^^ it's been 8 months for me already, almost nine (if you don't consider a slip up about 2 months ago where I rolled once) and I'm still having sleep problems, ED problems, which is depressing in of itself. Depression too I must admit, thinking problems, and I seem to be lacking frontal lobe functions, especially when it comes to socializing, I can't "feel" anyone emotionally, I'm flat.
What about this;
"Our results demonstrate that the serotonin reuptake inhibitor fluoxetine increases the density of serotonin innervation of cortical and limbic forebrain areas shown by both 5-HT and SERT ICC, for reasons unrelated to the regulation of TPH-2 or SERT in serotonin cell bodies of projection neurons in dorsal and median raphe. Similar effects were seen with the serotonin reuptake enhancer tianeptine. Serotonergic antidepressants that target non-serotonin amines, such as desipramine, do not share the effects of fluoxetine and tianeptine on serotonin fiber density. It is possible that the effects of neurotransmitter-specific antidepressants on monoamine fiber density are selective to their cognate neurotransmitter system, as also suggested by a study on 6-OHDA lesioned rats in which desipramine was shown to promote sprouting of central catecholaminergic fibers visualized with glyoxylic acid-induced fluorescence (Nakamura 1990). It should be emphasized, however, that all these effects must be demonstrated in normal animals, because lesioned monoamine systems may be primed to the restorative effects of antidepressants or trophic peptides (Koliatsos et al. 2000).
Under the experimental conditions of this study, serotonin antidepressants increased the density of 5-HT-immunoreactive axons without a parallel increase in the mRNA expression of the 5-HT-synthesizing enzyme TPH-2. They also increased SERT fiber density without significant effects in SERT mRNA expression in the raphe complex. Both patterns would argue against a mere effect of serotonergic compounds on 5-HT and SERT content of serotonin fibers and would support the idea of a structural effect of these compounds on serotonin axons, i.e. sprouting. However, this straightforward interpretation is applicable primarily to the case of SERT. TPH-2 activity, i.e. the rate-limiting step in 5-HT biosynthesis, is under complex regulation not only by levels of TPH-2 mRNA, but also a number of post-transcriptional factors, including brain levels of tryptophan (Neckers et al. 1977; Fernstrom 1982; Gartside et al. 1992) and phosphorylation of the enzyme by protein kinases (Stenfors and Ross 2002). Although, in the present study, we did not directly examine whether serotonin antidepressant treatments increased tryptophan levels or TPH-2 phosphorylation in the brain, several pharmacological studies have shown decreased brain levels of tryptophan (Neckers et al. 1977; Nakayama et al. 2003) and 5-HT (Durand et al. 1999; Stenfors et al. 2001; Yamane et al. 2001; Nakayama et al. 2003) after chronic administration of a number of serotonin reuptake inhibitors including chlomipramine, sertraline, paroxetine and citalopram.
Our three-dimensional analysis of anterogradely filled dorsal raphe terminals shows increased branching of these terminals in the index site of piriform cortex in fluoxetine-treated animals. This finding lends further support to the idea that serotonin antidepressants cause structural, as opposed to biochemical, changes in serotonin axons. A number of neurotoxic models of serotonin injury suggest that serotonin terminals may be especially prone to regenerative sprouting (Fischer et al. 1995; Mamounas et al. 1995; Mamounas et al. 2000) and we propose that this phenomenon, which is limited to terminal axons, may be the key structural effect of serotonin antidepressants.
The brain-derived neurotrophic factor (BDNF), a robust trophic signal for serotonin neurons (Mamounas et al. 1995; Lyons et al. 1999; Madhav et al. 2001), is a prime candidate for causing serotonin fiber sprouting (Mamounas et al. 1995; Lyons et al. 1999; Mattson et al. 2004). BDNF itself is regulated by levels of synaptically available 5-HT and subsequent 5-HT signaling (Nibuya et al. 1995; Zetterstrom et al. 1999). In some studies, BDNF and its transducing receptor element trkB have been found to be up-regulated by chronic treatment with antidepressants, including serotonin reuptake inhibitors (Nibuya et al. 1995). In unpublished experiments, we have not found significant differences in BDNF or trkB mRNA expression in neocortex and neostriatum between animals treated with fluoxetine and liposyn by northern blotting and RT–PCR; however, BDNF in situ hybridization and ICC show increased mRNA and protein signal in layer V pyramids and pyramidal neurons in layer II of piriform cortex in animals treated with fluoxetine (Koliatsos V. E., Bora S. H. and Zhou L., personal observations). Together, these findings indicate that, if BDNF up-regulation and increased BDNF signaling is part of the mechanism of serotonin axon changes we observed in this study, these trophic events are likely to be limited to circumscribed forebrain sites and specific cortical layers.
A precisely localized, trophic mechanism of sprouting is also a plausible explanation for the concordant effects of fluoxetine and tianeptine, i.e. two antidepressant compounds with opposite pharmacological effects on serotonin reuptake. In general, the relationships between brain 5-HT concentrations and BDNF expression are very complex, e.g. acute increases in 5-HT with p-chloroamphetamine, or with the monoamine oxidase inhibitor tranylcypromine, or the combined administration of tranylcypromine and l-tryptophan, lower BDNF expression in some brain areas such as dentate gyrus, but increase BDNF mRNA expression in medial frontal cortex (Zetterstrom et al. 1999). Interestingly, 5-HT depletion with high-dose p-chloroamphetamine can also result in BDNF mRNA increases in the parietal and frontal cortex (Zetterstrom et al. 1999). Therefore, both higher (such as caused by serotonin reuptake inhibitors) and lower (such as effected by tianeptine) concentrations of extracellular 5-HT may induce BDNF expression in areas studied in this paper, such as the fronto-parietal cortex. Caution with this hypothesis is advised by a previous study showing no correlation between tianeptine treatment and BDNF mRNA level in various hippocampal subfields with in situ hybridization (Kuroda and McEwen 1998); however, the enormously complex regulation of BDNF by antidepressants in this brain area (Nibuya et al. 1995; Zetterstrom et al. 1999) warrants further investigations with quantitative PCR in carefully microdissected preparations of hippocampal subfields.
Cortical laminae IV-V and the shell region of accumbens, i.e. sites in which the effects of serotonin antidepressants on serotonin fiber density are especially obvious, are also prime targets for 5-HT-induced activation of the forebrain after treatment with dexfenfluramine (Lyons et al. 1999). Thus, it appears that increases in serotonin fiber density correlate, at least on the basis of pharmacological and anatomical evidence, with increased postsynaptic effects of serotonin. A local up-regulation of BDNF induced by certain antidepressants may provide a possible link between increased serotonin neurotransmission and fiber sprouting. For example, in the case of the neocortex, agonism at the major postsynaptic serotonin site 5-HT2A which is especially concentrated in upper layer V (Blue et al. 1988) appears to cause a selective induction of BDNF in that cortical layer (Vaidya et al. 1997). However, the BDNF action site and BDNF induction site may be different, given the avid anterograde transport of this neurotrophin (Conner et al. 1997), and the exact local regulation and transduction of this neurotrophin with antidepressant treatments must be studied in considerable anatomical detail. In concert, our findings suggest that serotonin antidepressants may cause very selective structural effects on central 5-HT axons and invite further studies on the role of neurotrophins as mediators of these effects."
This almost seems to mediate that SSRIs can sprout axons in regions MDMA damages.
I was thinking a short term treatment, as in between 4-6 months, NO longer.
