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1.
Psychopharmacology (Berl) ; 201(2): 203-18, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18712364

RESUMO

RATIONALE: Serotonin transporter (SERT) knockout (-/-) mice have an altered phenotype in adulthood, including high baseline anxiety and depressive-like behaviors, associated with increased baseline extracellular serotonin levels throughout life. OBJECTIVES: To examine the effects of increases in serotonin following the administration of the serotonin precursor 5-hydroxy-L-tryptophan (5-HTP) in SERT wild-type (+/+), heterozygous (+/-), and -/- mice. RESULTS: 5-HTP increased serotonin in all five brain areas examined with approximately 2- to 5-fold increases in SERT+/+ and +/- mice, and with greater 4.5- to 11.7-fold increases in SERT-/- mice. Behaviorally, 5-HTP induced exaggerated serotonin syndrome behaviors in SERT-/-, mice with similar effects in male and female mice. Studies suggest promiscuous serotonin uptake by the dopamine transporter (DAT) in SERT-/- mice, and here, the DAT blocker GBR 12909 enhanced 5-HTP-induced behaviors in SERT-/- mice. Physiologically, 5-HTP induced exaggerated temperature effects in SERT-deficient mice. The 5-HT1A antagonist WAY 100635 decreased 5-HTP-induced hypothermia in SERT+/+ and +/- mice with no effect in SERT-/- mice, whereas the 5-HT7 antagonist SB 269970 decreased this exaggerated response in SERT-/- mice only. WAY 100635 and SB 269970 together completely blocked 5-HTP-induced hypothermia in SERT+/- and -/- mice. CONCLUSIONS: These studies demonstrate that SERT-/- mice have exaggerated neurochemical, behavioral, and physiological responses to further increases in serotonin, and provide the first evidence of intact 5-HT7 receptor function in SERT-/- mice, with interesting interactions between 5-HT1A and 5-HT7 receptors. As roles for 5-HT7 receptors in anxiety and depression were recently established, the current findings have implications for understanding the high anxiety and depressive-like phenotype of SERT-deficient mice.


Assuntos
Química Encefálica/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Serotonina/deficiência , Serotonina/metabolismo , 5-Hidroxitriptofano/farmacologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Encéfalo/anatomia & histologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Catecolaminas/antagonistas & inibidores , Catecolaminas/classificação , Clorgilina/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Ácido Hidroxi-Indolacético/análise , Ácido Hidroxi-Indolacético/metabolismo , Hipotermia/induzido quimicamente , Masculino , Camundongos , Camundongos Knockout , Inibidores da Monoaminoxidase/farmacologia , Fenóis/farmacologia , Piperazinas/farmacologia , Piperazinas/toxicidade , Piridinas/farmacologia , Serotonina/análogos & derivados , Serotonina/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Agonistas do Receptor de Serotonina/farmacologia , Síndrome da Serotonina/induzido quimicamente , Sulfonamidas/farmacologia , Tranilcipromina/farmacologia
2.
Neuropharmacology ; 49(6): 798-810, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16183083

RESUMO

To evaluate the consequences of inactivation of the serotonin transporter (SERT) gene on 5-HT homeostasis and function, 5-HT synthesis and turnover rates were measured using the decarboxylase inhibition method in multiple brain regions (frontal cortex, striatum, brainstem, hippocampus and hypothalamus) from mice with a genetic disruption of SERT. 5-HT synthesis rates were increased 30-60% in the different brain regions of SERT -/- mice compared to littermate +/+ control mice despite 55-70% reductions in tissue 5-HT concentrations. Brain regions that possessed a greater capacity to increase synthesis and turnover (frontal cortex, striatum) demonstrated lesser reductions in tissue 5-HT. Female SERT -/- mice had greater increases (79%) in brain 5-HT synthesis than male -/- mice did (25%), a finding associated with higher brain tryptophan concentrations in females. Despite increased 5-HT synthesis, there was no change in either TPH2 or TPH1 mRNA levels or in maximal in vitro TPH activity in the brainstem of SERT -/- mice. Catecholamine homeostasis as reflected in brain tissue concentrations and in synthesis and turnover of dopamine and norepinephrine was unchanged in SERT -/- mice. Taken together, the results demonstrate a markedly altered homeostatic situation in SERT -/- mice that lack 5-HT reuptake, resulting in markedly depleted tissue stores that are inadequately compensated for by increased 5-HT synthesis, with brain region and gender specificity observed.


Assuntos
Encéfalo/metabolismo , Dinâmica não Linear , Proteínas da Membrana Plasmática de Transporte de Serotonina/deficiência , Serotonina/metabolismo , Animais , Aorta/metabolismo , Northern Blotting/métodos , Encéfalo/anatomia & histologia , Encéfalo/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão/métodos , Dopamina/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Hidroxi-Indolacético/metabolismo , Rim/metabolismo , Levodopa/metabolismo , Fígado/metabolismo , Pulmão/metabolismo , Masculino , Metildopa/análogos & derivados , Metildopa/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Biológicos , Miocárdio/metabolismo , Noretandrolona/metabolismo , Pâncreas/metabolismo , RNA Mensageiro/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/fisiologia , Fatores Sexuais , Baço/metabolismo , Fatores de Tempo , Triptofano Hidroxilase/genética , Triptofano Hidroxilase/metabolismo
3.
FASEB J ; 19(11): 1537-9, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15972295

RESUMO

Neural stem cells (NSCs) obtained from the midbrain region of embryonic (E14) mice were initially cultured with basic fibroblast growth factor (bFGF), Sonic hedgehog, and FGF-8 in a serum-free N-2 culture medium to foster differentiation into a serotonergic-like phenotype. During the initial differentiating phase, these progenitor cells expressed En1, Pax3, and Pax5 mRNA. Subsequently, a single serotonin [5-hydroxytryptamine (5-HT)] and tryptophan hydroxylase-positive clone was isolated, which gave rise to cells that developed serotonergic properties. Sixty percent of these progenitor cells expressed the serotonin transporter (SERT), as indicated by specific ligand binding of [125I]-RTI-55. To further evaluate SERT functionality, we showed that these progenitor cells possessed specific [3H]-5-HT uptake activity. Implantation of the serotonergic-like progenitors into the hippocampus of adult mice genetically lacking SERT was followed by migration of these cells into adjacent brain regions, and survival of the cells at 8 weeks was accompanied by a gradual increase in density of SERT protein expression, which was not found in vehicle-injected, control mice. These findings suggest that this serotonergic-like NSC model will be a useful contribution to the development of cell biotechnology in regard to the expression of missing genes such as SERT in the adult brain.


Assuntos
Neurônios/citologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/fisiologia , Serotonina/análise , Transplante de Células-Tronco , Células-Tronco/citologia , Animais , Fator Neurotrófico Derivado do Encéfalo/farmacologia , Diferenciação Celular , Sobrevivência Celular , Células Cultivadas , Cocaína/análogos & derivados , Cocaína/metabolismo , Feminino , Canais Iônicos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/biossíntese , Triptofano Hidroxilase/análise
4.
J Neurosci Res ; 79(6): 756-71, 2005 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-15672416

RESUMO

To study the neurochemical and behavioral effects of altered brain-derived neurotrophic factor (BDNF) expression on a brain serotonin system with diminished serotonin transport capability, a double-mutant mouse model was developed by interbreeding serotonin transporter (SERT) knockout mice with BDNF heterozygous knockout mice (BDNF +/-), producing SERT -/- x BDNF +/- (sb) mice. Prior evidence implicates serotonin and SERT in anxiety and stress responses. Some studies have shown that BDNF supports serotonergic neuronal development, leading to our hypothesis that reduced BDNF availability during development might exaggerate the consequences of absent SERT function. In the present study, brain serotonin and 5-hydroxyindol acetic acid concentrations in male sb mice were significantly reduced in the hippocampus and hypothalamus compared with wild-type control SB mice, BDNF-deficient Sb mice, and serotonin transporter knockout sB mice. The sb mice had significantly increased anxiety-like behaviors compared with SB, Sb, and sB mice as measured on the elevated plus maze test. These sb mice also had significantly greater increases in plasma adrenocorticotrophic hormone than mice with other genotypes after a stressful stimulus. Analysis of neuronal morphology showed that hypothalamic and hippocampal neurons exhibited 25-30% reductions in dendrites in sb mice compared with SB control mice. These findings support the hypothesis that genetic changes in BDNF expression interact with serotonin and other circuits that modulate anxiety and stress-related behaviors. Thus, this double-mutant mouse model should prove valuable in studying other gene x gene consequences for brain plasticity as well as in evaluating epistatic interactions of BDNF and serotonin transporter gene polymorphisms in neuropsychiatric disorders.


Assuntos
Monoaminas Biogênicas/metabolismo , Fator Neurotrófico Derivado do Encéfalo/deficiência , Encéfalo/metabolismo , Glicoproteínas de Membrana/deficiência , Proteínas de Membrana Transportadoras/deficiência , Proteínas do Tecido Nervoso/deficiência , Estresse Fisiológico/metabolismo , Hormônio Adrenocorticotrópico/sangue , Animais , Comportamento Animal/fisiologia , Western Blotting/métodos , Tamanho Corporal/genética , Encéfalo/citologia , Encéfalo/ultraestrutura , Química Encefálica/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Contagem de Células , Cromatografia Líquida de Alta Pressão/métodos , Eletroquímica/métodos , Comportamento Exploratório/fisiologia , Regulação da Expressão Gênica/genética , Genótipo , Aprendizagem em Labirinto/fisiologia , Glicoproteínas de Membrana/genética , Proteínas de Membrana Transportadoras/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout/fisiologia , Proteínas do Tecido Nervoso/genética , Neurônios/citologia , Medição da Dor/métodos , Radioimunoensaio/métodos , Distribuição Aleatória , Tempo de Reação/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina , Coloração pela Prata/métodos , Coloração e Rotulagem/métodos
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