Synaptic Adaptations of CA1 Pyramidal Neurons Induced by a Highly Effective Combinational Antidepressant Therapy

Autor: Martine Ammassari-Teule, Cristina Marchetti, Leonardo Restivo, Maria A. Rubinacci, Silvia Middei, Hélène Marie, Elisiana Tafi
Rok vydání: 2010
Předmět:
Imipramine
Patch-Clamp Techniques
Dendritic Spines
Green Fluorescent Proteins
Enzyme-Linked Immunosorbent Assay
Mice
Transgenic
AMPA receptor
In Vitro Techniques
Biology
Synaptic Transmission
Drug Administration Schedule
Mice
chemistry.chemical_compound
Glutamatergic
Escape Reaction
Excitatory Amino Acid Agonists
medicine
Animals
Cyclic adenosine monophosphate
Rats
Wistar
CA1 Region
Hippocampal
Swimming
Biological Psychiatry
Rolipram
Behavior
Animal
Dose-Response Relationship
Drug
Brain-Derived Neurotrophic Factor
Pyramidal Cells
Immobility Response
Tonic
Long-term potentiation
Antidepressive Agents
Electric Stimulation
Rats
Mice
Inbred C57BL
Drug Combinations
Monoamine neurotransmitter
Animals
Newborn
Gene Expression Regulation
chemistry
Synapses
Synaptic plasticity
Antidepressant
Proto-Oncogene Proteins c-fos
Neuroscience
medicine.drug
Zdroj: Biological Psychiatry. 67:146-154
ISSN: 0006-3223
Popis: Background Antidepressants (AD) need to be chronically administered (weeks to months) to provide beneficial effects. Evidence suggests that combined administration of inhibitors of monoamine reuptake and phosphodiesterase type 4 allows a highly effective therapeutic action. Also, this coadministration more rapidly boosts the cyclic adenosine monophosphate (cAMP) pathway, which is normally activated during chronic treatment of single compounds. Little is known, however, about how this augmentation therapy affects the core mechanism of glutamatergic plasticity. We therefore investigated how in vivo combinational subchronic rolipram and imipramine (scRI) treatment affects depressive behavior, cAMP-dependent transcription, and glutamatergic transmission in the hippocampus, a region critically implicated in depression. Methods Antidepressant properties of scRI were investigated through the forced swim test. Changes in cAMP-dependent transcription and synaptic transmission of CA1 pyramidal cells were explored with green fluorescent protein, enzyme-linked immunosorbent assay, electrophysiology recordings, and Golgi-Cox staining. Results We demonstrate that scRI displays robust antidepressant properties compared with single-drug treatments and increases hippocampal c-Fos expression and brain-derived neurotrophic factor protein levels. These effects are accompanied by a specific increase in alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N -methyl-D-aspartate receptors in already existing synapses. Finally, both acute and subchronic treatments led to enhancement of long-term potentiation but differently affected spine density and morphology, with scRI administration specifically resulting in a large increase in stubby spines. Conclusions We conclude that scRI is highly effective in providing antidepressive effects, including the hippocampal transcriptional alterations normally observed with longer single-drug treatments. Furthermore, we identified scRI-induced modifications in glutamatergic transmission that probably underlie the beneficial action of this combinational therapy.
Databáze: OpenAIRE
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