RESUMEN
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.
Asunto(s)
Aminoácidos/farmacología , Antidepresivos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Fluoxetina/farmacología , Neuronas/efectos de los fármacos , Receptores de Glutamato Metabotrópico/agonistas , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Animales , Animales Recién Nacidos , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Cerebelo/citología , Cerebelo/efectos de los fármacos , AMP Cíclico/metabolismo , ADN Complementario/biosíntesis , ADN Complementario/genética , Sinergismo Farmacológico , Inmunohistoquímica , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Madre/efectos de los fármacosAsunto(s)
Adyuvantes Farmacéuticos/administración & dosificación , Antidepresivos Tricíclicos/administración & dosificación , Fármacos actuantes sobre Aminoácidos Excitadores/administración & dosificación , Hipocampo/efectos de los fármacos , Imipramina/administración & dosificación , Receptores de Glutamato Metabotrópico/efectos de los fármacos , Aminoácidos/administración & dosificación , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Trastorno Depresivo/tratamiento farmacológico , Modelos Animales de Enfermedad , Interacciones Farmacológicas , Quimioterapia Combinada , Hipocampo/citología , Hipocampo/metabolismo , Técnicas In Vitro , Ratones , Neuronas/efectos de los fármacos , Ratas , Ratas Endogámicas , Receptor Cross-Talk/efectos de los fármacos , Receptores de Glutamato Metabotrópico/metabolismo , Factores de Tiempo , Xantenos/administración & dosificaciónRESUMEN
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.