Article

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 When FLX treatment was withdrawn for 90 days in those LH-FLX animals in which reversion of despair had been observed at day 25, recurrence of despaired behavior was found accompanied by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.

0 Followers
 · 
72 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Heart failure (HF) is characterized by a blood supply which is insufficient to meet the body's demand. HF can potentially affect the brain and is associated with a high prevalence of depression. However, the mechanisms by which the two are related remain largely unclear. Structural abnormalities of the ventral hippocampus have been observed in depression but have never been reported in HF. In this study, we thus investigated structural brain abnormality in HF using voxel-based morphometry (VBM) and histological analysis in a rat model of HF. T2-weighted images were obtained in rats with HF (n = 20) and sham rats (n = 17) and VBM was used to produce gray matter concentration (GMC) maps. Twenty-four hour locomotor activity was used as a sign of depressive behavior. Brains of HF and sham rats (n = 8, each) were fixed and histologically analyzed for the measurement of neurogenesis, the number of astrocytes and neurite outgrowth in the ventral hippocampus. VBM demonstrated significant GMC decrease in the hippocampus, which was restricted to the ventral segment. Similarly, neurogenesis and neurite outgrowth were significantly decreased and the number of astrocytes was significantly increased in HF rats as compared with sham rats in the ventral hippocampus. GMC values in the ventral hippocampus were significantly and negatively correlated with 24 hour locomotor activity in HF rats. In conclusion, the present study has demonstrated for the first time that the structural abnormality of the ventral hippocampus is associated with depressive symptoms in HF rats.
    NeuroImage 01/2015; 105. DOI:10.1016/j.neuroimage.2014.10.040 · 6.13 Impact Factor
  • 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.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: There is substantial interest in the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine in psychiatric research, as it exerts psychotomimetic and antidepressant effects in rodents and humans. Here we investigated proteomic changes in brain and serum after acute treatment of rats with ketamine using two targeted proteomic profiling methods. Multiplex immunoassay profiling of serum identified altered levels of IL-4, TNFα and FGF-9, suggesting a link between ketamine exposure and peripheral inflammation and growth factor dysregulation. Selected reaction monitoring mass spectrometry (SRM-MS) profiling of rat brain tissue found that proteomic changes occurred in the frontal cortex and to a greater extent in the hippocampus. This mainly involved changes in signalling kinases and proteases such as PKCβ, neurochondrin (NCDN), calcineurin (PP2BC), ERK1 and MTOR. Furthermore, altered levels were found for proteins associated with neurotransmitter metabolism (AATM, COMT), synaptic vesicle endo-/exocytosis (NSF, SYN1, PACN1) and consistent with previous global proteomic studies, we confirmed known changes in mitochondrial complex I (NDUFS1), prohibitin (PHB) and neurofilament proteins (NFL, AINX). Taken together, the proteomic changes parallel those described in human psychiatric pathology. The results will help to elucidate ketamine's mechanism of action, which will facilitate development of novel drugs for the treatment of schizophrenia and major depressive disorder.
    Journal of Proteome Research 11/2014; 14(1). DOI:10.1021/pr5009493 · 5.00 Impact Factor

Full-text (2 Sources)

Download
14 Downloads
Available from
Oct 8, 2014