreased IBAT UCP-3 mRNA to 30-40% of control. Neither AMPT-ME nor 6HDA significantly altered mRNA encoding gastrocnemius muscle UCP-3, IBAT UCP-1, or IBAT and epididymal UCP-2. In summary, AMPT-ME and 6HDA increased plasma leptin and upregulated leptin mRNA expression. AMPT-ME also resulted in complex tissue and subtype-specific modulation of adipose UCP mRNA. These data are consistent with interaction between leptin and sympathetic nerve activity (SNA) in regulation of fat cell energy utilization. However, the in vivo modulation of leptin and UCPs appears complex and, beyond a causal effect of SNA per se, may depend on concurrent changes in plasma insulin, glucose, and circulatory hemodynamics.


Assuntos
Proteínas de Transporte/metabolismo , Jejum/fisiologia , Leptina/metabolismo , Proteínas de Membrana/metabolismo , Inibição Neural/fisiologia , Sistema Nervoso Simpático/fisiologia , Tecido Adiposo/metabolismo , Adrenérgicos/farmacologia , Animais , Canais Iônicos , Leptina/sangue , Leptina/genética , Metiltirosinas/farmacologia , Proteínas Mitocondriais , Oxidopamina/farmacologia , Isoformas de Proteínas/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Valores de Referência , Proteína Desacopladora 1
14.
J Neurosci ; 18(9): 3470-9, 1998 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-9547254

RESUMO

Locomotor activity is a polygenic trait that varies widely among inbred strains of mice (). To characterize the role of D2 dopamine receptors in locomotion, we generated F2 hybrid (129/Sv x C57BL/6) D2 dopamine receptor (D2R)-deficient mice by gene targeting and investigated the contribution of genetic background to open-field activity and rotarod performance. Horizontal activity of D2R-/- mice was approximately half that of drug-naive, strain-matched controls but was significantly greater than haloperidol-treated controls, which were markedly hypokinetic. Wild-type 129/SvEv and C57BL/6 mice with functional D2 receptors had greater interstrain differences in spontaneous activity than those among the F2 hybrid mutants. Incipient congenic strains of D2R-deficient mice demonstrated an orderly gene dosage reduction in locomotion superimposed on both extremes of parental background locomotor activity. In contrast, F2 hybrid D2R-/- mice had impaired motor coordination on the rotarod that was corrected in the congenic C57BL/6 background. Wild-type 129/SvEv mice had the poorest rotarod ability of all groups tested, suggesting that linked substrain 129 alleles, not the absence of D2 receptors per se, were largely responsible for the reduced function of the F2 hybrid D2R-/- and D2R+/- mice. Neurochemical and pharmacological studies revealed unexpectedly normal tissue striatal monoamine levels and no evidence for supersensitive D1, D3, or D4 dopamine receptors in the D2R-/- mice. However, after acute monoamine depletion, akinetic D2R+/- mice had a significantly greater synergistic restoration of locomotion in response to SKF38393 and quinpirole compared with any group of D2R+/+ controls. We conclude that D2R-deficient mice are not a model of Parkinson's disease. Our studies highlight the interaction of multiple genetic factors in the analysis of complex behaviors in gene knock-out mice.


Assuntos
Adaptação Fisiológica , Dosagem de Genes , Atividade Motora/genética , Receptores de Dopamina D2/deficiência , Animais , Corpo Estriado/fisiologia , Antagonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2 , Feminino , Haloperidol/farmacologia , Masculino , Metiltirosinas/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Movimento/fisiologia , Vias Neurais/fisiologia , Desempenho Psicomotor/fisiologia , Reserpina/farmacologia , Substância Negra/fisiologia
15.
Biol Psychiatry ; 42(3): 181-90, 1997 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-9232210

RESUMO

This study evaluated the effect of an acute reduction in catecholamine synthesis produced by alpha-methyl-para-tyrosine (AMPT), a tyrosine hydroxylase inhibitor, on cocaine-induced euphoria. In a blinded, placebo-controlled study, AMPT (1 g p.o. T.I.D.) was given to 10 non-treatment-seeking cocaine abusers prior to intranasal administration of 2 mg/kg cocaine. AMPT, but not placebo, reduced plasma levels of the dopamine metabolite homovanillic acid and the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol. AMPT also elevated prolactin levels, indicating inhibition of the tuberoinfundibular dopamine system. AMPT pretreatment produced a trend toward diminished cocaine "high" AMPT also tended to lower heart rate and blood pressure responses to cocaine, but had no effect on serum cocaine levels. Although we cannot rule out the therapeutic potential of the depletion strategy, our results with AMPT alone, at this dose, do not strongly support it.


Assuntos
Cocaína , Inibidores Enzimáticos/farmacologia , Euforia/efeitos dos fármacos , Metiltirosinas/farmacologia , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia , Administração Oral , Adulto , Nível de Alerta/efeitos dos fármacos , Nível de Alerta/fisiologia , Difenidramina/farmacologia , Dopamina/fisiologia , Método Duplo-Cego , Euforia/fisiologia , Feminino , Ácido Homovanílico/sangue , Humanos , Masculino , Metoxi-Hidroxifenilglicol/sangue , Pessoa de Meia-Idade , Norepinefrina/sangue , Norepinefrina/fisiologia , Prolactina/sangue , Transtornos Relacionados ao Uso de Substâncias/psicologia , alfa-Metiltirosina
16.
Arch Physiol Biochem ; 105(1): 3-9, 1997 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-9224540

RESUMO

Dopamine (DA) is thought to modulate the transduction of the hypoxic stimulus by the glomus cell in the carotid body (CB). The hypothesis tested here is that presynaptic DA D2 receptors (D2's) located on the type 1 cell function as autoreceptors to control DA release and/or synthesis. The aim of the study was to compare the effects of blocking D2's with haloperidol and DA synthesis with alpha methyl paratyrosine (AMPT) on the in vitro carotid body DA response to hypoxia. 54 CB's sampled from adult rabbits were incubated for one hour in a surviving medium bubbled with either 100% O2 or 8% O2 Sixteen CB's served as control (100% O2: n = 8, 8% O2: n = 8), 18 (100% O2: n = 8, 8% O2: n = 10) were sampled from rabbits pretreated with AMPT and 20 (100% O2: n = 12, 8% O2: n = 8) were incubated with micromolar concentrations of haloperidol. At the end of exposure. DA contained in the carotid body (DACB) and released in the surviving medium (DAr) were measured by HPLC. In 100% O2 DACB was not different between either AMPT or haloperidol and control, but DAr was significantly higher in the haloperidol group compared with control (mean +/- SE: 26.6 +/- 7.4 versus 7.6 +/- 2.0 pmol/h, P < 0.02). In 8% O2, control DACB (576 +/- 133 pmol/CB) was significantly higher than AMPT or haloperidol (respectively 228 +/- 29.6 and 246 +/- 49.9 pmol/CB, P < 0.01) and control DAr (234 +/- 72.3 pmol/h) was also significantly higher than AMPT or haloperidol (respectively 28.8 +/- 5.2 and 40.6 +/- 11.4 pmol/h, P < 0.01). Finally, DAr was significantly larger in 8% O2 than in 100% O2 in control and AMPT groups (P < 0.01), but not in the haloperidol group. The increase in DAr by haloperidol in the resting CB is consistent with the blockade of D2's regulating DA release. The decreased DAr in 8% O2 after AMPT suggests that increased DA synthesis contributes to maintain DA secretion by the type I cell exposed to short term hypoxia. The lack of difference in DAr between 8% O2 and 100% O2 after haloperidol probably reflects non specific--i.e., D2 independent--effect of micromolar concentration of haloperidol on DA synthesis and/or sodium-calcium exchangers during hypoxia.


Assuntos
Corpo Carotídeo/metabolismo , Antagonistas de Dopamina/farmacologia , Dopamina/metabolismo , Haloperidol/farmacologia , Hipóxia/metabolismo , Metiltirosinas/farmacologia , Análise de Variância , Animais , Corpo Carotídeo/efeitos dos fármacos , Antagonistas dos Receptores de Dopamina D2 , Inibidores Enzimáticos/farmacologia , Técnicas In Vitro , Coelhos , Tirosina 3-Mono-Oxigenase/antagonistas & inibidores , alfa-Metiltirosina
17.
J Auton Pharmacol ; 17(1): 35-41, 1997 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-9201558

RESUMO

1. This study investigates possible mechanisms through which imipramine (IMI) exerts its antienuretic effect. The micturition reflex in response to bladder distension produced by saline infusion was examined in anaesthetized rats. 2. The amplitude and frequency of micturition reflex contractions were reduced by peripheral administration of IMI, but the micturition reflex was abolished after its intracerebroventricular (i.c.v.) administration. A muscarinic antagonist, atropine, displayed an inhibitory effect similar to that of IMI. A muscarinic agonist, carbachol, produced a dose-related rightward shift of the dose-response curve to IMI. Both IMI i.c.v. and the muscarinic antagonist l-methylscopolamine i.c.v. elevated the threshold of volume and pressure for micturition initiation, indicating that IMI and muscarinic antagonists mainly exert a central inhibitory effect on the micturition reflex. 3. In addition, to evaluate the role of central monoaminergic neurotransmission on micturition, the acetylcholine depletor hemicholinium-3 (HC-3), the catecholamines depletor alpha-methyl-p-tyrosine (AMPT), and the serotonin depletor p-chlorophenylalanine (PCPA) were examined alone or in combination with IMI. The micturition threshold was increased by treatment with HC-3, but not by AMPT or PCPA. In HC-3 treated rats, the inhibitory effect of IMI on the micturition reflex was more prolonged than in normal rats. After administration of IMI, the recovery from the cessation of micturition reflex contractions was facilitated by carbachol in normal rats, but not in HC-3 treated rats. This indicates that acetylcholine plays a facilitatory role in initiating micturition reflex contractions. 4. Acute treatment with IMI decreased the frequency and increased the volume threshold of micturition reflex contraction. Acute and chronic treatment with IMI prolonged the cessation period of micturition by IMI. 5. These results suggest that IMI exerts an inhibitory action on the micturition reflex by a central cholinergic mechanism. Muscarinic receptors located at the supraspinal level are tonically stimulated during distension-induced micturition reflex.


Assuntos
Inibidores da Captação Adrenérgica/farmacologia , Antidepressivos Tricíclicos/farmacologia , Enurese/tratamento farmacológico , Imipramina/farmacologia , Micção/efeitos dos fármacos , Inibidores da Captação Adrenérgica/administração & dosagem , Inibidores da Captação Adrenérgica/uso terapêutico , Animais , Antidepressivos Tricíclicos/administração & dosagem , Antidepressivos Tricíclicos/uso terapêutico , Atropina/administração & dosagem , Atropina/farmacologia , Atropina/uso terapêutico , Colinérgicos/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Inibidores Enzimáticos/farmacologia , Feminino , Fenclonina/farmacologia , Hemicolínio 3/farmacologia , Imipramina/administração & dosagem , Imipramina/uso terapêutico , Injeções Intraperitoneais , Injeções Intravenosas , Injeções Intraventriculares , Metiltirosinas/farmacologia , Antagonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/uso terapêutico , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , N-Metilescopolamina , Parassimpatolíticos/administração & dosagem , Parassimpatolíticos/farmacologia , Ratos , Ratos Sprague-Dawley , Derivados da Escopolamina/administração & dosagem , Derivados da Escopolamina/farmacologia , Serotoninérgicos/farmacologia , alfa-Metiltirosina
18.
Am J Physiol ; 272(2 Pt 2): R656-61, 1997 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-9124491

RESUMO

The effect of prolonged fasting on sympathetic activity was examined in rat white adipose tissue (WAT) and, for comparison purposes, in interscapular brown adipose tissue (IBAT). Preliminary experiments showed that 6-hydroxydopamine or tyramine administration to fed animals produced similar reductions in norepinephrine (NE) content of WAT and IBAT. Fasting for 48 h did not affect tissue NE content significantly, but induced a threefold increase in [3H]NE uptake by retroperitoneal and epididymal adipose tissue, contrasting with a 50% reduction in IBAT. Measured with DL-alpha-methyl-p-tyrosine, NE fractional rates of turnover were faster and calculated turnover rates were three times higher in retroperitoneal and epididymal tissue from fasted rats than in tissues from fed controls. In experiments with [3H]NE, although fractional rates did not change significantly, calculated NE turnover also increased in retroperitoneal and epididymal tissue after food deprivation. In contrast, in IBAT, NE turnover either did not change (measured with DL-alpha-methyl-p-tyrosine) or, in the experiments with [3H]NE, decreased significantly after fasting. These and other data suggest that a centrally controlled selective activation of WAT sympathetic fibers contributes to fasting lipolysis.


Assuntos
Tecido Adiposo/inervação , Jejum , Sistema Nervoso Simpático/fisiologia , Tecido Adiposo/metabolismo , Tecido Adiposo Marrom/metabolismo , Animais , Ingestão de Alimentos , Epididimo , Masculino , Metiltirosinas/farmacologia , Norepinefrina/metabolismo , Ratos , Ratos Wistar , Espaço Retroperitoneal , Simpatomiméticos/farmacologia , Fatores de Tempo , Tiramina/farmacologia
19.
Biol Psychiatry ; 41(1): 58-64, 1997 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-8988796

RESUMO

This study was designed to determine the behavioral effects of a reduction in catecholamine and indoleamine function in healthy subjects. Eight healthy subjects received the tyrosine hydroxylase inhibitor, alpha-methyl-para-tyrosine (AMPT) in combination with a full-strength tryptophan-depleting amino acid drink during one 4-day test session, and AMPT and tryptophan-supplemented amino acid drink (n = 2), or a 25% strength tryptophan-depleting amino acid drink (n = 6) during a second 4-day test session. The combined administration of AMPT and the tryptophan-free amino acid drink did not produce statistically significant or even clinically noticeable changes in mood among the healthy subjects. The implications of these observations for the monoamine hypotheses of depression are discussed.


Assuntos
Afeto/efeitos dos fármacos , Catecolaminas/fisiologia , Inibidores Enzimáticos/farmacologia , Metiltirosinas/farmacologia , Triptofano/fisiologia , Tirosina 3-Mono-Oxigenase/antagonistas & inibidores , Administração Oral , Adulto , Afeto/fisiologia , Aminoácidos/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tirosina 3-Mono-Oxigenase/fisiologia , alfa-Metiltirosina
20.
Naunyn Schmiedebergs Arch Pharmacol ; 355(1): 30-5, 1997 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9007839

RESUMO

We measured the minimum amount of endogenous dopamine (EDA), necessary for the expression of rotational behavior induced by D2 receptor stimulation in striatal or medial forebrain bundle (MFB) lesioned rats. We correlated these results with the minimum dose of D1 receptor agonists needed to substitute EDA in its permissive role for D2 motor effects to take place. Rats with unilateral quinolinic acid (QA) striatal or 6-hydroxydopamine (6-OHDA) MFB lesions were given increasing doses of the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (AMPT) in combination with a fixed dose of the D2 receptor agonist quinpirole (trans-(-)-4aR-4,4a,5,6,7,8,8a,9-Octahydro-5-propyl-1H-pyrazolo(3, 4-g) quinoline hydrochloride) and tested for rotational behavior. The animals were later sacrificed and striata removed; EDA was measured by high performance liquid chromatography (HPLC). Rotational responses were abolished by increasing doses of AMPT inducing a stepwise depletion of EDA. EDA content and rotational behavior to D2 stimulation showed a high degree of correlation. There was an abrupt reduction in rotational behavior at dopamine levels of 50-60% of controls in both animal models. In addition, striatal or MFB lesioned rats which were maximally depleted of dopamine by AMPT pretreatment received a fixed dose of quinpirole and then challenged with increasing doses of a D1 receptor agonist SKF 38393 ((+/-)-1-Phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride). Rotational behavior was restored by SKF 38393 in both animal models in a dose-dependent fashion. Our results confirm the need for simultaneous D1/D2 stimulation in the generation of rotational behavior in both animal models. Moreover, they demonstrate the existence of a threshold level of D1 stimulation necessary to exert its permissive role on D2 mediated responses.


Assuntos
Dopamina/análise , Receptores de Dopamina D1/fisiologia , Receptores de Dopamina D2/fisiologia , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Animais , Comportamento Animal , Feminino , Metiltirosinas/farmacologia , Quimpirol/farmacologia , Ratos , Ratos Wistar , Rotação , alfa-Metiltirosina
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