ABSTRACT
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.
Subject(s)
Amino Acids/pharmacology , Antidepressive Agents/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Fluoxetine/pharmacology , Neurons/drug effects , Receptors, Metabotropic Glutamate/agonists , Selective Serotonin Reuptake Inhibitors/pharmacology , Animals , Animals, Newborn , Cell Differentiation/drug effects , Cell Proliferation/drug effects , Cells, Cultured , Cerebellum/cytology , Cerebellum/drug effects , Cyclic AMP/metabolism , DNA, Complementary/biosynthesis , DNA, Complementary/genetics , Drug Synergism , Immunohistochemistry , Mitogen-Activated Protein Kinases/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Rats , Rats, Sprague-Dawley , Reverse Transcriptase Polymerase Chain Reaction , Stem Cells/drug effectsSubject(s)
Adjuvants, Pharmaceutic/administration & dosage , Antidepressive Agents, Tricyclic/administration & dosage , Excitatory Amino Acid Agents/administration & dosage , Hippocampus/drug effects , Imipramine/administration & dosage , Receptors, Metabotropic Glutamate/drug effects , Amino Acids/administration & dosage , Animals , Bridged Bicyclo Compounds, Heterocyclic/administration & dosage , Depressive Disorder/drug therapy , Disease Models, Animal , Drug Interactions , Drug Therapy, Combination , Hippocampus/cytology , Hippocampus/metabolism , In Vitro Techniques , Mice , Neurons/drug effects , Rats , Rats, Inbred Strains , Receptor Cross-Talk/drug effects , Receptors, Metabotropic Glutamate/metabolism , Time Factors , Xanthenes/administration & dosageABSTRACT
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.
