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: 7.05). 08/2008; 33(8):1896-908. DOI: 10.1038/sj.npp.1301596
Source: PubMed


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 When FLX treatment was withdrawn for 90 days in those LH-FLX animals in which reversion of despair had been observed at day 25, recurrence of despaired behavior was found accompanied by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

Download full-text


Available from: Silvia Wikinski, Oct 08, 2014
  • Source
    • "The prevalence of depression is increased in HF patients (Rutledge et al., 2006), whereas depression complicated with HF is associated with increased risk of mortality and rehospitalization in patients with HF (Jiang et al., 2001; Rutledge et al., 2006). Antidepressants and exercise training improve symptoms in patients with depression (Ströhle, 2009; Fournier et al., 2010), increase gray matter, neurogenesis and neurite outgrowth in the hippocampus (Malberg et al., 2000; Redila and Christie, 2006; van Praag et al., 2005; Reinés et al., 2008; Erickson et al., 2011; Arnone et al., 2013) and recover the proliferation of astrocytes induced by depression (Iwata et al., 2011; Eyre et al., 2013). "
    [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.
    Full-text · Article · Jan 2015 · NeuroImage
  • Source
    • "increased extracellular serotonin concentration subsequent to the inhibition of neuronal reuptake could be the first step in a cascade of events (Djordjevic et al. 2012; Reines et al. 2008, among others). CRF regulation of serotonin neurotransmission and signaling has been described. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Rationale Stress is a common antecedent reported by people suffering major depression. In these patients, extrahypothalamic brain areas, like the hippocampus and basolateral amygdala (BLA), have been found to be affected. The BLA synthesizes CRF, a mediator of the stress response, and projects to hippocampus. The main hippocampal target for this peptide is the CRF subtype 1 receptor (CRF1). Evidence points to a relationship between dysregulation of CRF/CRF1 extrahypothalamic signaling and depression. Objective Because selective serotonin reuptake inhibitors (SSRIs) are the first-line pharmacological treatment for depression, we investigated the effect of chronic treatment with the SSRI fluoxetine on long-term changes in CRF/CRF1 signaling in animals showing a depressive-like behavior. Methods Male Wistar rats were exposed to the learned helplessness paradigm (LH). After evaluation of behavioral impairment, the animals were treated with fluoxetine (10 mg/kg i.p.) or saline for 21 days. We measured BLA CRF expression with RT-PCR and CRF1 expression in CA3 and the dentate gyrus of the hippocampus with in situ hybridization. We also studied the activation of one of CRF1’s major intracellular signaling targets, the extracellular signal-related kinases 1 and 2 (ERK1/2) in CA3. Results In saline-treated LH animals, CRF expression in the BLA increased, while hippocampal CRF1 expression and ERK1/2 activation decreased. Treatment with fluoxetine reversed the changes in CRF and CRF1 expressions, but not in ERK1/2 activation. Conclusion In animals exposed to the learned helplessness paradigm, there are long-term changes in CRF and CRF1 expression that are restored with a behaviorally effective antidepressant treatment.
    Full-text · Article · Sep 2012 · Psychopharmacology
  • Source
    • "This speculation is corroborated by our finding that fluoxetine is also able to counteract both the trauma-induced synaptic protein loss and the behavioral symptoms (Figure 6). Besides fluoxetine [38], [39],other antidepressants, neuroleptics, the anxiolytic neuropeptide S, and mifepristone have also been found to increase synapsin and synaptophysin expression [36], [38], [40]–[43]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Despite intensive research efforts, the molecular pathogenesis of posttraumatic stress disorder (PTSD) and especially of the hippocampal volume loss found in the majority of patients suffering from this anxiety disease still remains elusive. We demonstrated before that trauma-induced hippocampal shrinkage can also be observed in mice exhibiting a PTSD-like syndrome. Aiming to decipher the molecular correlates of these trans-species posttraumatic hippocampal alterations, we compared the expression levels of a set of neurostructural marker proteins between traumatized and control mice at different time points after their subjection to either an electric footshock or mock treatment which was followed by stressful re-exposure in several experimental groups. To our knowledge, this is the first systematic in vivo study analyzing the long-term neuromolecular sequelae of acute traumatic stress combined with re-exposure. We show here that a PTSD-like syndrome in mice is accompanied by a long-lasting reduction of hippocampal synaptic proteins which interestingly correlates with the strength of the generalized and conditioned fear response but not with the intensity of hyperarousal symptoms. Furthermore, we demonstrate that treatment with the serotonin reuptake inhibitor (SSRI) fluoxetine is able to counteract both the PTSD-like syndrome and the posttraumatic synaptic protein loss. Taken together, this study demonstrates for the first time that a loss of hippocampal synaptic proteins is associated with a PTSD-like syndrome in mice. Further studies will have to reveal whether these findings are transferable to PTSD patients.
    Full-text · Article · Aug 2012 · PLoS ONE
Show more

Similar Publications