RESUMO
We examined the interaction between the selective serotonin reuptake inhibitor, fluoxetine, and group-II metabotropic glutamate (mGlu) receptors using progenitor cells isolated from cultured cerebellar granule cells, considered as an in vitro model of antidepressant-drug induced neurogenesis. These cells expressed mGlu3 receptors negatively coupled to adenylyl cyclase. A 72-h treatment with either fluoxetine or low concentrations of mGlu2/3 receptor agonists (LY379268 or 2R,4R-APDC) enhanced cell proliferation. The action of fluoxetine was mediated by the activation of 5-HT(1A) receptors. We found a strong synergism between fluoxetine and LY379268 in enhancing cell proliferation and inhibiting cAMP formation. The increased cell proliferation induced by fluoxetine+LY379268 was abrogated by the cAMP analogue, 8-Br-cAMP, as well as by drugs that inhibit the mitogen-activated protein kinase and phosphatidyilinositol-3-kinase pathways. Interestingly, fluoxetine and LY379268 also acted synergistically in promoting neuronal differentiation when progenitor cells were incubated in the presence of serum. These data support the hypothesis that a combination between classical antidepressants and mGlu2/3 receptor agonists may be helpful in the experimental treatment of depression.
Assuntos
Aminoácidos/farmacologia , Antidepressivos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Fluoxetina/farmacologia , Neurônios/efeitos dos fármacos , Receptores de Glutamato Metabotrópico/agonistas , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Animais , Animais Recém-Nascidos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Cerebelo/citologia , Cerebelo/efeitos dos fármacos , AMP Cíclico/metabolismo , DNA Complementar/biossíntese , DNA Complementar/genética , Sinergismo Farmacológico , Imuno-Histoquímica , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células-Tronco/efeitos dos fármacosAssuntos
Adjuvantes Farmacêuticos/administração & dosagem , Antidepressivos Tricíclicos/administração & dosagem , Fármacos Atuantes sobre Aminoácidos Excitatórios/administração & dosagem , Hipocampo/efeitos dos fármacos , Imipramina/administração & dosagem , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Aminoácidos/administração & dosagem , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Transtorno Depressivo/tratamento farmacológico , Modelos Animais de Doenças , Interações Medicamentosas , Quimioterapia Combinada , Hipocampo/citologia , Hipocampo/metabolismo , Técnicas In Vitro , Camundongos , Neurônios/efeitos dos fármacos , Ratos , Ratos Endogâmicos , Receptor Cross-Talk/efeitos dos fármacos , Receptores de Glutamato Metabotrópico/metabolismo , Fatores de Tempo , Xantenos/administração & dosagemRESUMO
Antidepressant drugs have a clinical latency that correlates with the development of neuroadaptive changes, including down-regulation of beta-adrenergic receptors in different brain regions. The identification of drugs that shorten this latency will have a great impact on the treatment of major depressive disorders. We report that the time required for the antidepressant imipramine to reduce the expression of beta-adrenergic receptors in the hippocampus is reduced by a co-administration with centrally active ligands of type 2/3 metabotropic glutamate (mGlu2/3) receptors. Daily treatment of mice with imipramine alone (10 mg/kg, i.p.) reduced the expression of beta-adrenergic receptors in the hippocampus after 21 days, but not at shorter times, as assessed by western blot analysis of beta1-adrenergic receptors and by the amount of specifically bound [3H]CGP-12177, a selective beta-adrenergic receptor ligand. Down-regulation of beta-adrenergic receptors occurred at shorter times (i.e. after 14 days) when imipramine was combined with low doses (0.5 mg/kg, i.p.) of the selective mGlu2/3 receptor agonist LY379268, or with the preferential mGlu2/3 receptor antagonist LY341495 (1 mg/kg, i.p.). Higher doses of LY379268 (2 mg/kg, i.p.) were inactive. This intriguing finding suggests that neuroadaptation to imipramine--at least as assessed by changes in the expression of beta1-adrenergic receptors--is influenced by drugs that interact with mGlu2/3 receptors and stimulates further research aimed at establishing whether any of these drugs can shorten the clinical latency of classical antidepressants.