Synaptic adaptations of CA1 pyramidal neurons induced by a highly effective combinational antidepressant therapy.
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.
Marchetti
Cristina
C
European Brain Research Institute, St. Lucia Foundation, Rome, Italy.
Tafi
Elisiana
E
Middei
Silvia
S
Rubinacci
Maria A
MA
Restivo
Leonardo
L
Ammassari-Teule
Martine
M
Marie
Hélène
H
D000818:Animals; D000831:Animals, Newborn; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D056547:CA1 Region, Hippocampal / Q000166:cytology*; D049229:Dendritic Spines / Q000187:drug effects / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004338:Drug Combinations; D004558:Electric Stimulation / Q000379:methods; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D004924:Escape Reaction / Q000187:drug effects; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D049452:Green Fluorescent Proteins; D007099:Imipramine / Q000494:pharmacology*; D046353:Immobility Response, Tonic / Q000187:drug effects; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018408:Patch-Clamp Techniques; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects* / Q000648:ultrastructure; D051381:Rats; D017208:Rats, Wistar; D020889:Rolipram / Q000494:pharmacology*; D013550:Swimming; D013569:Synapses / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects
D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D004338:Drug Combinations; D018690:Excitatory Amino Acid Agonists; D016760:Proto-Oncogene Proteins c-fos; D049452:Green Fluorescent Proteins; D020889:Rolipram; D007099:Imipramine