Antidepressant fluoxetine suppresses neuronal growth from both vertebrate and invertebrate neurons and perturbs synapse formation between Lymnaea neurons

Abstract

Current treatment regimes for a variety of mental disorders involve various selective serotonin reuptake inhibitors such as Fluoxetine (Prozac). Although these drugs may 'manage' the patient better, there has not been a significant change in the treatment paradigm over the years and neither have the outcomes improved. There is also considerable debate as to the effectiveness of various selective serotonin reuptake inhibitors and their potential side-effects on neuronal architecture and function. In this study, using mammalian cortical neurons, a dorsal root ganglia cell line (F11 cells) and identified Lymnaea stagnalis neurons, we provide the first direct and unequivocal evidence that clinically relevant concentrations of Fluoxetine induce growth cone collapse and neurite retraction of both serotonergic and non-serotonergic neurons alike in a dose-dependent manner. Using intracellular recordings and calcium imaging techniques, we further demonstrate that the mechanism underlying Fluoxetine-induced effects on neurite retraction from Lymnaea neurons may involve lowering of intracellular calcium and a subsequent retardation of growth cone cytoskeleton. Using soma-soma synapses between identified presynaptic and postsynaptic Lymnaea neurons, we provide further direct evidence that clinically used concentrations of Fluoxetine also block synaptic transmission and synapse formation between cholinergic neurons. Our study raises alarms over potentially devastating side-effects of this antidepressant drug on neurite outgrowth and synapse formation in a developing/regenerating brain. Our data also demonstrate that drugs such as Fluoxetine may not just affect communication between serotonergic neurons but that the detrimental effects are widespread and involve neurons of various phenotypes from both vertebrate and invertebrate species.

Mercury-induced toxicity of rat cortical neurons is mediated through N-methyl-D-Aspartate receptors

“…Therefore, a detailed evaluation of the effect of HgCl 2 at these concentrations may still be required. Specially, the effect of HgCl 2 on the motile structure of growth cones, the length of neurite elongation, and cell viability would need to be monitored using proper neuronal model types in which these parameters can be easily measured as shown in our previous study [57]. …”

Antidepressant Pharmacotherapy – Do the Benefits Outweigh the Risks?

“…These trophic factor-mediated intracellular Ca 2+ oscillations required for excitatory synapse formation were inhibited in the presence of fluoxetine, indicating that fluoxetine prevents the expression of proteins involved in synaptogenesis (Xu et al, 2010). Attesting to this, we found that the expression and synaptic localization of synaptophysin, a synaptic vesicle-associated protein and presynaptic biomarker, were significantly reduced in synapses formed in the presence of fluoxetine, but not citalopram (Getz et al, 2011).…”

“…To this end, Lymnaea serotonergic or non-serotonergic neurons were cultured under control conditions (in the presence of growth media containing neurotrophic factors), or in the presence of SSRIs over a therapeutically-relevant dosage range. The neuronal ability to initiate and elongate neurite processes, spread branches and form active growth cones was monitored under these two conditions (Xu et al, 2010). We found that neurons cultured in growth media alone established extensive neurite outgrowth (massive branches with active growth cones), while neurons cultured in the presence of fluoxetine exhibited only minimal branches and shorter processes at lower doses (< 3 μg/mL), and no growth at higher concentrations (> 3 μg/mL).…”

“…These pharmacological characteristics lent to the formulation of our hypothesis that different SSRIs would exert characteristic non-specific neuronal side effects, and, because of its lesser selectivity profile, that fluoxetine would exert a more detrimental effect on synaptic physiology than citalopram. Using a combination of intracellular and patch-clamp electrophysiological recordings, calcium imaging, immunocytochemistry and various neuroimaging techniques, we have for the first time demonstrated that clinically-relevant concentrations of fluoxetine, but not citalopram (dosage range up to 5 μg/mL; Bolo et al, 2000), exhibit detrimental effects on neurite outgrowth, synapse formation, synaptic transmission and synaptic plasticity, and that the negative effects of fluoxetine on synaptic function involves a direct perturbation of both preand post-synaptic machinery (Xu et al, 2010;Getz et al, 2011).…”

“…The Mechanism: Optimal calcium transients in growth cones have been shown to be essential for the regulation of the polymerization and depolymerisation status of cytoskeletal proteins including F-actin, and thus affect growth cone motility and behaviour (Spira et al, 2001;Welnhofer et al, 1999;Henley & Poo, 2004). In the presence of trophic factors, the growth cones of Lymnaea neurons exhibit small spontaneous Ca 2+ transients, and these Ca 2+ transients were eliminated within minutes of exposure to fluoxetine (Xu et al, 2010). Furthermore, immunocytochemical labeling identified that the fluoxetine-induced inhibition of spontaneous Ca 2+ transients and collapse of growth cones was accompanied by a breakdown of the F-actin cytoskeleton.…”