Fluoxetine and olanzapine have synergistic effects in the modulation of fibroblast growth factor 2 expression within the rat brain.
BACKGROUND
The combination of the antidepressant fluoxetine (FLX) and the atypical antipsychotic olanzapine (OLA) appears to be more effective for the treatment of resistant depression than single drugs. We hypothesize that such combination may determine a specific modulation of neuroplastic genes, which could contribute to therapeutic activity.


METHODS
We investigated the expression of the neurotrophic molecule basic fibroblast growth factor 2 (FGF-2) after acute or chronic administration of FLX and OLA, alone or in combination. Ribonuclease (RNase) protection assay and Western blot analysis were employed to determine FGF-2 expression in different brain structures and to identify the intracellular pathways possibly involved in FGF-2 modulation.


RESULTS
After single injection, we found that FGF-2 mRNA levels were selectively upregulated in the prefrontal cortex only when the two drugs were coadministered, an effect paralleled by a significant increase of phosphorylated protein kinase B (P-Akt) levels. Conversely, chronic treatment with a combination of FLX and OLA (FLX+OLA) increased FGF-2 mRNA levels in prefrontal cortex, as well as in hippocampus and striatum.


CONCLUSIONS
Based on these data, we hypothesize a role of endogenously synthesized FGF-2 in the effects of FLX/OLA combination on brain function and plasticity, which could contribute to its superior efficacy for the treatment of resistant depression.
Maragnoli
Maria Elisabetta
ME
Center of Neuropharmacology and Center of Excellence for Neurodegenerative Disorders, Department of Pharmacological Sciences, University of Milan, Milan, Italy.
Fumagalli
Fabio
F
Gennarelli
Massimo
M
Racagni
Giorgio
G
Riva
Marco Andrea
MA
D000704:Analysis of Variance; D000818:Animals; D001569:Benzodiazepines / Q000008:administration & dosage* / Q000494:pharmacology; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004334:Drug Administration Schedule; D004338:Drug Combinations; D004357:Drug Synergism; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism*; D005473:Fluoxetine / Q000008:administration & dosage* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D000077152:Olanzapine; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D013997:Time Factors
D001569:Benzodiazepines; D017362:Cyclic AMP Response Element-Binding Protein; D004338:Drug Combinations; D016222:Fibroblast Growth Factor 2; D005473:Fluoxetine; D000077152:Olanzapine; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D017367:Selective Serotonin Reuptake Inhibitors; C494920:Akt1 protein, rat