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1.
Sci Rep ; 8(1): 15546, 2018 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-30341390

RESUMO

The combined effects of cervical electrical stimulation alone or in combination with the monoaminergic agonist buspirone on upper limb motor function were determined in six subjects with motor complete (AIS B) injury at C5 or above and more than one year from time of injury. Voluntary upper limb function was evaluated through measures of controlled hand contraction, handgrip force production, dexterity measures, and validated clinical assessment batteries. Repeated measure analysis of variance was used to evaluate functional metrics, EMG amplitude, and changes in mean grip strength. In aggregate, mean hand strength increased by greater than 300% with transcutaneous electrical stimulation and buspirone while a corresponding clinically significant improvement was observed in upper extremity motor scores and the action research arm test. Some functional improvements persisted for an extended period after the study interventions were discontinued. We demonstrate that, with these novel interventions, cervical spinal circuitry can be neuromodulated to improve volitional control of hand function in tetraplegic subjects. The potential impact of these findings on individuals with upper limb paralysis could be dramatic functionally, psychologically, and economically.


Assuntos
Buspirona/administração & dosagem , Terapia por Estimulação Elétrica , Mãos/fisiologia , Movimento , Recuperação de Função Fisiológica , Agonistas do Receptor de Serotonina/administração & dosagem , Traumatismos da Medula Espinal/terapia , Adolescente , Adulto , Terapia Combinada , Potencial Evocado Motor , Feminino , Força da Mão , Humanos , Masculino , Lesões do Pescoço/terapia , Adulto Jovem
2.
Nutr Neurosci ; 21(3): 185-194, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27868798

RESUMO

OBJECTIVES: In the last few decades, therapeutic uses of medicinal compounds present in food as a normal constituent has risen substantially, largely because of their fewer side effects and adequate efficacy. This study is designed to investigate a role of brain serotonin (5-HT) and dopamine (DA) in the potential nootropic, anxiolytic, and other beneficial effects of Nigella sativa (NS) and Olea europaea (OE) oil in rat models. METHODS: Animals were treated with NS and OE oil orally at doses of 0.1 ml/kg and 0.25 ml/kg for 5 weeks. Food intake and body weight change, anxiety-like effects in elevated plus maze and activity in a novel and familiar environment were monitored weekly. Effects on learning and memory after 5 weeks treatment were monitored using Morris water maze test. Neurochemical analysis was carried using HPLC-ECD method. RESULTS: NS and OE oil administration enhanced learning and memory in Morris water maze test and the effects were greater in NS than OE oil-treated animals. Low dose of OE oil increased exploration in an open field, higher dose of OE oil and both doses of NS oil produced no consistent effect on open field exploration. Effects of both oils on anxiety-like behavior, food and water intake, and activity in activity box were either not consistent or did not occur. The treatment increased homovanillic acid (HVA). 5-HT levels increased in high dose of NS oil and low dose of OE oil-treated groups. Low dose NS oil decreased 5-HT. DISCUSSION: The present study suggests that active components in NS and OE oil may prove useful in treating impaired cognition. OE oil may produce psychostimulant-like effect. Modulation of DA and serotonin neurotransmission seems important in the pharmacological effect of these oils.


Assuntos
Suplementos Nutricionais , Aprendizagem , Memória , Nigella sativa/química , Nootrópicos/uso terapêutico , Olea/química , Óleos de Plantas/administração & dosagem , Animais , Ansiolíticos/administração & dosagem , Ansiolíticos/efeitos adversos , Ansiolíticos/uso terapêutico , Ansiedade/prevenção & controle , Comportamento Animal , Encéfalo/metabolismo , Suplementos Nutricionais/efeitos adversos , Agonistas de Dopamina/administração & dosagem , Agonistas de Dopamina/efeitos adversos , Agonistas de Dopamina/uso terapêutico , Etnofarmacologia , Ácido Homovanílico/agonistas , Ácido Homovanílico/metabolismo , Masculino , Aprendizagem em Labirinto , Medicina Tradicional , Neurônios/metabolismo , Nootrópicos/administração & dosagem , Nootrópicos/efeitos adversos , Paquistão , Óleos de Plantas/efeitos adversos , Óleos de Plantas/uso terapêutico , Distribuição Aleatória , Ratos Wistar , Agonistas do Receptor de Serotonina/administração & dosagem , Agonistas do Receptor de Serotonina/efeitos adversos , Agonistas do Receptor de Serotonina/uso terapêutico
3.
Pharmacol Rep ; 69(5): 846-850, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28623708

RESUMO

BACKGROUND: The aim of this experiment was to investigate a long-lasting local anesthetic bupivacaine combined with serotonin at inducing cutaneous antinociception. METHODS: The skin antinociception, characterized by an inhibition of the cutaneous trunci muscle reflex (CTMR) following the pinprick on the dorsal skin of rats, was evaluated. The cutaneous antinociceptive effects of bupivacaine alone, serotonin alone, or bupivacaine co-injected with serotonin in a dose-dependent fashion were constructed, while the drug-drug interactions were evaluated by isobologram. RESULTS: Subcutaneous serotonin, as well as the local anesthetic bupivacaine provoked dose-related cutaneous antinociception. On an equipotent basis (50% effective dose [ED50]), the relative potency was bupivacaine (0.43 [0.37-0.50] µmol)>serotonin (1.27 [1.15-1.40] µmol) (p<0.01). At the equi-anesthetic doses (ED75, ED50 and ED25), the duration of bupivacaine was similar to that of serotonin at producing cutaneous antinociceptive effects. Co-administration of bupivacaine and serotonin displayed a synergistic antinociception. CONCLUSIONS: The preclinical data demonstrated that serotonin is less potent in eliciting cutaneous antinociceptive effects but has the similar duration of action, compared with bupivacaine. We also found a more significant depth of the sensory block with bupivacaine+serotonin than bupivacaine alone.


Assuntos
Anestésicos Locais/farmacologia , Bupivacaína/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Serotonina/farmacologia , Analgesia , Anestesia Local , Anestésicos Locais/administração & dosagem , Anestésicos Locais/farmacocinética , Animais , Bupivacaína/administração & dosagem , Bupivacaína/farmacocinética , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Injeções Subcutâneas , Masculino , Dor/tratamento farmacológico , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Serotonina/administração & dosagem , Serotonina/farmacocinética , Agonistas do Receptor de Serotonina/administração & dosagem , Agonistas do Receptor de Serotonina/farmacocinética
4.
IUBMB Life ; 68(12): 985-993, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27797140

RESUMO

5-Hydroxytryptamine 2C (5-HT2C ) receptor agonists have been suggested to possess an antipsychotic activity in several acute preclinical tests of antipsychotic drugs with low extra-pyramidal side effect liability. However, little is known about the long-term effect associated with chronic use of 5-HT2C receptor agonists. The present study examined whether repeated activation of 5-HT2C receptor with a highly selective 5-HT2C receptor agonist MK212 would induce a long-term change in its antipsychotic-like activity (either a sensitization or tolerance) in the conditioned avoidance response and MK801-induced hyperlocomotion tests. Sprague-Dawley rats were first tested under the intraperitoneal (i.p.) treatment of MK212 (0.25, 0.5, 1.0 mg/kg) for 5 consecutive days. Three days later, when all rats were injected with a low dose of MK 212 (0.25 mg/kg) and tested for avoidance responding, rats that had been pretreated with 1.0 and 0.5 mg/kg MK212 made significantly fewer avoidance responses than those that had been treated with vehicle (0.9% saline). However, this past drug exposure-induced group difference was not significant in the MK801-induced hyperlocomotion test. Overall, results from this study suggest that repeated treatment of MK212 is capable of inducing a dose-dependent sensitization of antipsychotic activity in conditioned avoidance response. The discrepancy in sensitization of MK212 in CAR and MK801-induce hyperlocomotion may be related to the different mechanism underlying the effect of MK212 in these two tests. © 2016 IUBMB Life, 68(12):985-993, 2016.


Assuntos
Antipsicóticos/administração & dosagem , Pirazinas/administração & dosagem , Agonistas do Receptor de Serotonina/administração & dosagem , Animais , Aprendizagem da Esquiva , Condicionamento Psicológico/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Masculino , Atividade Motora/efeitos dos fármacos , Ratos Sprague-Dawley
5.
Drug Alcohol Depend ; 156: 29-37, 2015 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-26386827

RESUMO

BACKGROUND: The purpose of this study was to evaluate the efficacy of buspirone, a partial 5-HT1A agonist, for treatment of cannabis dependence. METHODS: One hundred seventy-five cannabis-dependent adults were randomized to receive either up to 60mg/day of buspirone (n=88) or placebo (n=87) for 12 weeks combined with a brief motivational enhancement therapy intervention and contingency management to encourage study retention. Cannabis use outcomes were assessed via weekly urine cannabinoid tests. RESULTS: Participants in both groups reported reduced cannabis craving over the course of the study; however, buspirone provided no advantage over placebo in reducing cannabis use. Significant gender by treatment interactions were observed, with women randomized to buspirone having fewer negative urine cannabinoid tests than women randomized to placebo (p=0.007), and men randomized to buspirone having significantly lower creatinine adjusted cannabinoid levels as compared to those randomized to placebo (p=0.023). An evaluation of serotonin allelic variations did not find an association with buspirone treatment response. CONCLUSIONS: Buspirone was not more efficacious than placebo in reducing cannabis use. Important gender differences were noted, with women having worse cannabis use outcomes with buspirone treatment. Considerations for future medication trials in this challenging population are discussed.


Assuntos
Buspirona/uso terapêutico , Abuso de Maconha/tratamento farmacológico , Agonistas do Receptor de Serotonina/uso terapêutico , Adulto , Alelos , Buspirona/administração & dosagem , Buspirona/efeitos adversos , Canabinoides/sangue , Terapia Combinada , Método Duplo-Cego , Feminino , Humanos , Masculino , Abuso de Maconha/psicologia , Motivação , Cooperação do Paciente , Psicoterapia , Receptor 5-HT1A de Serotonina/genética , Agonistas do Receptor de Serotonina/administração & dosagem , Agonistas do Receptor de Serotonina/efeitos adversos , Caracteres Sexuais , Resultado do Tratamento , Adulto Jovem
6.
Cerebellum ; 14(2): 86-96, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25315739

RESUMO

Neurodevelopmental impairment in the serotonergic system may be involved in autism spectrum disorder. Yokukansan is a traditional herbal remedy for restlessness and agitation in children, and mother-infant co-administration (MICA) to both the child and the nursing mother is one of the recommended treatment approaches. Recent studies have revealed the neuropharmacological properties of Yokukansan (YKS), including its 5-HT1A (serotonin) receptor agonistic effects. We investigated the influence of YKS treatment on behavior in a novel environment and on brain monoamine metabolism during the nursing period in an animal model of neurodevelopmental disorders, prenatally BrdU (5-bromo-2'-deoxyuridine)-treated rats (BrdU-rats). YKS treatment did not influence locomotor activity in BrdU-rats but reduced grooming in open-field tests. YKS treatment without MICA disrupted the correlation between locomotor behaviors and rearing and altered levels of serotonin and its metabolite in the cerebellum. These effects were not observed in the group receiving YKS treatment with MICA. These data indicate a direct pharmacological effect of YKS on the development of grooming behavior and profound effects on cerebellar serotonin metabolism, which is thought to be influenced by nursing conditions.


Assuntos
Cerebelo/efeitos dos fármacos , Medicamentos de Ervas Chinesas/administração & dosagem , Asseio Animal/efeitos dos fármacos , Hipnóticos e Sedativos/administração & dosagem , Agitação Psicomotora/tratamento farmacológico , Agonistas do Receptor de Serotonina/administração & dosagem , Serotonina/metabolismo , Animais , Animais Recém-Nascidos , Transtorno do Espectro Autista , Bromodesoxiuridina , Cerebelo/crescimento & desenvolvimento , Cerebelo/metabolismo , Defecação/efeitos dos fármacos , Modelos Animais de Doenças , Dopamina/metabolismo , Comportamento Exploratório/efeitos dos fármacos , Feminino , Lactação , Masculino , Mães , Atividade Motora/efeitos dos fármacos , Agitação Psicomotora/metabolismo , Distribuição Aleatória , Ratos Sprague-Dawley , Micção/efeitos dos fármacos
7.
PLoS One ; 8(1): e53142, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23326391

RESUMO

Serotonin (5-HT) is a central inhibitor of food intake in mammals. Thus far, the intracellular mechanisms for the effect of serotonin on appetite regulation remain unclear. It has been recently demonstrated that reactive oxygen species (ROS) in the hypothalamus are a crucial integrative target for the regulation of food intake. To investigate the role of ROS in the serotonin-induced anorexigenic effects, conscious mice were treated with 5-HT alone or combination with Trolox (a ROS scavenger) or Apocynin (an NADPH oxidase inhibitor) by acute intracerebroventricular injection. Both Trolox and Apocynin reversed the anorexigenic action of 5-HT and the 5-HT-induced hypothalamic ROS elevation. The mRNA and protein expression levels of pro-opiomelanocortin (POMC) were dramatically increased after ICV injection with 5-HT. The anorexigenic action of 5-HT was accompanied by markedly elevated hypothalamic MDA levels and GSH-Px activity, while the SOD activity was decreased. Moreover, 5-HT significantly increased the mRNA expression of UCP-2 but reduced the levels of UCP-3. Both Trolox and Apocynin could block the 5-HT-induced changes in UCP-2 and UCP-3 gene expression. Our study demonstrates for the first time that the anorexigenic effect of 5-HT is mediated by the generation of ROS in the hypothalamus through an NADPH oxidase-dependent pathway.


Assuntos
Ingestão de Alimentos/efeitos dos fármacos , NADPH Oxidases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Serotonina/farmacologia , Acetofenonas/farmacologia , Animais , Antioxidantes/farmacologia , Western Blotting , Cromanos/farmacologia , Expressão Gênica/efeitos dos fármacos , Glutationa Peroxidase/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Injeções Intraventriculares , Canais Iônicos/genética , Canais Iônicos/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Serotonina/administração & dosagem , Agonistas do Receptor de Serotonina/administração & dosagem , Agonistas do Receptor de Serotonina/farmacologia , Superóxido Dismutase/metabolismo , Proteína Desacopladora 2 , Proteína Desacopladora 3
8.
Fundam Clin Pharmacol ; 27(1): 104-12, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21793900

RESUMO

Previous work has shown that intraperitoneal administration of riparin III (ripIII) reduces immobility time in the forced swimming test (FST), which suggests potential antidepressant activity. As the mechanism of action is not completely understood, this study is aimed at investigating the antidepressant-like action of ripIII. Following intraperitoneal administration of ripIII at doses of 25 and 50 mg/kg, there were decreases in the immobility time in the FST and tail suspension test without accompanying changes in ambulation (data not shown). The pretreatment of mice with sulpiride (50 mg/kg, i.p.), prazosin (1 mg/kg, i.p.), yohimbine (1 mg/kg, i.p.), and p-chlorophenylalanine (PCPA, 100 mg/kg, i.p. for, four consecutive days) significantly prevented the anti-immobility effect of ripIII in the FST. On the other hand, the anti-immobility effect of ripIII (50 mg/kg, v.o.) was not altered by pretreatment of mice with SCH23390 (15 µg/kg, i.p.) Furthermore, ripIII potentiated the sleeping latency and sleeping time of the pentobarbital-induced sleeping time test and also potentiated apomorphine (16 mg/kg, i.p.)-induced hypothermia in mice. In conclusion, the present study provides evidence that the antidepressant-like effect of ripIII is dependent on its interaction with the serotonergic, noradrenergic (α1- and α2- receptors), and dopaminergic (dopamine D2 receptors) systems.


Assuntos
Antidepressivos/uso terapêutico , Benzamidas/uso terapêutico , Encéfalo/efeitos dos fármacos , Depressão/tratamento farmacológico , Neurônios/efeitos dos fármacos , Tiramina/análogos & derivados , Administração Oral , Agonistas de Receptores Adrenérgicos alfa 1/administração & dosagem , Agonistas de Receptores Adrenérgicos alfa 1/uso terapêutico , Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Animais , Antidepressivos/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Benzamidas/administração & dosagem , Encéfalo/metabolismo , Brasil , Depressão/metabolismo , Agonistas de Dopamina/administração & dosagem , Agonistas de Dopamina/uso terapêutico , Etnofarmacologia , Frutas/química , Frutas/crescimento & desenvolvimento , Guiana , Lauraceae/química , Lauraceae/crescimento & desenvolvimento , Masculino , Camundongos , Neurônios/metabolismo , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Agonistas do Receptor de Serotonina/administração & dosagem , Agonistas do Receptor de Serotonina/uso terapêutico , Tiramina/administração & dosagem , Tiramina/uso terapêutico
9.
J Neurophysiol ; 106(3): 1341-54, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21653706

RESUMO

In quadrupeds, spinalization in the thoracic region severely impairs postural control in the hindquarters. The goal of this study was to improve postural functions in chronic spinal rabbits by regular application of different factors: intrathecal injection of the 5-HT(2) agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), epidural electrical spinal cord stimulation (EES), and specific postural training (SPT). The factors were used either alone (SPT group) or in combination (DOI+SPT, EES+SPT, and DOI+EES+SPT groups) or not used (control group). It was found that in none of these groups did normal postural corrective movements in response to lateral tilts of the supporting platform reappear within the month of treatment. In control group, reduced irregular electromyographic (EMG) responses, either correctly or incorrectly phased in relation to tilts, were observed. By contrast, in DOI+SPT and EES+SPT groups, a gradual threefold increase in the proportion of correctly phased EMG responses (compared with control) was observed. The increase was smaller in DOI+EES+SPT and SPT groups. Dissimilarly to these long-term effects, short-term effects of DOI and EES were weak or absent. In addition, gradual development of oscillatory EMG activity in the responses to tilts, characteristic for the control group, was retarded in DOI+SPT, EES+SPT, DOI+EES+SPT, and SPT groups. Thus regular application of the three tested factors and their combinations caused progressive, long-lasting plastic changes in the isolated spinal networks, resulting in the facilitation of spinal postural reflexes and in the retardation of the development of oscillatory EMG activity. The facilitated reflexes, however, were insufficient for normal postural functions.


Assuntos
Terapia por Estimulação Elétrica , Extremidades/fisiologia , Equilíbrio Postural/fisiologia , Agonistas do Receptor de Serotonina/administração & dosagem , Traumatismos da Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/terapia , Animais , Terapia por Estimulação Elétrica/métodos , Eletromiografia/métodos , Injeções Espinhais , Masculino , Equilíbrio Postural/efeitos dos fármacos , Coelhos , Vértebras Torácicas
10.
Pharm Biol ; 48(2): 234-40, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20645848

RESUMO

CONTEXT: Ficus religiosa Linn (Moraceae) is a variety of fig tree. Its figs are known to contain a high serotonergic content, and modulation of serotonergic neurotransmission plays a crucial role in the pathogenesis of amnesia. Thus, the present study was envisaged. OBJECTIVE: To investigate the effect of the methanol extract of figs of Ficus religiosa (FRFE) on scopolamine-induced anterograde and retrograde amnesia in mice. MATERIALS AND METHODS: Transfer latency (TL) to the preferred niche in the elevated plus-maze (EPM) and learning avoidance of passive behavior to avoid punishment in the modified passive avoidance paradigm (MPA) served as behavioral models for the assessment of memory. Scopolamine (1 mg/kg, i.p.) was administered before training for induction of anterograde amnesia and before retrieval for induction of retrograde amnesia in both models. TL in the EPM, step down latency (SDL), number of trials, and number of mistakes in the MPA were determined in vehicle control, FRFE treated (10, 50, and 100 mg/kg, i.p.), and standard groups (piracetam 200 mg/kg, i.p.). Cyproheptadine, a non-selective 5-HT(1/2) blocker (4 mg/kg, i.p.), was administered along with the FRFE to investigate the involvement of serotonergic pathways in the anti-amnesic effect of FRFE. RESULTS AND DISCUSSION: FRFE resulted in a significant improvement of memory, as its treatment attenuated the scopolamine-induced anterograde and retrograde amnesia dose-dependently. Further, cyproheptadine pretreatment significantly reversed the anti-amnesic effect of FRFE. CONCLUSION: FRFE has anti-amnesic activity against scopolamine-induced amnesia, in a dose-dependent manner. Inhibition of the anti-amnesic effect of FRFE by cyproheptadine substantiates the involvement of serotonergic pathways for its activity.


Assuntos
Amnésia Anterógrada/prevenção & controle , Amnésia Retrógrada/prevenção & controle , Ficus/química , Nootrópicos/uso terapêutico , Fitoterapia , Extratos Vegetais/uso terapêutico , Escopolamina/toxicidade , Amnésia Anterógrada/induzido quimicamente , Amnésia Retrógrada/induzido quimicamente , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Frutas/química , Índia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Medicina Tradicional , Memória/efeitos dos fármacos , Camundongos , Nootrópicos/administração & dosagem , Nootrópicos/química , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Tempo de Reação/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/administração & dosagem , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/uso terapêutico , Fatores de Tempo
11.
Neurotherapeutics ; 7(2): 159-63, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20430314

RESUMO

SUMMARY: Migraine is a common, multisymptom disorder that can severely impact the daily activities of migraineurs. Triptans (primarily sumatriptan) are the most commonly prescribed treatment for migraine and are considered a relatively safe and effective initial therapy. Unfortunately, current sumatriptan formulations (i.e., oral, nasal, subcutaneous) may be associated with limitations that can result in patients' delaying or avoiding treatment. For oral formulations, these limitations include difficulty in taking an oral medication due to the nausea and vomiting that often accompany migraine, and inconsistent absorption, whereas nasal and subcutaneous formulations may be associated with low bioavailability and an undesirable rate of adverse events, respectively. An alternative to current formulations is transdermal drug delivery, particularly iontophoresis. Transdermal delivery has several advantages over current formulations, including avoidance of the gastrointestinal tract, controlled and sustained delivery, and convenient administration. This article reviews the in vitro, in vivo, and preclinical data supporting the use of iontophoresis for the delivery of sumatriptan, as well as the recent clinical data for Zelrix (NuPathe Inc., Conshohocken, PA), an iontophoretic sumatriptan patch currently in phase III development for the treatment of migraine.


Assuntos
Transtornos de Enxaqueca/tratamento farmacológico , Agonistas do Receptor de Serotonina/administração & dosagem , Sumatriptana/administração & dosagem , Doença Aguda , Administração Cutânea , Animais , Ensaios Clínicos Fase III como Assunto , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Iontoforese/métodos , Agonistas do Receptor de Serotonina/farmacocinética , Sumatriptana/farmacocinética , Resultado do Tratamento
12.
J Pharmacol Sci ; 110(4): 415-23, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19602846

RESUMO

Polyethylene glycol electrolyte lavage solution (PEG-ELS) is widely used for colon cleansing prior to colonoscopy and colonic surgery. It has recently been shown that coadministration of PEG-ELS and mosapride citrate hydrate (mosapride), a selective 5-HT(4)-receptor agonist, is clinically useful for barium enema examination as it allows adequate barium coating. However, there is no report showing that mosapride has beneficial effects on colon cleansing and its underlying mechanism in experimental animals. In the present study, we investigated the effects of mosapride on colonic transit and on the colon cleansing action of PEG-ELS in guinea pigs. Mosapride (10 - 20 mg/kg, i.g.) significantly enhanced colonic transit rate in guinea pigs. Although PEG-ELS alone showed adequate colon cleansing action, excess fluid remained in the colon. Coadministration of mosapride (20 mg/kg) and PEG-ELS, regardless of mosapride timing, reduced colonic content weight (dry residue and water amount) as compared to PEG-ELS alone. These findings suggest that mosapride enhances the colon cleansing action of PEG-ELS via an increase in colonic transit in guinea pigs, that is, it reduces not only fecal residue but also excessive fluid in the colonic lumen. It is therefore believed that coadministration of mosapride and PEG-ELS can allow better visualization in barium enema examination.


Assuntos
Benzamidas/farmacologia , Colo/efeitos dos fármacos , Trânsito Gastrointestinal/efeitos dos fármacos , Morfolinas/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Animais , Benzamidas/administração & dosagem , Colo/metabolismo , Colonoscopia , Relação Dose-Resposta a Droga , Eletrólitos/administração & dosagem , Cobaias , Masculino , Morfolinas/administração & dosagem , Polietilenoglicóis/administração & dosagem , Agonistas do Receptor 5-HT4 de Serotonina , Agonistas do Receptor de Serotonina/administração & dosagem , Irrigação Terapêutica/métodos
13.
Appetite ; 52(1): 44-50, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18721836

RESUMO

5-Hydroxytryptamine (5-HT; serotonin) system is the major neurotransmitter system of interest in research on anorexia nervosa (AN). The AN patients show extreme dieting weight loss, hyperactivity and low basal levels of 5-hydroxyindoleacetic acid (5-HIAA), a major metabolite of 5-HT in the cerebrospinal fluid (CSF). Studies on animal models show that diet restriction (DR) decreases 5-HT metabolism in the brain and hypothalamus which is not necessarily associated with a decrease in the availability of essential amino acid tryptophan (TRP) the precursor of serotonin. To further investigate the mechanism involved in DR-induced decreases of 5-HT the present study uses 8-hydroxy-(2-di-n-propylamino) tetralin (8-OH-DPAT), a selective 5-HT-1A agonist, as a probe to monitor the responsiveness of negative feedback control over 5-HT metabolism. Effects of DR and of 8-OHDPAT on TRP, 5-HT and 5-HIAA concentrations are determined in the hypothalamus, a region of the brain known to role in the regulation of appetite. Animals of DR group given access to food 2h daily for 6 days exhibited 21.6% decrease in the body weight compared to freely feeding (FF) controls. The levels of TRP in the plasma and of 5-HT in the hypothalamus decreased. No effect was found on the levels of TRP in the hypothalamus. 8-OH-DPAT-induced decreases of 5-HT and 5-HIAA were greater in DR than FF group. 8-OH-DPAT-induced hyperactivity was also greater in DR than FF group. The results show that DR-induced decreases of 5-HT are due to an increase in the responsiveness of negative feedback control over 5-HT and not due to smaller availability of TRP. DR-induced increase in activity and 8-OH-DPAT-induced greater hyperactivity in DR than FF group may also be due to exaggerated negative feedback control over 5-HT. It is suggested that drugs decreasing the responsiveness of negative feedback control over 5-HT may be of use for the treatment and prevention of AN in under weight patients on restricted diet.


Assuntos
Anorexia Nervosa/fisiopatologia , Química Encefálica/fisiologia , Retroalimentação Fisiológica/fisiologia , Privação de Alimentos , Agitação Psicomotora/etiologia , Serotonina/análise , 8-Hidroxi-2-(di-n-propilamino)tetralina/administração & dosagem , Animais , Anorexia Nervosa/etiologia , Feminino , Ácido Hidroxi-Indolacético/análise , Hipotálamo/química , Hipotálamo/efeitos dos fármacos , Ratos , Ratos Wistar , Agonistas do Receptor de Serotonina/administração & dosagem
14.
Nutr Neurosci ; 11(6): 277-82, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19000381

RESUMO

8-Hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), a 5-hydroxytryptamine (5-HT)-1A selective agonist was used to investigate a possible role of somatodendritic serotonin-1A receptors in the precipitation of hyperphagia and decreases of 5-HT metabolism associated with long-term consumption of sugar rich-diet. In the first part of study, dose-related hyperphagic effects of 8-OH-DPAT were monitored in freely feeding rats. In the second part of study, rats were fed freely on a sugar-rich diet (prepared by mixing standard rodent diet with table sugar in the ratio of 3:1 [w/w]) for 5 weeks. Hyperphagic effects of 8-OH-DPAT were monitored in sugar-rich diet and normal diet treated rats by injecting the drug at a dose of 0.25 mg/kg body weight, a dose that produced significant hyperphagia. Effects of 8-OH-DPAT on decreasing 5-HT metabolism in the hypothalamus were also investigated in the two groups. Results showed that administration of 8-OH-DPAT at a dose of 0.25 mg/kg body weight elicited hyperphagia and decreased 5-HT metabolism in normal diet treated animals but the effects in sugar-rich diet treated animals were smaller and not significant suggesting a decrease in the effectiveness of somatodendritic 5-HT-1A receptors, which provide a feedback control over the synthesis and release of 5-HT in terminal region. A possible mechanism involved in sugar-diet induced decreases of 5-HT metabolism is discussed.


Assuntos
Sacarose Alimentar/efeitos adversos , Hiperfagia/etiologia , Receptor 5-HT1A de Serotonina/fisiologia , Serotonina/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralina/administração & dosagem , Animais , Sacarose Alimentar/administração & dosagem , Ingestão de Alimentos/efeitos dos fármacos , Retroalimentação Fisiológica , Ácido Hidroxi-Indolacético/análise , Hiperfagia/fisiopatologia , Hipotálamo/química , Hipotálamo/efeitos dos fármacos , Hipotálamo/fisiopatologia , Masculino , Ratos , Ratos Wistar , Serotonina/análise , Agonistas do Receptor 5-HT1 de Serotonina , Agonistas do Receptor de Serotonina/administração & dosagem , Triptofano/análise
15.
Brain ; 131(Pt 12): 3380-94, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18952677

RESUMO

Appearance of dyskinesia is a common problem of long-term l-DOPA treatment in Parkinson's disease patients and represents a major limitation for the pharmacological management of the motor symptoms in advanced disease stages. We have recently demonstrated that dopamine released from serotonin neurons is responsible for l-DOPA-induced dyskinesia in 6-hydroxydopamine (6-OHDA)-lesioned rats, raising the possibility that blockade of serotonin neuron activity by combination of 5-HT(1A) and 5-HT(1B) agonists could reduce l-DOPA-induced dyskinesia. In the present study, we have investigated the efficacy of 5-HT(1A) and 5-HT(1B) agonists to counteract l-DOPA-induced dyskinesia in 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP)-treated macaques, the gold standard model of Parkinson's disease. In addition, we have studied the ability of this treatment to prevent development of l-DOPA-induced dyskinesia in 6-OHDA-lesioned rats. The results demonstrate the existence of a potent synergistic effect between 5-HT(1A) and 5-HT(1B) agonists in their ability to dampen l-DOPA-induced dyskinesia in the MPTP-treated macaques. Sub-threshold doses of the drugs, which individually produced no effect, were able to reduce the abnormal involuntary movements by up to 80% when administered in combination, without affecting the anti-parkinsonian properties of l-DOPA. Furthermore, chronic administration of low doses of the 5-HT(1) agonists in combination was able to prevent development of dyskinesia, and reduce the up-regulation of FosB after daily treatment with l-DOPA in the rat 6-OHDA model. Our results support the importance of a clinical investigation of the effect of 5-HT(1A) and 5-HT(1B) agonists, particularly in combination, in dyskinetic l-DOPA-treated Parkinson's disease patients.


Assuntos
Antiparkinsonianos/efeitos adversos , Discinesia Induzida por Medicamentos/prevenção & controle , Levodopa/efeitos adversos , Agonistas do Receptor 5-HT1 de Serotonina , Agonistas do Receptor de Serotonina/uso terapêutico , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , 8-Hidroxi-2-(di-n-propilamino)tetralina/administração & dosagem , 8-Hidroxi-2-(di-n-propilamino)tetralina/uso terapêutico , Animais , Antiparkinsonianos/uso terapêutico , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Esquema de Medicação , Avaliação Pré-Clínica de Medicamentos/métodos , Quimioterapia Combinada , Discinesia Induzida por Medicamentos/etiologia , Feminino , Levodopa/uso terapêutico , Macaca fascicularis , Atividade Motora/efeitos dos fármacos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/tratamento farmacológico , Proteínas Proto-Oncogênicas c-fos/metabolismo , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Receptores de N-Metil-D-Aspartato/metabolismo , Agonistas do Receptor de Serotonina/administração & dosagem , Resultado do Tratamento
16.
Pain ; 139(3): 533-540, 2008 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-18723285

RESUMO

Sumatriptan and the other triptan drugs target the serotonin receptor subtypes1B, 1D, and 1F (5-HT(1B/D/F)), and are prescribed widely in the treatment of migraine. An anti-migraine action of triptans has been postulated at multiple targets, within the brain and at both the central and peripheral terminals of trigeminal "pain-sensory" fibers. However, as triptan receptors are also located on "pain-sensory" afferents throughout the body, it is surprising that triptans only reduce migraine pain in humans, and experimental cranial pain in animals. Here we tested the hypothesis that sumatriptan can indeed reduce non-cranial, somatic and visceral pain in behavioral models in mice. Because sumatriptan must cross the blood brain barrier to reach somatic afferent terminals in the spinal cord, we compared systemic to direct spinal (intrathecal) sumatriptan. Acute nociceptive thresholds were not altered by sumatriptan pre-treatment, regardless of route. However, in behavioral models of persistent inflammatory pain, we found a profound anti-hyperalgesic action of intrathecal, but not systemic, sumatriptan. By contrast, sumatriptan was completely ineffective in an experimental model of neuropathic pain. The pronounced activity of intrathecal sumatriptan against inflammatory pain in mice raises the possibility that there is a wider spectrum of therapeutic indications for triptans beyond headache.


Assuntos
Analgésicos não Narcóticos/uso terapêutico , Dor/tratamento farmacológico , Agonistas do Receptor de Serotonina/uso terapêutico , Sumatriptana/uso terapêutico , Ácido Acético/administração & dosagem , Ácido Acético/toxicidade , Analgésicos não Narcóticos/administração & dosagem , Analgésicos não Narcóticos/farmacocinética , Animais , Barreira Hematoencefálica , Carragenina/toxicidade , Avaliação Pré-Clínica de Medicamentos , Formaldeído/toxicidade , Temperatura Alta/efeitos adversos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Inflamação/induzido quimicamente , Inflamação/fisiopatologia , Injeções Intraperitoneais , Injeções Espinhais , Injeções Subcutâneas , Masculino , Camundongos , Neuralgia/tratamento farmacológico , Dor/fisiopatologia , Limiar da Dor/efeitos dos fármacos , Nervo Fibular/lesões , Estimulação Física/efeitos adversos , Agonistas do Receptor de Serotonina/administração & dosagem , Agonistas do Receptor de Serotonina/farmacocinética , Sumatriptana/administração & dosagem , Sumatriptana/farmacocinética , Nervo Sural/lesões , Tato
17.
Behav Neurosci ; 122(4): 943-8, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18729648

RESUMO

Voluntary exercise has been associated with reduced anxiety across several animal models. Manipulation of central 5-HT can alter anxiety-like behaviors and administration of the 5-HT agonist metachlorophenylpiperazine (mCPP) increases anxiety in rodents and humans. To examine whether the anxiolytic effect of exercise is associated with an alteration in 5-HT systems, we examined the anxiogenic effect of mCPP in exercising and nonexercising mice. C57BL/6J mice were given 2 weeks of free access to either a functioning or nonfunctioning running wheel. Mice were then tested for acoustic startle following systemic injection of either 0, 0.1, 0.3, or 1 mg/kg of mCPP. Consistent with its anxiogenic properties, mCPP produced a dose-dependent increase in acoustic startle in nonexercising mice. However, this anxiogenic effect was blunted in exercising mice. These findings suggest that exercise may help to reduce anxiety by altering 5-HT systems, perhaps by down-regulating postsynaptic 5HT 2B/2C receptors.


Assuntos
Ansiedade/induzido quimicamente , Ansiedade/reabilitação , Condicionamento Físico Animal/métodos , Piperazinas/administração & dosagem , Reflexo de Sobressalto/fisiologia , Agonistas do Receptor de Serotonina/administração & dosagem , Estimulação Acústica/métodos , Análise de Variância , Animais , Comportamento Animal , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Reflexo de Sobressalto/efeitos dos fármacos
18.
Prog Neuropsychopharmacol Biol Psychiatry ; 32(6): 1516-20, 2008 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-18558456

RESUMO

Behavioral and psychological symptoms of dementia (BPSD) are commonly seen in patients with Alzheimer's disease (AD) and other forms of senile dementia. BPSD have a serious impact on the quality of life of dementia patients, as well as their caregivers. However, an effective drug therapy for BPSD has not been established. Recently, the traditional Japanese medicine Yokukansan (YKS, Yi-gan san in Chinese) has been reported to improve BPSD in a randomized, single-blind, placebo-controlled study. Moreover, abnormalities of the serotonin (5-HT) system such as 5-HT2A receptors have been reported to be associated with BPSD of AD patients. In the present study, we investigated the effect of YKS on head-twitch response induced by 2,5-dimethoxy-4-iodoamphetamine (DOI, 5 mg/kg, i.p.) in mice, a behavioral response that is mediated, in part, by 5-HT2A receptors. Acute treatment with YKS (100 and 300 mg/kg, p.o.) had no effect on the DOI-induced head-twitch response, whilst 14 days repeated treatment with YKS (300 mg/kg, p.o.) significantly inhibited this response. Moreover, repeated treatment with YKS (300 mg/kg, p.o.) decreased expression of 5-HT2A receptors in the prefrontal cortex, which is part of the circuitry mediating the head-twitch response. These findings suggest that the inhibition of DOI-induced head-twitch response by YKS may be mediated, in part, by altered expression of 5-HT2A receptors in the prefrontal cortex, which suggests the involvement of the 5-HT system in psychopharmacological effects of YKS.


Assuntos
Anfetaminas/antagonistas & inibidores , Anfetaminas/toxicidade , Comportamento Animal/efeitos dos fármacos , Demência/induzido quimicamente , Demência/psicologia , Medicamentos de Ervas Chinesas/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Receptor 5-HT2A de Serotonina/biossíntese , Agonistas do Receptor de Serotonina/toxicidade , Anfetaminas/administração & dosagem , Animais , Western Blotting , Catalepsia/induzido quimicamente , Catalepsia/psicologia , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/administração & dosagem , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Camundongos , Microinjeções , Atividade Motora/efeitos dos fármacos , Equilíbrio Postural/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/efeitos dos fármacos , Agonistas do Receptor de Serotonina/administração & dosagem
19.
Neurosci Lett ; 438(3): 281-5, 2008 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-18490105

RESUMO

Epidural electrical stimulation (ES) at spinal cord segment L2 can produce coordinated step-like movements in completely spinalized adult rats [R.M. Ichiyama, Y.P. Gerasimenko, H. Zhong, R.R. Roy, V.R. Edgerton, Hindlimb stepping movements in complete spinal rats induced by epidural spinal cord stimulation, Neurosci. Lett. 383 (2005) 339-344]. Plantar placement of the paws, however, was rarely observed. Here, we sought to determine the dose dependence of a 5-HT agonist (quipazine) on stepping kinematics when administered in combination with ES. Six adult female Sprague-Dawley rats received a complete mid-thoracic spinal cord transection and were implanted with epidural electrodes at the L2 spinal cord level. Quipazine (i.p.) was tested at doses of 0.1, 0.2, 0.3, 0.4, and 0.5 mg/kg. Rats were placed in a body weight support system, allowing them to walk bipedally on a moving treadmill belt (7 cm/s). 3D step kinematics analysis revealed that coordinated alternating bilateral stepping was induced by L2 stimulation (50 Hz) alone and by quipazine alone. Furthermore, the combination treatment produced significantly greater numbers of plantar steps and improved quality of stepping compared to either intervention alone. Both number and quality of stepping peaked at the intermediate dose of 0.3-0.4 mg/kg. The results indicate that quipazine and ES can have complementary effects on spinal circuits and that quipazine dosage is an important factor in differentially modulating these circuitries to improve the quality of the bipedal stepping on a treadmill belt.


Assuntos
Terapia por Estimulação Elétrica , Locomoção , Quipazina/administração & dosagem , Agonistas do Receptor de Serotonina/administração & dosagem , Traumatismos da Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/terapia , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/efeitos da radiação , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Espaço Epidural , Feminino , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Locomoção/efeitos da radiação , Extremidade Inferior/fisiopatologia , Extremidade Inferior/efeitos da radiação , Região Lombossacral , Desempenho Psicomotor/efeitos dos fármacos , Desempenho Psicomotor/efeitos da radiação , Ratos , Ratos Sprague-Dawley
20.
J Neurophysiol ; 98(5): 2525-36, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17855582

RESUMO

We hypothesized that epidural spinal cord stimulation (ES) and quipazine (a serotonergic agonist) modulates the excitability of flexor and extensor related intraspinal neural networks in qualitatively unique, but complementary, ways to facilitate locomotion in spinal cord-injured rats. To test this hypothesis, we stimulated (40 Hz) the S(1) spinal segment before and after quipazine administration (0.3 mg/kg, ip) in bipedally step-trained and nontrained, adult, complete spinal (mid-thoracic) rats. The stepping pattern of these rats was compared with control rats. At the stimulation levels used, stepping was elicited only when the hindlimbs were placed on a moving treadmill. In nontrained rats, the stepping induced by ES and quipazine administration was non-weight bearing, and the cycle period was shorter than in controls. In contrast, the stepping induced by ES and quipazine in step-trained rats was highly coordinated with clear plantar foot placement and partial weight bearing. The effect of ES and quipazine on EMG burst amplitude and duration was greater in flexor than extensor motor pools. Using fast Fourier transformation analysis of EMG bursts during ES, we observed one dominant peak at 40 Hz in the medial gastrocnemius (ankle extensor), whereas there was less of dominant spectral peak in the tibialis anterior (ankle flexor). We suggest that these frequency distributions reflect amplitude modulation of predominantly monosynaptic potentials in the extensor and predominantly polysynaptic pathways in the flexor muscle. Quipazine potentiated the amplitude of these responses. The data suggest that there are fundamental differences in the circuitry that generates flexion and extension during locomotion.


Assuntos
Terapia por Estimulação Elétrica , Locomoção , Quipazina/administração & dosagem , Agonistas do Receptor de Serotonina/administração & dosagem , Traumatismos da Medula Espinal/terapia , Medula Espinal , Animais , Comportamento Animal , Fenômenos Biomecânicos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Eletrodos Implantados , Eletromiografia/métodos , Espaço Epidural , Feminino , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Locomoção/efeitos da radiação , Atividade Motora/efeitos dos fármacos , Atividade Motora/efeitos da radiação , Ratos , Ratos Sprague-Dawley , Reflexo/efeitos dos fármacos , Reflexo/efeitos da radiação , Análise Espectral , Medula Espinal/efeitos dos fármacos , Medula Espinal/fisiologia , Medula Espinal/efeitos da radiação
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