Maintenance treatment with fluoxetine is necessary to sustain normal levels of synaptic markers in an experimental model of depression: correlation with behavioral response.

Instituto de Investigaciones Farmacológicas (ININFA), CONICET, Universidad de Buenos Aires, Buenos Aires, Argentina.
Neuropsychopharmacology (Impact Factor: 7.83). 08/2008; 33(8):1896-908. DOI: 10.1038/sj.npp.1301596
Source: PubMed

ABSTRACT Dysfunction of hippocampal plasticity has been proposed to play a critical role in the pathophysiology of depression. However, antidepressant drug effects on synaptic plasticity and cytoskeletal remodeling remain controversial. The aim of the present study was to evaluate in animals exposed to the learned helplessness (LH) paradigm, an accepted experimental model of depression, the effect of chronic treatment with fluoxetine (FLX) on synaptic and cytoskeletal proteins known to undergo plastic changes. Synaptophysin (SYN), postsynaptic density 95 (PSD-95), axon growth-associated protein 43 (GAP-43), and cytoskeletal proteins (intermediate neurofilaments and MAP-2) were studied in the hippocampus by immunohistochemistry. Whereas LH animals treated 21 days with saline (LH-S group) displayed diminished SYN and PSD-95 immunostainings in the CA3 but not in the DG, chronic treatment with FLX not only reversed the despaired behavior induced by exposure to LH paradigm, but also fully recovered SYN and PSD-95 labeling to control values. Similar results were obtained for the axonal remodeling marker GAP-43. FLX treatment did not modify either the decreased light neurofilament subunit (NFL) observed in the hippocampus of LH animals or any other cytoskeletal protein studied. When FLX treatment was withdrawn for 90 days in those LH-FLX animals in which reversion of despair had been observed at day 25, recurrence of despaired behavior was found accompanied by decreased SYN, PSD-95, and NFL labelings. Results indicate that the synapse remodeling induced by FLX in the CA3 region could underlie its behavioral efficacy despite the absence of cytoskeletal remodeling and that the stability of synaptic changes would depend on the continuous administration of the drug.


Available from: Silvia Wikinski, Oct 08, 2014
  • [Show abstract] [Hide abstract]
    ABSTRACT: Depressive symptoms are common in older adults and are particularly prevalent in those with or at elevated risk for dementia. Although the heritability of depression is estimated to be substantial, single nucleotide polymorphism-based genome-wide association studies of depressive symptoms have had limited success. In this study, we PERFORMED genome-wide gene- and pathway-based analyses of depressive symptom burden. Study participants included non-Hispanic Caucasian subjects (n = 6,884) from three independent cohorts, the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Health and Retirement Study (HRS), and the Indiana Memory and Aging Study (IMAS). Gene-based meta-analysis identified genome-wide significant associations (ANGPT4 and FAM110A, q-value = 0.026; GRM7-AS3 and LRFN5, q-value = 0.042). Pathway analysis revealed enrichment of association in 105 pathways, including multiple pathways related to ERK/MAPK signaling, GSK3 signaling in bipolar disorder, cell development, and immune activation and inflammation. GRM7, ANGPT4, and LRFN5 have been previously implicated in psychiatric disorders, including the GRM7 region displaying association with major depressive disorder. The ERK/MAPK signaling pathway is a known target of antidepressant drugs and has important roles in neuronal plasticity, and GSK3 signaling has been previously implicated in Alzheimer's disease and as a promising therapeutic target for depression. Our results warrant further investigation in independent and larger cohorts and add to the growing understanding of the genetics and pathobiology of depressive symptoms in aging and neurodegenerative disorders. In particular, the genes and pathways demonstrating association with depressive symptoms may be potential therapeutic targets for these symptoms in older adults.
    Journal of Alzheimer's disease: JAD 02/2015; DOI:10.3233/JAD-148009 · 3.61 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: According to the neuroplastic hypothesis of the depression, antidepressant drugs can trigger plastic mechanisms in the adult brain, which may revert the reduction of neuronal plasticity produced by depression. However, there is controversy on the efficacy of these drugs on older patients. With the present study we seek to explore the effects of the antidepressant fluoxetine, a selective serotonin reuptake inhibitor, on neuronal plasticity in the medial prefrontal cortex (mPFC) in middle aged rats. This plasticity may be mediated by the polysialylated form of the neural cell adhesion molecule (PSA-NCAM), which is expressed in the adult mPFC, associated to inhibitory elements. PSA-NCAM expressing interneurons can be found in the mPFC of rodents and humans and they belong to different subpopulations of interneurons, defined by the expression of calcium binding proteins and neuropeptides. Most of them express serotonin type 3 receptors (5HT3), but not 5HT1A or 5HT2A. Moreover, previous results from our group have shown changes in the expression of PSA-NCAM and synaptophysin (SYN) in this cortical region after chronic treatment with fluoxetine in young rats (3 months old). These effects are mediated by 5HT3 receptors, since their pharmacological blockade prevent the changes induced by fluoxetine. In the present study, we analyze the expression of these and other plasticity related molecules in the same region, such as glutamic acid decarboxylase (GAD67) and vesicular glutamate transporter 1 (VGLUT1) after chronic fluoxetine treatment (14 days) in middle aged rats (8 months old). These rats were injected intraperitoneally daily with a dose of 10 mg/Kg of fluoxetine in standard stabulary conditions. We observed the typical significant changes in the weight of fluoxetine treated rats (p = 0.00057). Using immunohistochemistry and a specialized software, we analyzed the expression of the different molecules and their density of puncta in the mPFC neuropil. Preliminary results show no significant change between the fluoxetine treated animals and the controls in the expression of PSA-NCAM (p= 0.24 for the puncta analysis and p = 0.43 for fluorescence intensity), SYN (p = 0.6 for puncta analysis and p = 0.71 for fluorescence intensity), GAD67 (p = 0.9 for puncta and p = 0.78 for fluorescence intensity), and VGLUT1 (p = 0.5 for puncta and p = 0.59 for fluorescence intensity) in the mPFC of these middle aged rats. Therefore, the changes in PSA-NCAM expression induced by antidepressants are compromised during aging and, consequently, may result in a reduced plastic response, which is reflected in the absence of changes in the expression of molecules related to general, inhibitory or excitatory neurotransmission. The effects of antidepressants on the expression of molecules related to neuronal structural plasticity in other brain regions of middle aged rats such as the somatosensory cortex, hippocampus or the amygdala, are currently being analyzed. These results invite to reconsider the efficacy of antidepressant drugs in older patients.
    European Neuropsychopharmacology, Amsterdam; 08/2010
  • Source
    Eicosapentaenoic acid: sources, health effects, and role in disease prevention, Edited by Theodore G. Bradley, Francisco P. Vargas, 01/2012: chapter Eicosapentaenoic acid and bone metabolism: pages 47-74; Nova Science Publishers.