Maintenance treatment with fluoxetine is necessary to sustain normal levels of synaptic markers in an experimental model of depression: correlation with behavioral response.
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 When FLX treatment was withdrawn for 90 days in those LH-FLX animals in which reversion of despair had been observed at day 25, recurrence of despaired behavior was found accompanied by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.
- [show abstract] [hide abstract]
ABSTRACT: Recurrent depression poses a problem for up to 80% of patients with major depressive disorder (MDD) during their lifetime. Therefore, the optimal treatment goal established by the American Psychiatric Association and the Agency for Health Care Policy and Research is remission and virtual elimination of symptoms. Patients who have a high risk of recurrence often require maintenance therapy and long-term treatment. As a result, identification of antidepressants that are effective in maintaining remission in patients over the long-term and have acceptable tolerability profiles is important. The efficacy of antidepressants in conferring full remission and long-term recovery is an important priority for clinicians. Both selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) have been examined for use in long-term treatment of MDD. Recently, 2 long-term (6 to 12 months), double-blind, placebo-controlled studies have shown that venlafaxine is effective in preventing relapse and recurrence. While long-term, head-to-head studies comparing SNRIs with SSRIs are rare, a recent open-label study compared venlafaxine to 4 SSRIs (fluoxetine, paroxetine, sertraline, or citalopram) in outpatients with MDD. The results show that the SNRI venlafaxine is comparable to the SSRIs in terms of remission rates, and venlafaxine may bring patients to remission earlier than SSRIs. Long-term treatment at maximally tolerated doses is also associated with similar incidence of common adverse events between venlafaxine and placebo and tolerability comparable to SSRIs. Thus, there is increasing evidence that venlafaxine and SSRIs are effective and well tolerated in long-term therapy. While it is unclear from the data if continued treatment with SNRIs confers advantages over SSRIs due to an early onset of remission, further studies will provide valuable insights into the efficacy of SNRIs and SSRIs in maintenance therapy.The Journal of Clinical Psychiatry 02/2004; 65 Suppl 17:29-33. · 5.81 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Brain-derived neurotrophic factor (BDNF) modulates synaptic connectivity by increasing synapse number and by promoting activity-dependent axon arbor growth. Patterned neuronal activity is also thought to influence the morphological maturation of axonal arbors by directly influencing the stability of developing synapses. Here, we used in vivo time-lapse imaging to examine the relationship between synapse stabilization and axon branch stabilization, and to better understand the participation of BDNF in synaptogenesis. Green fluorescent protein (GFP)-tagged synaptobrevin II was used to visualize presynaptic specializations in individual DsRed2-labeled Xenopus retinal axons arborizing in the optic tectum. Neutralizing endogenous tectal BDNF with function-blocking antibodies significantly enhanced GFP-synaptobrevin cluster elimination, a response that was paralleled by enhanced branch elimination. Thus, synapse dismantling was associated with axon branch pruning when endogenous BDNF levels were reduced. To obtain a second measure of the role of BDNF during synapse stabilization, we injected recombinant BDNF in tadpoles with altered glutamate receptor transmission in the optic tectum. Tectal injection of the NMDA receptor antagonists APV or MK801 transiently induced GFP-synaptobrevin cluster dismantling, but did not significantly influence axon branch addition or elimination. BDNF treatment rescued synapses affected by NMDA receptor blockade: BDNF maintained GFP-synaptobrevin cluster density by maintaining their addition rate and rapidly inducing their stabilization. Consequently, BDNF influences synaptic connectivity in multiple ways, promoting not only the morphological maturation of axonal arbors, but also their stabilization, by a mechanism that influences both synapses and axon branches.Development 11/2005; 132(19):4285-98. · 6.21 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: The hippocampus, an important integration center for learning and memory in the mammalian brain, undergoes neurological changes in response to a variety of stimuli that are suggestive of ongoing synaptic reorganization. Accordingly, the aim of this study was to identify markers of synaptic plasticity using rapid and reliable techniques such as radioimmunocytochemistry and confocal microscopy, thereby providing a "birds-eye view" of the whole hippocampus under hypercorticosteronemic conditions. The regulation of microtubule-associated protein 2, synaptophysin and postsynaptic density-95 was examined in two different animal models of hypercorticosteronemia: corticosterone administration and streptozotocin-induced diabetes using both a short-term (1 week) and long-term (5 weeks) treatment. Glucocorticoids and/or hyperglycemia increased synaptophysin expression in CA1, CA3 and the dentate gyrus, regions that exhibit synaptic plasticity in response to glucocorticoid exposure. In these models, postsynaptic density-95 expression increased in the CA3 region, particularly in the diabetic rats, while microtubule-associated protein 2 exhibited more selective changes. Fluoro-Jade histochemistry did not detect neuronal damage, suggesting that glucocorticoids and/or hyperglycemia induce plastic and not irreversible neuronal changes at these time points. Collectively, these results demonstrate that changes in the expression and distribution of synaptic proteins provide another measure of synaptic plasticity in the rat hippocampus in response to glucocorticoid exposure, changes that may accompany or contribute to neuroanatomical, neurochemical, and behavioral changes observed in experimental models of type 1 diabetes.Neuroscience 02/2005; 136(2):477-86. · 3.12 Impact Factor