19 replies to this topic

[Mind_Paralysis]

Yeah, I saw somebody wonder about this recently, and it got me thinking - surely there should be SOME data on this?

 

Resultant increased levels of BDNF post-treatment with anti-depressants could be an indicator of anti-depressant potency, to some extent.

 

So, I started digging, and this is what I have so far:
 

"The Roles of BDNF in the Pathophysiology of Major Depression and in Antidepressant Treatment"

 

http://www.ncbi.nlm....les/PMC3022308/

 

 

These alterations of BDNF levels or neuronal plasticity in MDD patients before and after antidepressant treatment can be measured through the examination of serum or plasma BDNF concentrations. BDNF levels can therefore be useful markers for clinical response or improvement of depressive symptoms, but they are not diagnostic markers of major depression.

 

I *think* the document above may have the info, but my SCT is making it impossible to read it closely enough to actually find the information, at the moment.

 

I also found some data on genetic research regarding BDNF-expression post anti-depressant use, but the results are limited to Asians, so may not be applicable to everyone. And I'm unsure if this study actually has much info that we can use in chasing down the BDNF-expression of SSRI's.

 

"Brain-derived neurotrophic factor Val66Met polymorphism association with antidepressant efficacy: a systematic review and meta-analysis"

http://www.ncbi.nlm....pubmed/25231750

 

 

What do you think, folks? Is there data out there on the neurogenic efficiency of SSRI's and other anti-depressants? Hypothetically, that information could be used to find the THE MOST potent SSRI, yes?

[Area-1255]

Yet there are tons of other neurotrophic substances; and not all of them have clear anti-depressant effects...I think SSRI's affect other factors which may normally be influenced by other things like Progesterone and Testosterone; e.g beta-endorphin, oxytocin etc

[NeuroNootropic]

Adding to this, how come there are no studies on bupropion and bdnf/neurogenesis? Even herbs like rhodiola have studies in rats that show an increase in bdnf and neurogenesis. Does bupropion not increase bdnf?

[gamesguru]

It's a bad answer, but... which ever one has the least side effects relative to the largest dose?  But I think the thinking is slightly flawed, or oversimplified, for if TrkB activation was good to increase without bound, large large doses of 7,8-dihydroflavone would be the best thing.

 

Antidepressant-like effects of curcumin in WKY rat model of depression is associated with an increase in hippocampal BDNF.
Curcumin is the principal active ingredient found in turmeric (Curcuma longa), a plant used in traditional Asian diets and herbal medicines. It is known to have a wide range of biological actions including antidepressant-like effects which have been observed in stress-induced depression models. This study was designed to investigate the antidepressant potential of curcumin in a non-induced model of depression. Moreover, since brain derived neurotrophic factor (BDNF) has been implicated in antidepressant effects of many drugs, we also evaluated the effects of curcumin on BDNF in the hippocampus. Adult male Wistar Kyoto (WKY) rats, a putative model of depression, were injected acutely or chronically (10d) with 50, 100, and 200mg/kg curcumin. Open field locomotor activity (OFLA) and forced swim test (FST), a measure of helplessness, were measured 1h after acute and 18-20h after last chronic injection. Results showed a dose-dependent reduction of immobility in the FST by curcumin in both acute and chronic studies, without any significant effect on OFLA. The effect of higher chronic curcumin dose in FST was still evident a week later. Chronic curcumin also resulted in a dose-dependent increase in hippocampal BDNF. This data provides evidence for an antidepressant-like effect of curcumin, possibly through increased neurotrophic activity, in the WKY model of depression, and support the notion that curcumin may prove an effective and lasting natural antidepressant.
The effect of acute exercise on serum brain-derived neurotrophic factor levels and cognitive function.
Brain-derived neurotrophic factor (BDNF) is one of a family of neurotrophic factors that participates in neuronal transmission, modulation and plasticity. Previous studies using animals have demonstrated that acute and chronic exercise leads to increases in BDNF in various brain regions.
To determine the effects of acute exercise on serum BDNF levels in humans, and to determine the relationship between exercise intensity and BDNF responses. Additionally, the relationship between changes in BDNF and cognitive function was examined.
Fifteen subjects (25.4 +/- 1.01 yr; 11 male, 4 female) performed a graded exercise test (GXT) for the determination of VO2max and ventilatory threshold (VTh) on a cycle ergometer. On separate days, two subsequent 30-min endurance rides were performed at 20% below the VTh (VTh - 20) and at 10% above the VTh (VTh + 10). Serum BDNF and cognitive function were determined before and after the GXT and endurance rides with an enzyme-linked immunosorbent assay (ELISA) and the Stroop tests, respectively.
The mean VO2max was 2805.8 +/- 164.3 mL x min(-1) (104.2 +/- 7.0% pred). BDNF values (pg x mL(-1)) increased from baseline (P<0.05) after exercise at the VTh + 10 (13%) and the GXT (30%). There was no significant change in BDNF from baseline after the VTh - 20. Changes in BDNF did not correlate with VO2max during the GXT, but they did correlate with changes in lactate (r=0.57; P<0.05). Cognitive function scores improved after all exercise conditions, but they did not correlate with BDNF changes.
BDNF levels in humans are significantly elevated in response to exercise, and the magnitude of increase is exercise intensity dependent. Given that BDNF can transit the blood-brain barrier in both directions, the intensity-dependent findings may aid in designing exercise prescriptions for maintaining or improving neurological health.

 

 

Chronic administration of the delta opioid receptor agonist (+)BW373U86 and antidepressants on behavior in the forced swim test and BDNF mRNA expression in rats.
Selective delta opioid receptor agonists have been shown to produce antidepressant-like behavioral effects and increase brain-derived neurotrophic factor (BDNF) mRNA expression when given acutely, but the chronic effects of delta agonists have been less well characterized.
The present study examined the effects of chronic exposure to the delta agonist (+)BW373U86 (BW) on antidepressant-like behavior in the forced swim test and on BDNF mRNA expression in comparison to chronic treatment with the antidepressants fluoxetine, desipramine, bupropion, and tranylcypromine.
Sprague-Dawley rats were treated chronic ally with one of the above treatments and were tested for antidepressant effects in the forced swim test, and assayed for BDNF mRNA expression by in situ hybridization.
Acute administration of 10 mg/kg BW produced a significant antidepressant-like effect in the forced swim test, while chronic (8- or 21-day) BW administration did not produce a significant antidepressant-like effect. When 10 mg/kg BW was administered for 8 days, it produced a significant increase in BDNF mRNA expression in the frontal cortex, while having no effect on BDNF expression when given for 21 days. Chronic bupropion and desipramine significantly decreased BDNF expression in the dentate gyrus of the hippocampus, while fluoxetine had no effect in any brain region.^{[???not sure which regions they looked at here, or if they had their heads screwed on right???]} Chronic tranylcypromine produced a significant increase in BDNF expression in the CA1 region of the hippocampus.
Chronic exposure to BW produces tolerance to most effects, although at differential rates. In addition, increased BDNF mRNA expression does not appear to be a common effect of chronic administration of various antidepressants.

The delta-opioid receptor agonist (+)BW373U86 regulates [acute] BDNF mRNA expression in rats.
delta-Opioid receptor agonists have antidepressant-like effects in behavioral models of depression. Chronic administration of classical antidepressants upregulates mRNA expression of brain-derived neurotrophic factor (BDNF) and its high-affinity tyrosine kinase receptor, TrkB in the frontal cortex and hippocampus of rats. Increases in BDNF and TrkB levels are thought to be important for the therapeutic effects of these drugs. Therefore, we examined the ability of the delta-opioid receptor agonist (+)BW373U86 to regulate BDNF and TrkB mRNA expression in frontal cortex, hippocampus, as well as, basolateral amygdala, endopiriform nucleus, and primary olfactory cortex. At 3h after a single administration of (+)BW373U86 animals were killed and BDNF and TrkB mRNA levels were examined by in situ hybridization. BDNF mRNA levels produced by (+)BW373U86 were compared to acute administration of the antidepressants desipramine and bupropion. A behaviorally antidepressant dose of  10 mg/kg  (+)BW373U86 increased BDNF mRNA expression in all regions examined; a smaller dose of (+)BW373U86 (1 mg/kg) significantly  increased BDNF  mRNA expression only in frontal cortex. The delta-opioid receptor an tagonist naltrindole blocked (+)BW373U86-mediated increases in BDNF mRNA expression. In addition, tolerance  developed to increased BDNF mRNA expression with repeated injection, except in frontal cortex. Midazolam was administered to some animals to prevent the convulsions produced by (+)BW373U86, but midazolam did not block delta-opioid receptor-mediated increases in BDNF mRNA expression in frontal cortex, hippocampus, or amygdala. Unlike desipramine and bupropion, (+)BW373U86 upregulated BDNF mRNA expression acutely (within 3 h after a single administration). These data support the concept that delta-opioid receptor agonists may have antidepressant potential, and could be good targets for the development of faster-acting antidepressants.

[Area-1255]

Depression seems to be largely another one of those disorders that results from a faulty regulation system of sympathetic nervous system activity. But psychosocial factors and even dietary factors have to be taken into consideration. If Cortisol related pathways are persistently upregulated - the body's homeostasis is impaired leading to behavioral changes.

This is evident not in just depression, but anxiety and schizoaffective disorder as well.

 

http://www.ncbi.nlm....pubmed/22564216

 

http://www.ncbi.nlm....pubmed/15961250

[Michael Rian]

I would also appreciate some ideas for starting a new antidepressant. I have tried various supplements and herbs but I am in a very low, suicidal depression. I see my doctor tomorrow and would like to research potential medication.

Thank you

[gamesguru]

Depression seems to be largely another one of those disorders that results from a faulty regulation system of sympathetic nervous system activity. But psychosocial factors and even dietary factors have to be taken into consideration. If Cortisol related pathways are persistently upregulated - the body's homeostasis is impaired leading to behavioral changes.

This is evident not in just depression, but anxiety and schizoaffective disorder as well.

http://www.ncbi.nlm....pubmed/22564216

http://www.ncbi.nlm....pubmed/15961250

 

Seems cortisol spikes mostly in the afternoon and in males, and that 'impaired reactivity' or receptor level is more significant a factor than elevated coritsol level.

 

 

Def have psychosocial issues, some exacerbated by cannabis

Without tooting my own horn too much, I spend $25-30 on food daily, organic/local veggies, pasture-raised meats, delicacies/exotic food, ok that's too much already

AND I exercise intensely, take tea, bacopa and ginkgo

Green tea and one of its constituents, Epigallocatechine-3-gallate, are potent inhibitors of human 11β-hydroxysteroid dehydrogenase type 1
The microsomal enzyme 11β-hydroxysteroid deydrogenase type 1 (11β-HSD1) catalyzes the interconversion of glucocorticoid receptor-inert cortisone to receptor- active cortisol, thereby acting as an intracellular switch for regulating the access of glucocorticoid hormones to the glucocorticoid receptor. There is strong evidence for an important aetiological role of 11β-HSD1 in various metabolic disorders including insulin resistance, diabetes type 2, hypertension, dyslipidemia and obesity. Hence, modulation of 11β-HSD1 activity with selective inhibitors is being pursued as a new therapeutic approach for the treatment of the metabolic syndrome. Since tea has been associated with health benefits for thousands of years, we sought to elucidate the active principle in tea with regard to diabetes type 2 prevention. Several teas and tea specific polyphenolic compounds were tested for their possible inhibition of cortisone reduction with human liver microsomes and purified human 11β-HSD1. Indeed we found that tea extracts inhibited 11β-HSD1 mediated cortisone reduction, where green tea exhibited the highest inhibitory potency with an IC50 value of 3.749 mg dried tea leaves per ml. Consequently, major polyphenolic compounds from green tea, in particular catechins were tested with the same systems. (-)-Epigallocatechin gallate (EGCG) revealed the highest inhibition of 11β-HSD1 activity (reduction: IC50 = 57.99 µM; oxidation: IC50 = 131.2 µM). Detailed kinetic studies indicate a direct competition mode of EGCG, with substrate and/or cofactor binding. Inhibition constants of EGCG on cortisone reduction were Ki = 22.68 µM for microsomes and Ki = 18.74 µM for purified 11β-HSD1. In silicio docking studies support the view that EGCG binds directly to the active site of 11β-HSD1 by forming a hydrogen bond with Lys187 of the catalytic triade. Our study is the first to provide evidence that the health benefits of green tea and its polyphenolic compounds may be attributed to an inhibition of the cortisol producing enzyme 11β-HSD1.

 

An acute, double-blind, placebo-controlled cross-over study of 320 mg and 640 mg doses of Bacopa monnieri (CDRI 08) on multitasking stress reactivity and mood
Little research exists in humans concerning the anxiolytic, antidepressant, sedative, and adaptogenic actions the traditional Ayurvedic medicine Bacopa monnieri (BM) possesses in addition to its documented cognitive-enhancing effects. Preclinical work has identified a number of acute anxiolytic, nootropic, and adaptogenic effects of BM that may also co-occur in humans. The current double-blind, placebo-controlled cross-over study assessed the acute effects of a specific extract of BM (KeenMind® - CDRI 08) in normal healthy participants during completion of a multitasking framework (MTF). Seventeen healthy volunteers completed the MTF, at baseline, then 1 h and 2 h after consuming a placebo, 320 mg BM and 640 mg of BM. Treatments were separated by a 7-day washout with order determined by Latin Square. Outcome measures included cognitive outcomes from the MTF, with mood and salivary cortisol measured before and after each completion of the MTF. Change from baseline scores indicated positive cognitive effects, notably at both 1 h post and 2 h post BM consumption on the Letter Search and Stroop tasks, suggesting an earlier nootropic effect of BM than previously investigated. There were also some positive mood effects and reduction in cortisol levels, pointing to a physiological mechanism for stress reduction associated with BM consumption. It was concluded that acute BM supplementation produced some adaptogenic and nootropic effects that need to be replicated in a larger sample and in isolation from stressful cognitive tests in order to quantify the magnitude of these effects. The study was registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12612000834853).

 

Reduction of rise in blood pressure and cortisol release during stress by Ginkgo biloba extract (EGb 761) in healthy volunteers
The standardized extract of Ginkgo biloba (EGb 761) was found not only to improve memory and aging associated cognitive deficits but also to exert beneficial effects on mood. An antistress action of the extract has been suggested but not directly proven. The present study was aimed to evaluate the effects of EGb 761 on salivary cortisol and blood pressure responses during stress in healthy young volunteers (n = 70) in a double blind placebo controlled design. A stress model involving a combination of static exercise (handgrip) and mental stimuli was used. Single treatment with EGb 761 (120 mg) reduced stress-induced rise in blood pressure without affecting the heart rate. Salivary cortisol responses showed differences with respect to the gender and the time of day of the stress exposure, with the activation only in male subjects in the afternoon. This activation was absent if they were treated with EGb 761. The performance in a short memory test with higher scores achieved by women remained unaffected by EGb 761 treatment. Thus, this study provides evidence that EGb 761 has an inhibitory action on blood pressure and it may influence cortisol release in response to some stress stimuli.

 

AND STILL have major depression issues, so i think there's more going on than cortisol, perhaps mitochondrial or endplasmic dysfunction, cytokines (not sure what co-regulates these) as a start...

Mitochondrial dysfunction, oxidative stress, and major depressive disorder [44 page PDF on the subject, have tried melatonin, pqq, coq10]
There is controversy about depression being a physical illness, in part because a reproducible, sensitive, and specific biologic marker is not available. However, there is evidence that mitochondrial dysfunction and oxidative stress may be associated with abnormal brain function and mood disorders, such as depression. This paper reviews selected human and animal studies providing evidence that intracellular mitochondrial metabolic dysfunction in specific brain regions is associated with major depressive disorder. This supports the hypothesis that chronic mitochondrial dysfunction in specific tissues may be associated with depression. Evaluation of mitochondrial dysfunction in specific tissues may broaden the perspective of depression beyond theories about neurotransmitters or receptor sites, and may explain the persistent signs and symptoms of depression.

 

Melatonin and mitochondrial function
Melatonin is a natural occurring compound with well-known antioxidant properties. In the last decade a new effect of melatonin on mitochondrial homeostasis has been discovered and, although the exact molecular mechanism for this effect remains unknown, it may explain, at least in part, the protective properties found for the indoleamine in degenerative conditions such as aging as well as Parkinson's disease, Alzheimer's disease, epilepsy, sepsis and other injuries such as ischemia-reperfusion. A common feature in these diseases is the existence of mitochondrial damage due to oxidative stress, which may lead to a decrease in the activities of mitochondrial complexes and ATP production, and, as a consequence, a further increase in free radical generation. A vicious cycle thus results under these conditions of oxidative stress with the final consequence being cell death by necrosis or apoptosis. Melatonin is able of directly scavenging a variety of toxic oxygen and nitrogen-based reactants, stimulates antioxidative enzymes, increases the efficiency of the electron transport chain thereby limiting electron leakage and free radical generation, and promotes ATP synthesis. Via these actions, melatonin preserves the integrity of the mitochondria and helps to maintain cell functions and survival.

 

Pathological parainflammation and endoplasmic reticulum stress in depression: potential translational targets through the CNS insulin, klotho and PPAR-γ systems
Major depression and bipolar disorder are heterogeneous conditions in which there can be dysregulation of (1) the stress system response, (2) its capacity for counterregulation after danger has passed and (3) the phase in which damaging molecules generated by the stress response are effectively neutralized. The response to stress and depressed mood share common circuitries and mediators, and each sets into motion not only similar affective and cognitive changes, but also similar systemic manifestations. We focus here on two highly interrelated processes, parainflammation and endoplasmic reticulum (ER) stress, each of which can potentially interfere with all phases of a normal stress response in affective illness, including adaptive neuroplastic changes and the ability to generate neural stem cells. Parainflammation is an adaptive response of the innate immune system that occurs in the context of stressors to which we were not exposed during our early evolution, including overfeeding, underactivity, aging, artificial lighting and novel foodstuffs and drugs. We postulate that humans were not exposed through evolution to the current level of acute or chronic social stressors, and hence, that major depressive illness is associated with a parainflammatory state. ER stress refers to a complex program set into motion when the ER is challenged by the production or persistence of more proteins than it can effectively fold. If the ER response is overwhelmed, substantial amounts of calcium are released into the cytoplasm, leading to apoptosis. Parainflammation and ER stress generally occur simultaneously. We discuss three highly interrelated mediators that can effectively decrease parainflammation and ER stress, namely the central insulin, klotho and peroxisome proliferator-activated receptor-γ (PPAR-γ) systems and propose that these systems may represent conceptually novel therapeutic targets for the amelioration of the affective, cognitive and systemic manifestations of major depressive disorder.

 

Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications
Mounting evidence indicates that inflammatory cytokines contribute to the development of depression in both medically ill and medically healthy individuals. Cytokines are important for development and normal brain function, and have the ability to influence neurocircuitry and neurotransmitter systems to produce behavioral alterations. Acutely, inflammatory cytokine administration or activation of the innate immune system produces adaptive behavioral responses that promote conservation of energy to combat infection or recovery from injury. However, chronic exposure to elevated inflammatory cytokines and persistent alterations in neurotransmitter systems can lead to neuropsychiatric disorders and depression. Mechanisms of cytokine behavioral effects involve activation of inflammatory signaling pathways in the brain that results in changes in monoamine, glutamate, and neuropeptide systems, and decreases in growth factors, such as brain-derived neurotrophic factor. Furthermore, inflammatory cytokines may serve as mediators of both environmental (e.g. childhood trauma, obesity, stress, and poor sleep) and genetic (functional gene polymorphisms) factors that contribute to depression's development. This review explores the idea that specific gene polymorphisms and neurotransmitter systems can confer protection from or vulnerability to specific symptom dimensions of cytokine-related depression. Additionally, potential therapeutic strategies that target inflammatory cytokine signaling or the consequences of cytokines on neurotransmitter systems in the brain to prevent or reverse cytokine effects on behavior are discussed.

[Area-1255]

 

Seems cortisol spikes mostly in the afternoon and in males, and that 'impaired reactivity' or receptor level is more significant a factor than elevated coritsol level.

 

 

Def have psychosocial issues, some exacerbated by cannabis

Without tooting my own horn too much, I spend $25-30 on food daily, organic/local veggies, pasture-raised meats, delicacies/exotic food, ok that's too much already

AND I exercise intensely, take tea, bacopa and ginkgo

 

 

Ginkgo is good for physical/physiological markers of stress; such as blood pressure and stress-related decline in cognitive function..however, due to it's GABA-A antagonistic nature, it can cause anxiety in some people...Although, GABA-B receptors don't seem to be affected by it - so it might really just be an issue in those with seizure disorders.
http://scholar.googl...AhUTLogKHQ9yA0c

 

http://musculardevel...df#.VgC7C99Viko

 

 

J Biol Chem. 2003 Dec 5;278(49):49279-85. Epub 2003 Sep 22.

Terpene trilactones from Ginkgo biloba are antagonists of cortical glycine and GABA(A) receptors.

Ivic L1, Sands TT, Fishkin N, Nakanishi K, Kriegstein AR, Strømgaard K.

Author information

 

Abstract

Glycine and gamma-aminobutyric acid, type A (GABA(A)) receptors are members of the ligand-gated ion channel superfamily that mediate inhibitory synaptic transmission in the adult central nervous system. During development, the activation of these receptors leads to membrane depolarization. Ligands for the two receptors have important implications both in disease therapy and as pharmacological tools. Terpene trilactones (ginkgolides and bilobalide) are unique constituents of Ginkgo biloba extracts that have various effects on the central nervous system. We have investigated the relative potency of these compounds on glycine and GABA(A) receptors. We find that most of the ginkgolides are selective and potent antagonists of the glycine receptor. Bilobalide, the single major component in G. biloba extracts, also reduces glycine-induced currents, although to a lesser extent. Both ginkgolides and bilobalide inhibit GABA(A) receptors, with bilobalide demonstrating a more potent effect. Additionally, we provide evidence that open channels are required for glycine receptor inhibition by ginkgolides. Finally, we employ molecular modeling to elucidate the similarities and differences in the structure of the terpene trilactones to account for the pharmacological properties of these compounds and demonstrate a striking similarity between ginkgolides and picrotoxinin, a GABA(A) and recombinant glycine alpha-homomeric receptor antagonist.

PMID:   14504293   [PubMed - indexed for MEDLINE]    Free full text

 

Eur J Pharmacol. 2003 Mar 7;464(1):1-8.

Bilobalide, a sesquiterpene trilactone from Ginkgo biloba, is an antagonist at recombinant alpha1beta2gamma2L GABA(A) receptors.

Huang SH1, Duke RK, Chebib M, Sasaki K, Wada K, Johnston GA.

Author information

 

Abstract

The sesquiterpene trilactone bilobalide is one of the active constituents of the 50:1 Ginkgo biloba leaf extract widely used to enhance memory and learning. Bilobalide was found to antagonise the direct action of gamma-aminobutyric acid (GABA) on recombinant alpha(1)beta(2)gamma(2L) GABA(A) receptors. The effect of bilobalide on the direct action of GABA at alpha(1)beta(2)gamma(2L) GABA(A) receptors expressed in Xenopus laevis oocytes using two-electrode voltage-clamp method was evaluated and compared with the effects of the classical GABA(A) receptor competitive antagonist bicuculline and noncompetitive antagonist picrotoxinin. Bilobalide (IC(50)=4.6+/-0.5 microM) was almost as potent as bicuculline and pictrotoxinin (IC(50)=2.0+/-0.1 and 2.4+/-0.5 microM, respectively) at alpha(1)beta(2)gamma(2L) GABA(A) receptors against 40 microM GABA (GABA EC(50)). While bilobalide and picrotoxinin were clearly noncompetitive antagonists, the potency of bilobalide decreased at high GABA concentrations suggesting a component of competitive antagonism.

PMID:   12600688   [PubMed - indexed for MEDLINE]  

 

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Brain Res. 2007 Jan 12;1128(1):70-8. Epub 2006 Nov 28.

Role of GABAergic antagonism in the neuroprotective effects of bilobalide.

Kiewert C1, Kumar V, Hildmann O, Rueda M, Hartmann J, Naik RS, Klein J.

Author information

 

Abstract

Bilobalide, a constituent of Ginkgo biloba, has neuroprotective properties. Its mechanism of action is unknown but it was recently found to block GABA(A) receptors. The goal of this study was to test the potential role of a GABAergic mechanism for the neuroprotective activity of bilobalide. In rat hippocampal slices exposed to NMDA, release of choline indicates breakdown of membrane phospholipids. NMDA-induced choline release was almost completely blocked in the presence of bilobalide (10 microM) and under low-chloride conditions. Bicuculline (100 microM), a competitive antagonist at GABA(A) receptors, reduced NMDA-induced choline release to a small extent (-23%). GABA (100 microM) partially antagonized the inhibitory action of bilobalide. Exposure of hippocampal slices to NMDA also caused edema formation as measured by increases of tissue water content. NMDA-induced edema formation was suppressed by bilobalide and by low-chloride conditions. Bicuculline exerted partial protection (by 30%) while GABA reduced bilobalide's effect by about one third. To investigate bilobalide's interaction with GABA(A) receptors directly, we measured binding of [(35)S]-TBPS to rat cortical membranes. TBPS binding was competitively inhibited by bilobalide in the low micromolar range (IC(50)=3.7 microM). As a functional test, we determined (36)chloride flux in rat corticohippocampal synaptoneurosomes. GABA (100 microM) significantly increased (36)chloride flux (+65%), and this increase was blocked by bilobalide, but with low potency (IC(50): 39 microM). We conclude that, while antagonism of GABA(A) receptors may contribute to bilobalide's neuroprotective effects, additional mechanisms must be postulated to fully explain bilobalide's actions.

PMID:   17134681   [PubMed - indexed for MEDLINE]    PMCID:   PMC1865101     Free PMC Article

[gamesguru]

Ginkgo is good for physical/physiological markers of stress; such as blood pressure and stress-related decline in cognitive function..however, due to it's GABA-A antagonistic nature, it can cause anxiety in some people...Although, GABA-B receptors don't seem to be affected by it - so it might really just be an issue in those with seizure disorders.
"The_testosterone-cortisol_ratio_A_hormonal_marker_for_proneness_to_social_aggression"

 

I should be a social butterfly if that ratio is all that matters.

I don't take ginkgo as often as I should, nor ginseng due to concerns of TH ↓, although also DBH ↓ ^[1]. 

Ginkgo tends to be overstimulating with the amount of tea I drink, and I feel as though the ginger + turmeric also contribute somehow to the stimulation.

 

Interactions of ginsenosides with ligand-bindings of GABA_A and GABA_B receptors
    1. Total saponin fraction decreased the affinity of specific [3H]muscimol binding without changes in Bmax. Ginsenoside Rb1 Rb2, Rc, Re, Rf and Rg1 inhibited the specific [3H]muscimol binding to the high-affinity site.
    2. Total saponin fraction increased the affinity of specific [3H]flunitrazepam binding. Ginsenoside Re and Rf enhanced specific [3H]flunitrazepam binding.
    3. Total saponin fraction decreased the affinity of specific [35S]TBPS binding without changes in Bmax. Ginsenosides did not affect specific or non-specific [35S]TBPS binding.
    4. Total saponin fraction decreased the affinity of specific [3H]baclofen binding without changes in Bmax. Ginsenoside Rc inhibited specific [3H]baclofen binding.

 

Baclofen, an agonist at peripheral GABAB receptors, induces antinociception via activation of TEA-sensitive potassium channels

Edited by gamesguru, 22 September 2015 - 03:02 AM.

[Mind_Paralysis]

A lot of interesting data in the thread, but it does get me thinking.

 

Just came across a study where they looked into the BDNF hypothesis of Depression, and compared it to the Serotonin-theory, and it seems as is the conclusion is that there's merit to both theories.

 

Personally, I'm starting to think it's actually something similar to the pathology of Schizophrenia - where there are two competing theories, the Glutamatergic and the Dopaminergic theories respectively. There's been a decades-long debate regarding that, and finally, the solution seems to have been found - Kynurenic Acid theory unifies the two, and establishes a clear connection between the two neurotransmitters.

 

Most likely, depression is the same. So, hypothetically, perhaps there's a yet to be discovered connecting process that creates a disturbance in both neurotransmitters and BDNF, in depression?

 

No idea what that might be, I must admit.

 

I just found this list of BDNF-enhancing compounds from some time back tho':

 

http://www.longecity...-increase-bdnf/

 

 

Notably, the only traditionally prescribed anti-depressants the author lists are the following:

 

Sertraline (SSRI)

 

-Agomelatine (MT agonist)

 

Escitalopram (SSRI)

 

Venlafaxine (SNRI)

 

-Imipramine (TCA)

 

-Mirtazapine (NaSSA)

 

 

There's a few that we can strike right off the bat here, because we KNOW they're no damn good.

 

Mirtazapine - turns you into a slow-moving tub of lard. Cut.

Imipramine - too many finicky side-effects, it's a TCA after all. Cut.

Agomelatine - too inefficient. Not really effective in treating severe depression.

 

That leaves us with three of the most commonly prescribed med's of them all:

 

Sertraline (SSRI) - discontinuation-symptoms are quite severe, known to cause insomnia. Cut.

Venlafaxine (SNRI) - known to have the WORST discontinuation-symptoms of them all. Insomnia. Cut!

 

Escitalopram (SSRI) - one of the most selective of all of the SSRI's, proven to be one of the most effective in a study a few years back.

 

"Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis"

http://www.thelancet...0046-5/fulltext

 

Going through all of this, I would say we have a preliminary WINNER!

ESCITALOPRAM!! : D

 

(brand names Lexapro and Cipralex for the fellow who asked for advice earlier)

 

Now then... what substances are there, which we know are synergistic with Escitalopram? Well, a few. Let's have a look:

 

Synergistic antidepressant-like action of gaboxadol and escitalopram.

http://www.ncbi.nlm....pubmed/22406239

 

Synergistic neurochemical and behavioural effects of acute intrahippocampal injection of brain-derived neurotrophic factor and antidepressants in adult mice.

http://www.dpag.ox.a...ications/426704

 

Injections with BDNF doesn't seem like a very practical solution tho'... Low-dose Gaboxadol however, does seem like it.

Does anybody know about any other compounds that are synergistic with other SSRI's? It might work with Escitalopram as well.

[gamesguru]

Just came across a study where they looked into the BDNF hypothesis of Depression, and compared it to the Serotonin-theory, and it seems as is the conclusion is that there's merit to both theories.

Personally, I'm starting to think it's actually something similar to the pathology of Schizophrenia - where there are two competing theories, the Glutamatergic and the Dopaminergic theories respectively. There's been a decades-long debate regarding that, and finally, the solution seems to have been found - Kynurenic Acid theory unifies the two, and establishes a clear connection between the two neurotransmitters.

Most likely, depression is the same. So, hypothetically, perhaps there's a yet to be discovered connecting process that creates a disturbance in both neurotransmitters and BDNF, in depression?

 

There's a few that we can strike right off the bat here, because we KNOW they're no damn good.

??Mirtazapine - turns you into a slow-moving tub of lard. Cut.??

Imipramine - too many finicky side-effects, it's a TCA after all. Cut.

Agomelatine - too inefficient. Not really effective in treating severe depression.

Sertraline (SSRI) - discontinuation-symptoms are quite severe, known to cause insomnia. Cut.

Venlafaxine (SNRI) - known to have the WORST discontinuation-symptoms of them all. Insomnia. Cut!

 

Escitalopram (SSRI) - one of the most selective of all of the SSRI's, proven to be one of the most effective in a study a few years back.

"Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis"

http://www.thelancet...0046-5/fulltext

 

Synergistic antidepressant-like action of gaboxadol and escitalopram.

http://www.ncbi.nlm....pubmed/22406239

Synergistic neurochemical and behavioural effects of acute intrahippocampal injection of brain-derived neurotrophic factor and antidepressants in adult mice.

http://www.dpag.ox.a...ications/426704

 

Injections with BDNF doesn't seem like a very practical solution tho, NOR 7,8-DIHYDROFLAVONE'... Low-dose Gaboxadol however, does seem like it.

Does anybody know about any other compounds that are synergistic with other SSRI's? It might work with Escitalopram as well.

Found this last night about blueberries and SSRIs and norepinephrine(albeit in a PTSD animal model):

"Traumatized rats fed a plain diet (no blueberries) did not show much of a serotonin increase, but instead demonstrated a predictable rise in norepinephrine—a neurotransmitter that often spikes in response to trauma."

"NE-induced increase in oxidative stress, nuclear condensation, calpain activity and lowering of SOD and CAT activities were prevented upon pretreatment with blueberry fraction"

 

Blueberries Show Promise as Treatment for Post-Traumatic Stress Disorder

Recently, we demonstrated that over-activation of norepinephrine (NE) along with serotonin (5-HT) as the possible reason for the lack of efficacy of SSRI. Hence, there is a need for novel therapeutic approaches for the treatment of PTSD. In this study, we investigated the neuroprotective role of blueberries (BB) in modulating neurotransmitter levels in PTSD. Rats were fed with a blueberry-enriched (2 percent) or a control diet. Rats were exposed to cats for one hour on days 1 and 11 of a 31-day schedule to simulate traumatic conditions. At the end of the study, the rats were euthanized and PFC and HC were isolated. We measured monoamines and their metabolites by high-performance liquid chromatography. In our PTSD model, NE levels were increased and 5-HT levels were decreased when compared to control. In contrast, a BB diet increased 5-HT without affecting NE levels.

My pot dealer takes citalopram and he's like way chill, at least compared to crazy wife lady.

 

Serotonin is BDNF-enhancing (so in a way it's merits to one theory!), except usually 5-HT2C, which is primarily inhibitory.

 

Most SSRIs upregualte BDNF, fluoxetine too[!].

Kynrenic acid blocks glutamate, 5-HT2C blocks dopamine, so maybe that's analogous to "kynurenic acid" of depression??

Also, GABA and dopamine co-regulate each other^{[addition source]}.  So that opens other avenues to research.

 

Serotonin 5-HT2C receptors as a target for the treatment of depressive and anxious states: focus on novel therapeutic strategies.
Serotonin (5-HT)2C receptors play an important role in the modulation of monoaminergic transmission, mood, motor behaviour, appetite and endocrine secretion, and alterations in their functional status have been detected in anxiodepressive states. Further, 5-HT2C sites are involved in the actions of several classes of antidepressant. At the onset of treatment, indirect activation of 5-HT2C receptors participates in the anxiogenic effects of selective 5-HT reuptake inhibitors (SSRIs) as well as their inhibition of sleep, sexual behaviour and appetite. Conversely, progressive down-regulation of 5-HT2C receptors parallels the gradual onset of clinical efficacy of SSRIs. Other antidepressants, such as nefazodone or mirtazapine, act as direct antagonists of 5-HT2C receptors. These observations underpin interest in 5-HT2C receptor blockade as a strategy for treating depressive and anxious states. This notion is supported by findings that 5-HT2C receptor antagonists stimulate dopaminergic and adrenergic pathways, exert  antidepressant  and anxiolytic actions in behavioural paradigms, and favour sleep and sexual functio n. In addition to selective antagonists, novel strategies for exploitation of 5-HT2C receptors embrace inverse agonists, allosteric modulators, ligands of homo/heterodimers, modulators of interactions with 'postsynaptic proteins', dual melatonin agonists/5-HT2C receptor antagonists and mixed 5-HT2C/alpha2-adrenergic antagonists. Intriguingly, there is evidence that stimulation of regionally discrete populations of 5-HT2C receptors is effective in certain behavioural models of antidepressant activity, and promotes neurogenesis in the hippocampus. This article explains how these ostensibly paradoxical actions of 5-HT2C antagonists and agonists can be reconciled and discusses both established and innovative strategies for the exploitation of 5-HT2C receptors in the improved management of depressed and anxious states.

 

The interaction between GABA and dopamine: implications for schizophrenia.
A role for gamma-aminobutyric acid (GABA) in the pathophysiology of schizophrenia was first suggested by Eugene Roberts in 1972. Since then considerable work has been accomplished in both the clinical and basic sciences regarding GABA and schizophrenia. Although it was originally thought that GABA might be useful in treating schizophrenia because of its inhibition of dopaminergic activity, recent data have shown that in certain models GABA has the opposite effect on dopaminergic functions. Regardless of the relationships of GABA to dopamine, neither biochemical nor pharmacological studies have been able to demonstrate a clear and reproducible GABA disturbance in schizophrenia. A number of problems contribute to the difficulty in studying GABA in schizophrenia, including the lack of specific and nontoxic GABA agonists as well as the complexity of the GABA system in brain. Interest in GABA research in schizophrenia appears to have waned, but several areas nevertheless appear promising for clinical investigation

 

New Insights into the Mechanisms Underlying the Effects of BDNF on Eating Behavior
Previous work indicated that hypothalamic BDNF participates in homeostatic processes that preserve energy levels essential for survival. Recently, we demonstrated an intimate involvement of BDNF in the regulation of hedonic feeding via the positive modulation of the mesolimbic dopamine pathway (Cordeira et al, 2010). This neural circuit mediates motivated and reward-seeking behaviors, including consumption of palatable food, and has well-established roles in drug addiction. Mice with selective deletion of Bdnf in the ventral tegmental area (VTA), a principal source of mesolimbic BDNF, consumed significantly more palatable high-fat food than control mice, while exhibiting normal intake of standard chow. Furthermore, evoked release of dopamine by mesolimbic fibers in the nucleus accumbens was diminished in mice lacking central BDNF, suggesting decreased VTA dopamine neuron activity and concomitant reductions in neurotransmitter release. It was proposed previously that hypoactivity of the mesolimbic system might result in reward deficiency syndrome and, behaviorally, in compensatory overeating to enhance a deficient dopaminergic system. In support of this model, hyperphagic leptin-deficient mice were also reported to have reduced evoked dopamine release in the nucleus accumbens (Fulton et al, 2006). Moreover, we found that administration of a dopamine-1 receptor agonist abrogated overeating in BDNF mutant mice. The results argue strongly that BDNF is a natural modulator of hedonic food intake and that dysregulation of BDNF signaling in the reward circuitry increases the drive to eat in the absence of a homeostatic requirement.

Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress.
Mice experiencing repeated  aggression  develop a long-lasting aversion to social contact, which can be normalized by chronic,  but not acute, administration of antidepressant. Using viral-mediated, mesolimbic dopamine pathway-specific knockdown of brain-derived neurotrophic factor (BDNF), we showed that ??BDNF is required for the development of this experience-dependent social aversion??. Gene profiling in the nucleus accumbens indicates that local knockdown of BDNF obliterates most of the effects of repeated aggression on gene expression within this circuit, with similar effects being produced by chronic treatment with antidepressant. These results establish an essential role for  ??BDNF in mediating  long-term neural and behavioral plasticity in response to aversive social experiences??. 

BDNF controls dopamine D3 receptor expression and triggers behavioural sensitization.
Brain-derived neurotrophic factor (BDNF), like other neurotrophins, is a polypeptidic factor initially regarded to be responsible for neuron proliferation, differentiation and survival, through its uptake at nerve terminals and retrograde transport to the cell body. A more diverse role for BDNF has emerged progressively from observations showing that it is also transported anterogradely, is released on neuron depolarization, and triggers rapid intracellular signals and action potentials in central neurons. Here we report that BDNF elicits long-term neuronal adaptations by controlling the responsiveness of its target neurons to the important neurotransmitter, dopamine. Using lesions and gene-targeted mice lacking BDNF, we show that BDNF from dopamine neurons is responsible for inducing normal expression of the dopamine D3 receptor in nucleus accumbens both during development and in adulthood. BDNF from corticostriatal neurons also induces behavioural sensitization, by triggering overexpression of the D3 receptor in striatum of hemiparkinsonian rats. Our results suggest that BDNF may be an important determinant of pathophysiological conditions such as drug addiction, schizophrenia or Parkinson's disease, in which D3 receptor expression is abnormal.

 

Modulation of striatal quinolinate neurotoxicity by elevation of endogenous brain kynurenic acid

nicotinylalanine exerts its effect by increasing levels of endogenous kynurenic acid in the brain. The results of this study suggest that agents which influence levels of endogenous excitatory amino acid antagonists such as kynurenic acid may be useful in preventing excitotoxic damage

 

Nicotinylalanine increases the formation of kynurenic acid in the brain and antagonizes convulsions

antagonism of the NMDA receptors. In fact, NAL antagonized sound-induced seizures and prevented death in DBA/2 mice. Pretreatment of the mice with D-serine (100 micrograms intracerebroventricularly), a glycine agonist and a competitive antagonist of KYNA, completely prevented the anticonvulsive action of NAL. These data suggest that changes in the extracellular concentration of KYNA in the brain are associated with a modulation of NMDA receptor function.

 

Effects of kynurenic acid as a glutamate receptor antagonist in the guinea pig.
Glutamate excitotoxicity is implicated in both the genesis of neural injury and noise-induced hearing loss (NIHL). Acoustic overstimulation may result in excessive synaptic glutamate, resulting in excessive binding to post-synaptic receptors and the initiation of a destructive cascade of cellular events, thus leading to neuronal degeneration and NIHL. The purpose of this study was to determine whether this apparent excitotoxicity can be attenuated by kynurenic acid (KYNA), a broad-spectrum glutamate receptor antagonist, and protect against noise-induced temporary threshold shifts (TTS). Guinea pigs were randomly assigned to three separate groups. Base-line compound action potentials (CAP) thresholds and cochlear microphonics (CM) were recorded. Group I was treated with physiologic saline as a vehicle control applied to the round window membrane that was followed by 110 dB SPL wide-band noise for 90 min. Group II received 5 mM KYNA followed by noise exposure, and group III received 5 mM KYNA alone without noise exposure. Post-drug and noise levels of CAP thresholds and CM were then obtained. Noise exposure in the control group caused a significant temporary threshold shift (TTS) of 30-40 dB across the frequencies tested (from 3 kHz to 18 kHz). Animals that received 5 mM KYNA prior to noise exposure (group II) showed statistically significant protection against noise-induced damage and demonstrated a minimal TTS ranging between 5 and 10 dB at the same frequencies. Animals in group III receiving KYNA without noise exposure showed no change in thresholds. Additionally, cochlear microphonics showed no considerable difference in threshold shifts when controls were compared to KYNA-treated animals. These results show that antagonizing glutamate receptors can attenuate noise-induced TTS, suggesting that glutamate excitotoxicity may play a role in acoustic trauma.

 

Fluctuations in endogenous kynurenic acid control hippocampal glutamate and memory.
Kynurenic acid (KYNA), an astrocyte-derived metabolite, antagonizes the α7 nicotinic acetylcholine receptor (α7nAChR) and, possibly, the glycine co-agonist site of the NMDA receptor at endogenous brain concentrations. As both receptors are involved in cognitive processes, KYNA elevations may aggravate, whereas reductions may improve, cognitive functions. We tested this hypothesis in rats by examining the effects of acute up- or downregulation of endogenous KYNA on extracellular glutamate in the hippocampus and on performance in the Morris water maze (MWM). Applied directly by reverse dialysis, KYNA (30-300 nM) reduced, whereas the specific kynurenine aminotransferase-II inhibitor (S)-4-(ethylsulfonyl)benzoylalanine (ESBA; 0.3-3 mM) raised, extracellular glutamate levels in the hippocampus. Co-application of KYNA (100 nM) with ESBA (1 mM) prevented the ESBA-induced glutamate increase. Comparable effects on hippocampal glutamate levels were seen after intra-cerebroventricular (i.c.v.) application of the KYNA precursor kynurenine (1 mM, 10 μl) or ESBA (10 mM, 10 μl), respectively. In separate animals, i.c.v. treatment with kynurenine impaired, whereas i.c.v. ESBA improved, performance in the MWM. I.c.v. co-application of KYNA (10 μM) eliminated the pro-cognitive effects of ESBA. Collectively, these studies show that KYNA serves as an endogenous modulator of extracellular glutamate in the hippocampus and regulates hippocampus-related cognitive function. Our results suggest that pharmacological interventions leading to acute ??reductions in hippocampal KYNA constitute an effective strategy for cognitive improvement??. This approach might be especially useful in the treatment of cognitive deficits in neurological and psychiatric diseases that are associated with increased brain KYNA levels.

 

The Brain Metabolite Kynurenic Acid Inhibits α7 Nicotinic Receptor Activity and Increases Non-α7 Nicotinic Receptor Expression

Edited by gamesguru, 22 September 2015 - 01:42 PM.

[Mind_Paralysis]

Cool that you've found the references for Nicotinylalanine and other KYNA -regulators. It's old news to me tho', since I looked into this months ago, when I was still actively researching the NMDA-network's connection to ADHD. (as you can see, they may also be a viable target for excitotoxicity such as in Alzheimers, and other diseases as well)

 

In essence, KYNA doesn't just bind together the theories regarding Schizo, it binds the theories regarding ADHD together as well.

 

Circadian rhytm disturbances, dopamine-problems, ketogenic diet, nmda-problems - they are all connected to the pathway that creates both Melatonin and KYNA.

 

Here are the humble results of my research:

http://www.longecity...c-acid-in-adhd/

 

But that's off-topic, so let's get back to BDNF and SSRI's.

 

The goal is still to find data on which SSRI's actually increase BDNF the MOST - what do we vaguer, fella's?

Edited by Stinkorninjor, 22 September 2015 - 04:14 PM.

[gamesguru]

What's wrong for example, just with throwing into the mix,,  Blueberries, bacopa/ginkgo/ginseng/tea, exercise,,  stuff  which enhances BDNF through independent mechanisms and would act synergistically?

 

I could say the same about nmda problems involved with DA/5-HT dysfunction.

 

Chapter 3 NMDA and Dopamine: Diverse Mechanisms Applied to Interacting Receptor Systems
N-methyl-D-aspartate (NMDA) and dopamine (DA) receptors and their interactions control an incredible variety of functions in the intact brain and, when abnormal, these interactions underlie and contribute to numerous disease states. These receptor interactions are relevant in such diverse functions as motor control, cognition and memory, neurodegenerative disorders, schizophrenia, and addiction. It is thus not surprising that a wealth of information has been generated by the neuroscience community interested in the coordinated functions of NMDA and DA receptors. This chapter will describe the numerous mechanisms underlying DA–NMDA receptor interactions, particularly in the striatum, the main focus of our investigations.
DA modulation of spontaneous or glutamate-induced action potentials in the caudate nucleus has been known for some time [1–3]. Since the discoveries of different subtypes of glutamate and DA receptors, the number of potential interactions and their mechanisms has multiplied because the functions of glutamate and DA receptor subtypes are governed by multiple factors that tap into different types of signaling systems. Thus, the outcomes of interactions of these receptor families can be very diverse.
It has been 10 years since we published our first review summarizing known DA–NMDA receptor interactions and their mechanisms [4]. Since then, exciting findings have added new levels of complexity. For example, in addition to intracellular interactions via second messenger pathways, recent studies revealed the presence of physical interactions between NMDA and DA receptors at the membrane and cytoplasm levels. Furthermore, the generation of mice deficient of specific DA receptors or NMDAR subunits and mice expressing enhanced green fluorescent protein (EGFP) under the control of specific DA receptor subtype promoters has provided new tools for studying relationships of DA and NMDA receptors.

 

 for example, excessive masturbation results in low dopamine, via 5-HT2C

Dopamine and serotonin: influences on male sexual behavior.
Steroid hormones regulate sexual behavior primarily by slow, genomically mediated effects. These effects are realized, in part, by enhancing the processing of relevant sensory stimuli, altering the synthesis, release, and/or receptors for neurotransmitters in integrative areas, and increasing the responsiveness of appropriate motor outputs. Dopamine has facilitative effects on sexual motivation, copulatory proficiency, and genital reflexes. Dopamine in the nigrostriatal tract influences motor activity; in the mesolimbic tract it activates numerous motivated behaviors, including copulation; in the medial preoptic area (MPOA) it controls genital reflexes, copulatory patterns, and specifically sexual motivation. Testosterone increases nitric oxide synthase in the MPOA; nitric oxide increases basal and female-stimulated dopamine release, which in turn facilitates copulation and genital reflexes. Serotonin (5-HT) is primarily inhibitory, although stimulation of 5-HT(2C) receptors increases erections and inhibits ejaculation, whereas stimulation of 5-HT(1A) receptors has the opposite effects: facilitation of ejaculation and, in some circumstances, inhibition of erection. 5-HT is released in the anterior lateral hypothalamus at the time of ejaculation. Microinjections of selective serotonin reuptake inhibitors there delay the onset of copulation and delay ejaculation after copulation begins. One means for this inhibition is a decrease in dopamine release in the mesolimbic tract.

Lateral hypothalamic serotonin inhibits nucleus accumbens dopamine: implications for sexual satiety.
Dopamine (DA) is released in several brain areas, including the nucleus accumbens (NAcc), before and during copulation in male rats . DA agonists administered into this area facilitate, and DA antagonists inhibit, numerous motivated behaviors, including male sexual behavior. Serotonin (5-HT) is generally inhibitory to male sexual behavior. We reported previously that 5-HT is released in the anterior lateral hypothalamic area (LHA(A)) and that a selective serotonin reuptake inhibitor microinjected into that area delayed and slowed copulation. Our present results, using high temporal resolution microdialysis, (1) confirm previous electrochemical evidence that extracellular levels of DA increase in the NAcc during copulation and decrease during the postejaculatory interval (PEI) and (2) reveal that LHA(A) 5-HT can inhibit both basal and female-elicited DA release in the NAcc. These findings suggest that the neural circuit promoting sexual quiescence during the PEI includes serotonergic input to the anterior LHA, which in turn inhibits DA release in the NAcc. These findings may also provide insights concerning the inhibitory control of other motivated behaviors activated by the NAcc and may have relevance for understanding the sexual side effects common to antidepressant medications.

 

as for melatonin:

 

MELATONIN COUNTERS THE 5-FLUOROURACIL-INDUCED DECREASE IN BRAIN SEROTONIN AND DOPAMINE LEVELS
It has been demonstrated that both 5-fluorouracil and melatonin inhibit rat liver tryptophan-2,3-dioxygenase activity. This study sought to examine the effects that this inhibition has on the levels of various neurotransmitters in the brain. By inhibiting TDO, melatonin increases brain serotonin levels. Melatonin also increases dopamine levels but does not alter norepinephrine levels. 5-Fluorouracil has been found to decrease brain levels of all three neurotransmitters (i.e. serotonin, norepinephrine and dopamine). This could be due to the antineoplastic inhibiting DNA synthesis and gene expression of the enzymes required in the synthesis of these neurotransmitters. The decrease in norepinephrine levels induced by 5-fluorouracil could also be due to decreases in serotonin and dopamine levels. Dopamine can be converted to norepinephrine, whose release can be induced by serotonin. Even though 5-fluorouracil and melatonin alter brain serotonin levels, neither drug alters the conversion of serotonin to the metabolite 5-hydroxy-indole acetic acid. The same is true for the dopamine metabolite 3,4-dihydroxyphenylacetic acid. By decreasing the levels of norepinephrine, serotonin and dopamine, 5-fluorouracil could contribute to the development or exacerbation of depression in cancer patients. Melatonin, if administered together with 5-fluorouracil, could counter this 5-fluorouracil-induced depression by significantly increasing brain serotonin and dopamine levels. The use of melatonin as adjunctive therapy with 5-fluorouracil to improve patients' quality of life needs to be investigated further.

 

Diurnal 5-HT Production and Melatonin Formation

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[Mind_Paralysis]

Oh yeah, nothing wrong with that, really - I actually got this thread mixed up with another one on a different board, where I listed training and romantic love as two known neurogenic processes.

 

The BLUEberries seems especially interesting btw!! Mainly because I want to try Strattera, but it often leads to anxiety and depression in many subjects, even if transitory, but if the study you referenced is correct, I might be able to counteract the NEGATIVE aspects of NE, by eating a lot of blueberries prior to starting treatment with Atomoxetine. Way cool. =) I like blueberries too.

 

Regarding exercise btw, as I recall, it's actually specific types of exercise that are said to be the most effective, isn't it? I believe it's actually cardio, not weight-lifting, and I think I even saw a study that listed specific training-methods, that yielded better results...

 

You recall seeing anything like that? I'll try to find it, because it would certainly be cool to OPTIMIZE the anti-depressant effects of exercise, yeah?

[gamesguru]

Generally medium-to-high intensity cardio is best, though weight training confers ~2/3 of the beneficial changes.  I usually do 2 miles on the elliptical after 30mins free weights, 6-7 days a week.

Can't find one study, but it concluded drop sets secreted more testosterone and resulted in faster changes of strength and body composition. (It was like 6RM on leg press, then rest 15 seconds two more reps, rest another 15 and two more vs.10RM leg press, so not a traditional drop set)

Another concluded squat was superior to leg press in secreting GH, and to bench press in secreting Test.  (that reference I found, but am not bothering to include)   These are more interesting:

Effects of resistance training on arterial stiffness: a meta-analysis.
BACKGROUND: Regular aerobic exercise prevents and reverses arterial stiffening, but the association between resistance training and arterial stiffness is unclear.
AIM: This study was performed to conduct a systematic review and meta-analysis of randomised controlled clinical trials (RCTs) assessing the associations between resistance training and changes in arterial stiffness.
METHODS: MEDLINE and SPORTDiscus databases were searched from January 1980 through to April 2011. RCTs evaluating the ability of resistance training to increase arterial stiffness in comparison with a control group were included in the meta-analysis. Two independent reviewers extracted data and assessed the quality of the included studies. Data from 185 reports of eight RCTs (193 participants) were included. Pooled mean differences in arterial stiffness indices (carotid arterial β stiffness and pulse wave velocity (PWV)) between intervention and control groups were calculated using a random-effects model.
RESULTS: The overall association of resistance training versus control with relative changes in carotid β index or PWV (eight studies; 193 participants) was 10.7% (95% CI 3.4% to 18.0%; I(2), 89%; heterogeneity, p<0.001). Five studies indicated that resistance training in young subjects (n=115) was significantly associated with an increase in stiffness index of 14.3% (95% CI 8.5% to 20.1%; I(2), 71%; heterogeneity, p<0.001) compared with controls. However, three studies showed that resistance training in middle-aged subjects (n=78) was not associated with changes in arterial stiffness. In addition, although high-intensity resistance training (n=87) was significantly associated with an increase in stiffness of 11.6%, moderate-intensity resistance training (n=106) showed no such association.
CONCLUSION: High-intensity resistance training is associated with increased arterial stiffness in young subjects with low baseline levels of arterial stiffness.

Resistance Training Is Associated With Lower Arterial Compliance and Higher Blood Pressure

 

 

also... (again just one study, needs confirming)

Bacopa monniera lowered norepinephrine and increased the 5-hydroxytryptamine levels in hippocampus, hypothalamus and cerebral cortex. The higher doses of Bacopa monniera extracts produced significantly greater anxiolytic effects compared to lorazepam (Xanax), a standard anxiolytic drug from benzodiazepine group (30).  However, acute and sub chronic (one week) treatment of Bacopa monnieri methanolic extract (10, 20 or 30 mg/kg) did not affect whole brain dopamine (DA) and serotonin (5-HT) turnover.

http://www.ijpsr.inf...3-04-12-005.pdf

-----------

Current evidence suggests BM acts via the following mechanisms—anti-oxidant neuroprotection (via redox and enzyme induction), acetylcholinesterase inhibition and/or choline acetyltransferase activation, β-amyloid reduction, increased cerebral blood flow, and neurotransmitter modulation (acetylcholine [ACh], 5-hydroxytryptamine [5-HT], dopamine [DA]).

 

problem is it's very serotonergic

Levels of 5-HT in the BM groups were almost double the control level

http://www.ncbi.nlm....les/PMC3746283/

Edited by gamesguru, 28 September 2015 - 05:59 PM.

[Multivitz]

To build something you need building blocks, not stimulation.
The sad fact that corporatism promotes it's intrests everywhere. To get the photons from the blood to the flesh, Silica is needed to create the microscopic channels. If your building blocks are a) missing b) have no friends c) are out of balance d) tainted e) preoccupied, then all the drugs in the world will have little to no effect. All that happens is the blood becomes acidic and parrasites come in to mop up the mess, then you're in more trouble (if you have a peripheral nervous system that can sense 'em?) Hope this helps.

[Mind_Paralysis]

To build something you need building blocks, not stimulation.
The sad fact that corporatism promotes it's intrests everywhere. To get the photons from the blood to the flesh, Silica is needed to create the microscopic channels. If your building blocks are a) missing b) have no friends c) are out of balance d) tainted e) preoccupied, then all the drugs in the world will have little to no effect. All that happens is the blood becomes acidic and parrasites come in to mop up the mess, then you're in more trouble (if you have a peripheral nervous system that can sense 'em?) Hope this helps.

 

I'm afraid it doesn't.

 

If it did, then Omega-3 supplements could cure all depression, and heal all traumatic brain-injury, since the brain is made up almost entirely of omega-3 fatty acids.

I thank you for wanting to help though.
 

[jack black]

Not sure if this fully answers the OP's question, but i came across this while searching on BDNF vs suicide:

 

 

Initially, we examined how BDNF is regulated in response to antidepressants. We treated rats with different classes of antidepressants (Dwivedi et al., 2006). We observed that desipramine (a norepinephrine blocker) and phenelzine (a monoamine oxidase inhibitor) increased mRNA levels of BDNF gene expression in both the frontal cortex and hippocampus, whereas fluoxetine (a serotonin reuptake blocker) increased the mRNA level of BDNF only in the hippocampus. Interestingly, we found that desipramine specifically increased the expression of BDNF transcripts I and III in both the frontal cortex and hippocampus; fluoxetine increased only exon II in the hippocampus; and phenelzine increased exons I and IV in the hippocampus but only exon I in the frontal cortex. We further examined whether antidepressants can reverse the CORT-mediated decrease in BDNF expression and, if so, whether the same BDNF transcripts regulate CORT-mediated down-regulation and antidepressant-mediated up-regulation of the BDNF gene (Dwivedi et al., 2006b). It was observed that all the antidepressants normalized the levels of CORT, although the degree of this reversal varied with different antidepressants. When examined, we found that desipramine reversed the CORT-induced decrease in BDNF expression in both the frontal cortex and hippocampus. Fluoxetine only partially reversed such a decrease in the hippocampus, but no effect was found in the frontal cortex. Phenelzine, on the other hand, reversed the CORT-induced decrease in BDNF partially in the frontal cortex and completely in the hippocampus. Interesting results were noted when individual BDNF transcripts were examined after antidepressant treatment to CORT-implanted rats. We found that all the antidepressants increased mRNA levels of those BDNF transcripts that were affected when the respective antidepressant was given to healthy rats without CORT treatment. For example, desipramine increased exons I and III in the frontal cortex and hippocampus, fluoxetine increased exon II in the hippocampus, and phenelzine increased exon I in the frontal cortex and exons I and IV in the hippocampus. Surprisingly, except for an increase in exon II by fluoxetine in the frontal cortex and in exon IV by phenelzine in the hippocampus, the CORT-mediated decrease in exons II and IV persisted even after antidepressant treatment. Interestingly, despite these different effects of CORT and antidepressants on BDNF transcripts, overall, all the antidepressants increased the level of BDNF mRNA in the brain of CORT-treated rats.

 from: http://www.ncbi.nlm....ooks/NBK107216/

 

Furthermore, I searched on BDNF vs Semax and Piracetam and found this info:

 

 

After drug administration, changes in the BDNF level were only observed in the hippocamp of LE mice, where it reached (pg/microg) 0.115 +/- 0.004 (for piracetam); 0.119 +/- 0.006 (for phenotropil); 0.123 +/- 0.007 (for semax); and 0.122 +/- 0.009 (for meclophenoxate). In the LE mice cortex, the BDNF content increased only after piracetam and semax injections (to 0.083 +/- 0.003 and 0.093 +/- 0.008, respectively, vs. 0.071 +/- 0.003 pg/microg in the control group; p < 0.0005). No changes were observed in the cortex of HE mice.

 

from: http://www.ncbi.nlm....pubmed/20095391

 

Frankly, i was surprised piracetam was almost as affective as Semax. Not sure how that compares to antidepressants.

Edited by jack black, 05 July 2016 - 03:28 AM.

[normalizing]

Cordycepin has been found to produce rapid, robust ketamine-like antidepressant effects in animal models of depression, and these effects, similarly to those of ketamine, are dependent on enhancement of AMPA receptor signaling

 

http://ijnp.oxfordjo...ent/19/4/pyv112

[Ruth]

Can someone please explain what a ACUTE Escitalopram 20mg and bupropion 100mg combination dose on BDNF and other biomarkers, remember this is acute.

May I add that pre-treatment Glycine(3,000mg), Ascorbic acid(3,000mg), no more than 100mg caffeine, 5ht-p/tryptophan mixture(300mg) has adjunction effects with both (ESC) and (BUPR)

Melatonin 10mg also effects biomarkers.

So can someone explain this neuromodulatory mixture?

https://www.ncbi.nlm...pubmed/21107318
https://www.ncbi.nlm...les/PMC4715838/
https://www.ncbi.nlm...pubmed/26009299
https://www.ncbi.nlm...les/PMC5596844/
https://www.ncbi.nlm...les/PMC4946063/
http://www.ingentaco...000001/art00004
https://academic.oup...11/3/381/760546
https://www.karger.com/Article/235985


Correlations Between Neuroendocrine Disorders and Biochemical Brain Metabolites Alterations in Antidepressant Treatment
LUMINITA AGEU1, CRISTINA TALPOS1, GHIZELA KANALAS1, SIMINA CRISAN1*, CARMEN LACRAMIOARA ZAMFIR2, VLADIMIR POROCH2*, MIRELA ANGHEL1 1 Victor Babes University of Medicine and Pharmacy, 2 Eftimie Murgu Sq., 300041 Timisoara, Romania 2 Grigore T. Popa University of Medicine and Pharmacy, 16 Universitatii Str., 700115 Iasi, Romania
We approach the theme of modern investigation and treatment strategies, based on biochemical, clinicalbiological, metabolic, pharmacogenetic, neuro-imagistic, and neuroendocrine integrative correlations in the management of depressive disorders. Our main objective was to investigate: the biochemical brain metabolites [N-acetyl-aspartate (NAA), gamma-aminobutyric acid (GABA), aspartate (Asp), creatine (CR), glutamine (Gln), glicerophosphocholine (GPC), phosphocholine (PC), phosphocreatine (PCr), taurine (Tau), N-methyl-D-aspartate (N-MDA), serine, glycine, choline (Cho)]; the neuroimagistic and neurobiological markers and the metabolic abnormalities in correlation with the molecular pharmacogenetic testing in children and adolescents treated with antidepressant medication. Our research was conducted between 2009-2016 on 90 children and adolescents with depressive disorders -45 children-G1, who benefited of pharmacogenetic testing tailored pharmacotherapy, and 45 without pharmacogenetic testing-G2. The patients were also evaluated by MR spectroscopy at baseline and after pharmacotherapy. The efficacy of the chosen therapy in correlation with the pharmacogenetic testing was evaluated by the mean change in the CDRS (Child Depression Rating Scale) total scores, in the CGI-S/I (Clinical Global Impression Severity/ Improvement), CGAS (Clinical Global Assessment of Functioning) and by the change of the relevant neurobiological markers and MR spectroscopy biochemical brain metabolites. Our results showed statistically significant differences in the clinical scores between the studied groups. Our research could represent a proof that the biochemical brain metabolites registered in depressive disorders modified values in the MR spectroscopy and the administration of antidepressants could determine metabolic and neuroendocrine abnormalities (changed lipid profiles, high insulin and plasma glucose levels, weight gain, obesity), especially when chosen without prior pharmacogenetic testing.
Keywords: biochemical metabolites, N-acetyl aspartate (NAA), gama-aminobutyric acid (GABA), metabolic abnormalities, antidepressants, pharmacogenetic testin

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