Acknowledgement - The many definitions and descriptions of processes I have supplied are based on Wikipedia entries.
Document #1
http://www.researchg...289a09b6b1a.pdf
Evaluation of Duloxetine as Micronuclei Inducer in an Acute and a Subchronic Assay in Mouse
Eduardo Madrigal-Bujaidar1), Isela Álvarez-González1), Eduardo Osiris Madrigal-Santillán2), José A Morales-González2)
Duloxetine is a widely used antidepressant worldwide. In the present report, we evaluated its capacity to induce micronucleated polychromatic erythrocytes (MNPEs) and micronucleated normochromatic erythrocytes (MNNEs) in mice. Two assays were performed, one with a single chemical administration and the other with daily chemical administration. In the first, we administered the antidepressant once to groups of 5 mice
by the intragastric (i.g.) route (2, 20, and 200 mg/kg) and performed the analysis at 24, 48, and 72 h postadministration. A control group administered i.g. distilled water was included in the assay, as well as another treated with the micronuclei-inducing chemical daunorubicin (2.5 mg/kg, injected intraperitoneally (i.p.)). In this assay, we found significant damage induced by duloxetine starting from the first time evaluated, showing the highest MNPE increase at the end of the assay. We observed a saturation effect as well, suggested by a decreasing relative efficiency with respect to each tested dose. In a second assay, we administered the antidepressant i.g. every day for 5 weeks (2, 6, and 12 mg/kg), and micronuclei analysis was performed at the end of each week. In this study, we also found a significant increase in both MNPEs and MNNEs which was clear by the second week of administration. Our results suggest that short-term as well as cumulative damage is produced by duloxetine. Thus, confirmation of the observed genotoxic potential in other models seems advisable, as well as caution when prescribing this antidepressant. Duloxetine, a potent serotonin and norepinephrine reuptake inhibitor which effectively desensitizes various autoreceptors and promotes neuroplasticity. The compound is used in stress urinary incontinence, and due to its analgesic efficacy it is also prescribed for chronic pain conditions such as diabetic
peripheral neuropathy, fibromyalgia, chronic low back pain,and osteoarthritis knee pain.
Translation -
Cymbalta causes the development of damaged red blod cells which may or may not benormal in color and have a very small nucleus (the nucleus contains the cells DNA).
Also, Cymbalta improves neuroplasticity. The brain's ability to reorganize itself by forming new neural connections throughout life. Neuroplasticity allows the neurons (nerve cells) in the brain to compensate for injury and disease and to adjust their activities in response to new situations or to changes in their environment. Brain reorganization takes place by mechanisms such as "axonal sprouting" in which undamaged axons grow new nerve endings to reconnect neurons whose links were injured or severed. Undamaged axons can also sprout nerve endings and connect with other undamaged nerve cells, forming new neural pathways to accomplish a needed function.
Cymbalta downregulates the activity of the bladder control nerves.
Document #2
https://www.ncbi.nlm...pubmed/18973814
Neurobehavioral and genotoxic parameters of duloxetine in mice using the inhibitory avoidance task and comet assay as experimental models.
Pereira P1, Gianesini J, da Silva Barbosa C, Cassol GF, Von Borowski RG, Kahl VF, Cappelari SE, Picada JN.
Abstract
Duloxetine is a potent inhibitor of serotonin and noradrenaline reuptake, with weak effects on dopamine reuptake, used in the treatment of major depression. It has been recognized that some antidepressants can affect memory in humans, but there is not study that report the duloxetine effect on memory using the inhibitory avoidance. The aim of this work was to investigate the effect of duloxetine on short- and long-term memory (STM and LTM) in the inhibitory avoidance task in mice. Duloxetine (10 and 20 mg/kg; i.p.) administered before or after the inhibitory avoidance training was not able to produce effects on STM e LTM (p>0.05). The group that received MK-801 (0.0625 mg/kg), an NMDA receptor antagonist, showed an impairment in STM and LTM (p<0.01). These effects were not reversed by duloxetine administration (p=0.114 and p=0.06, respectively). Duloxetine effect on memory 5 days after i.p. administration was also investigated. After this treatment both duloxetine doses used were unable to affect STM or LTM in the inhibitory avoidance task (p=0.371 and p=0.807, respectively). DNA damages were evaluated in brain tissues and blood by the comet assay, after subacute treatment (10 or 20 mg/kg by 5 days). Duloxetine did not induce genotoxic effects. However, when the cells were treated ex vivo hydrogen peroxide, a pro-oxidant effect on brain tissue from treated animals was observed with significantly higher DNA damage in comparison to untreated animals, suggesting increased susceptibility to injuries by reactive oxygen species in brain after treatment with duloxetine. Duloxetine did not produce any effect on memory after acute and subacute administration, suggesting that this antidepressant does not affect either memory acquisition or consolidation.
Translation - Cymbalta did not cause DNA damage.
Document #3
https://www.ncbi.nlm...les/PMC4713700/
Effects of duloxetine on microRNA expression profile in frontal lobe and hippocampus in a mouse model of depression
Our data showed that miRNA expression profile in frontal lobe and hippocampus was affected by duloxetine in mice model of depression. The effect was especially pronounced in the hippocampus, suggesting that hippocampus might be the action site of duloxetine, which presumably worked by regulating the expression of miRNA levels.
(This study shows the direct effect of Cymbalta on miRNA (used in translating DNA code) in the hippocampus (one of the emotional centers in the brain). Duloxetine in particular has been reported to induce embryotoxicity in aquatic organisms.
Moreover, as no explanation has been proposed for DNA/chromosomal damage induced by duloxetine and other antidepressants, the detection of specific molecular lesions or
the involved biochemical routes is a matter of research.
Translation - RNA 'reads' the genes in the DNA and then produces the appropriate product. For example if a certain part of the DNA is for a digestive protein the RNA would actually copy that part of the DNA and then use that information to produce the desired protein. A microRNA ( miRNA) is a small RNA molecule that functions in stopping the RNA process and post-'copying' transcription mechanisms that are used by cells to increase or decrease the production of specific gene products (such as proteins or RNA). In simple terms Cymbalta regulates DNA product manufacturing in the frontal lobe and hippocampus.
The frontal lobe is located at the front of the brain contains most of the dopamine-sensitive neurons (nerve cells) in the cerebral cortex. The dopamine system is associated with reward, attention, short-term memory tasks, planning, and motivation. Dopamine tends to limit and select sensory information arriving from the thalamus to the forebrain.
The hippocampus is the part of the brain that is involved in memory forming, organizing, and storing. It is particularly important in forming new memories and connecting emotions and senses to memories. Because of this it is the center for memory based psychological learned responses (such as PTSD). It is also the center of the human fear circuits. The hippocampus receives input from neurotransmitter systems, including serotonin, norepinephrine, and dopamine systems. It also receives cholinergic input (responds to the neurotransmitter acetylcholine) from the medial septum, which regulates the hippocampal physiological state. The hippocampus is highly involved in sleep patterns including REM sleep. There is evidence that humans having experienced severe, long-lasting traumatic stress show atrophy (shrinking fur to lack of use) of the hippocampus more than of other parts of the brain.
Document #4
https://www.ncbi.nlm.../pubmed/9686935
Naunyn Schmiedebergs Arch Pharmacol. 1998 Jun;357(6):600-10.
Effect of long-term administration of duloxetine on the function of serotonin and noradrenaline terminals in the rat brain.
Rueter LE1, Kasamo K, de Montigny C, Blier P.
Abstract
Duloxetine, an inhibitor of both 5-hydroxytryptamine (5-HT) and noradrenaline (NA) reuptake processes, has been developed as a potential antidepressant drug. The present study was initiated to investigate the functioning of multiple components of the 5-HT and NA systems following the long-term administration of duloxetine. In rats treated for 21 days with duloxetine (20 mg/kg/day), the recovery times of dorsal hippocampus CA3 pyramidal neurons from microiontophoretic applications of 5-HT and NA were significantly increased, indicating ongoing reuptake blockade with the minipump in place delivering the drug. The remaining experiments were performed following a 48-h washout. Electrically evoked release of [3H]5-HT from preloaded slices was enhanced in the midbrain, presumably due to a desensitization of the somatodendritic 5-HT1D and 5-HT1A autoreceptors. In addition, evoked release of [3H]5-HT was increased in the hippocampus, which could have been due to the desensitization of the alpha2-adrenergic heteroreceptors located on the 5-HT terminals. In contrast, there was no change in the evoked release of [3H]5-HT in the frontal cortex despite decreased functioning of the 5-HT transporter found in this brain region. Similar to changes in 5-HT release, electrically evoked release of [3H]NA was enhanced in the hippocampus and frontal cortex of rats treated chronically with duloxetine. These increases in [3H]NA release were most likely due to the desensitization of the alpha2-adrenergic autoreceptor in the hippocampus and to the desensitization of the NA transporter in the frontal cortex, respectively. These data suggest that long-term administration of duloxetine is able to induce changes in the 5-HT and NA systems that lead to enhanced release of both 5-HT and NA in some limbic brain areas. Duloxetine, therefore, may be a useful antidepressant compound.
Translation - This research proves that Cymbalat affects the seratonin reuptake proteins. It also shows an increase in seratonin in the hippocampus and no change in seratonin in the frontal cortex. Other studies show that past the 2 month state seratonin levels drop with Cymbalta usage.
Document #5
https://www.ncbi.nlm...les/PMC3362535/
Stress-Induced Changes of Hippocampal NMDA Receptors: Modulation by Duloxetine Treatment
Francesca Calabrese,1 Gianluigi Guidotti,1 Raffaella Molteni,1 Giorgio Racagni,1,3 Michele Mancini,2 and Marco Andrea Riva1,3,*
Abstract
It is now well established that the glutamatergic system contributes to the pathophysiology of depression. Exposure to stress, a major precipitating factor for depression, enhances glutamate release that can contribute to structural abnormalities observed in the brain of depressed subjects. On the other hand, it has been demonstrated that NMDA antagonists, like ketamine, exert an antidepressant effect at preclinical and clinical levels. On these bases, the purpose of our study was to investigate whether chronic mild stress is associated with specific alterations of the NMDA receptor complex, in adult rats, and to establish whether concomitant antidepressant treatment could normalize such deficits. We found that chronic stress increases the expression of the obligatory GluN1 subunit, as well as of the accessory subunits GluN2A and GluN2B at transcriptional and translational levels, particularly in the ventral hippocampus. Concomitant treatment with the antidepressant duloxetine was able to normalize the increase of glutamatergic receptor subunit expression, and correct the changes in receptor phosphorylation produced by stress exposure. Our data suggest that prolonged stress, a condition that has etiologic relevance for depression, may enhance glutamate activity through post-synaptic mechanisms, by regulating NMDA receptors, and that antidepressants may in part normalize such changes. Our results provide support to the notion that antidepressants may exert their activity in the long-term also via modulation of the glutamatergic synapse.
Translation - High glutamate (neurotransmitter) in the hippocampus contributes to depresssion. Cymbalta returns the glutamate gene function to normal activity in the hippocampus. Glutamate is an amino acid, one of the twenty amino acids used to construct proteins, and as a consequence is found in high concentration in every part of the body. In the nervous system it plays a special additional role as a neurotransmitter: a chemical that nerve cells use to send signals to other cells. In fact glutamate is by a wide margin the most abundant neurotransmitter in the vertebrate nervous system. It is used by every major excitatory information-transmitting pathway in the vertebrate brain, accounting in total for well over 90% of the synaptic connections in the human brain. It is no wonder that Cymbalta can cause such varied side effects and withdrawal symptoms as it can potentially effect all nerve cells in the brain and nervous system.
Comment - Is it no wonder that Cymbalta has such a tremendous and varied effect on the human body while on the srug or during recovery/withdrawal afterward.
Document #6
J Biol Chem. 2014 Sep 5; 289(36): 25177–25185.
Synergistic Regulation of Glutamatergic Transmission by Serotonin and Norepinephrine Reuptake Inhibitors in Prefrontal Cortical Neurons
Eunice Y. Yuen,‡ Luye Qin,‡ Jing Wei,‡§ Wenhua Liu,‡ Aiyi Liu,‡ and Zhen Yan‡§,1
Abstract
The monoamine system in the prefrontal cortex has been implicated in various mental disorders and has been the major target of anxiolytics and antidepressants. Clinical studies show that serotonin and norepinephrine reuptake inhibitors (SNRIs) produce better therapeutic effects than single selective reuptake inhibitors, but the underlying mechanisms are largely unknown. Here, we found that low dose SNRIs, by acting on 5-HT1A and α2-adrenergic receptors, synergistically reduced AMPA receptor (AMPAR)-mediated excitatory postsynaptic currents and AMPAR surface expression in prefrontal cortex pyramidal neurons via a mechanism involving Rab5/dynamin-mediated endocytosis of AMPARs. The synergistic effect of SNRIs on AMPARs was blocked by inhibition of activator of G protein signaling 3, a G protein modulator that prevents reassociation of Gi protein α subunit and prolongs the βγ-mediated signaling pathway. Moreover, the depression of AMPAR-mediated excitatory postsynaptic currents by SNRIs required p38 kinase activity, which was increased by 5-HT1A and α2-adrenergic receptor co-activation in an activator of G protein signaling 3-dependent manner. These results have revealed a potential mechanism for the synergy between the serotonin and norepinephrine systems in the regulation of glutamatergic transmission in cortical neurons.
Translation - Cymbalta, by affecting both seratonin and alpha adrenaline receptors, affects glutamate receptor signaling in the prefrontal cortex of the brain.
Document #7
https://www.ncbi.nlm...pubmed/26135544
Antihyperalgesic effect of duloxetine and amitriptyline in rats after peripheral nerve injury: Influence of descending noradrenergic plasticity.
Hoshino H1, Obata H2, Saito S3.
Abstract
Antidepressants such as serotonin-noradrenaline reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs) are frequently used for the management of neuropathic pain. Noradrenaline (NA) and serotonin (5-HT) increase in the spinal cord by reuptake inhibition is considered to be main mechanism of the therapeutic effect of antidepressants in neuropathic pain. In the present study, we examined the analgesic effects of duloxetine (SNRI) and amitriptyline (TCA) in a rat model of neuropathic pain induced by spinal nerve ligation (SNL). Intraperitoneal administration of duloxetine and amitriptyline dose-dependently (3,10 and 30 mg/kg) suppressed hyperalgesia induced by SNL. In vivo microdialysis in the lumbar spinal dorsal horn revealed that NA and 5-HT concentrations increased after intraperitoneal administration of duloxetine and amitriptyline (10 mg/kg, respectively). We further determined NA and 5-HT contents in homogenized samples from the ipsilateral dorsal spinal cord after SNL. Although the NA content in SNL rats 2 weeks after ligation was higher than that in SNL rats 4 weeks after ligation, the analgesic efficacy of duloxetine and amitriptyline was similar between two groups. The present study suggests that NA/5-HT increase in the spinal cord is crucial in the antihyperalgesic effect of duloxetine and amitriptyline. The plastic change of the descending noradrenergic system does not obviously affect the analgesic efficacy of duloxetine and amitriptyline.
Translation -Cymbalta increases seratonin and noradrenaline levels in the spinal cord and reduces associated spinal pain.
Document #8
https://www.ncbi.nlm...pubmed/25154730
Eur J Pain. 2015 May;19(5):649-60. doi: 10.1002/ejp.586. Epub 2014 Aug 25.
A selective α2 B adrenoceptor agonist (A-1262543) and duloxetine modulate nociceptive neurones in the medial prefrontal cortex, but not in the spinal cord of neuropathic rats.
Chu KL1, Xu J, Frost J, Li L, Gomez E, Dart MJ, Jarvis MF, Meyer MD, McGaraughty S.
Abstract
The noradrenergic system contributes to pain modulation, but the roles of its specific adrenoceptors are still being defined. We have identified a novel, potent (rat EC50 = 4.3 nM) and selective α2B receptor agonist, A-1262543, to further explore this adrenoceptor subtype's contribution to pathological nociception.
METHODS: Systemic administration of A-1262543 (1-10 mg/kg, intraperitoneal) dose-dependently attenuated mechanical allodynia in animals with a spinal nerve ligation injury. To further explore its mechanism of action, the activity of nociceptive neurones in the spinal cord and medial prefrontal cortex (mPFC) were examined after injection of 3 mg/kg of A-1262543 (intravenous, i.v.). These effects were compared with duloxetine (3 mg/kg, i.v.), a dual noradrenaline (NA) and serotonin (5-HT) reuptake inhibitor.
RESULTS: Systemic administration of A-1262543 or duloxetine did not alter the spontaneous or evoked firing of spinal wide dynamic range and nociceptive-specific neurones in the neuropathic rats, indicating that neither compound engaged spinal, peripheral or descending pathways. In contrast to the lack of effect on spinal neurones, both A-1262543 and duloxetine reduced the evoked and spontaneous firing of 'pain-responsive' (PR) neurones in the mPFC. Duloxetine, but not A-1262543, also inhibited the firing of pain non-responsive (nPR) neurones in the mPFC probably reflecting duloxetine's contribution to modulating non-pain endpoints.
CONCLUSIONS: These data highlight that activation of the α2B adrenoceptor as well as inhibiting NA and 5-HT reuptake can result in modulating the ascending nociceptive system, in particular, dampening the firing of PR neurones in the mPFC.
Translation - Cymbalta does not effect the pain sensing nerves in the spinal cord but does reduce the activity of the nerves bringing signals back up to the prefrontal cortex and thus reducing the perception of pain.
Document #9
https://www.ncbi.nlm...les/PMC3171868/
Br J Pharmacol. 2011 Sep; 164(1): 159–169.
A spinal mechanism of action for duloxetine in a rat model of painful diabetic neuropathy
T Mixcoatl-Zecuatl and CG Jolivalt
These results support the involvement of spinal 5-HT2A receptors in the ability of duloxetine to ameliorate painful diabetic neuropathy. Our data also suggest that the role of 5-HT2A receptors depends on the level of the neuraxis at which activation takes place, with peripheral activation contributing to tactile allodynia in diabetic rats, whereas spinal activation of this receptor alleviates tactile allodynia. The development of selective peripheral 5-HT2A receptor antagonists may offer a novel approach for the treatment of diabetic neuropathic pain.
Translation - Cymbalta seratonin receptor control helps control pain in peripheral (around the outside) nerves.
Document #10
https://www.ncbi.nlm...pubmed/24933334
Pharmacol Biochem Behav. 2014 Sep;124:238-44. doi: 10.1016/j.pbb.2014.06.005. Epub 2014 Jun 14.
Augmentation of antidepressant effects of duloxetine and bupropion by caffeine in mice.
Kale PP1, Addepalli V2.
Abstract
There is an unmet need in the treatment of depression suggesting requirement of new therapeutic approaches having better efficacy and safety profile. Patients receiving antidepressant therapy generally consume caffeine in the form of tea or coffee. The objective of the present study was to evaluate the augmentation of antidepressant effects of duloxetine and/or bupropion with caffeine. Male Swiss Albino mice received treatment of normal saline (10 ml/kg), 'caffeine alone' (10mg/kg), 'duloxetine alone' (10mg/kg), 'bupropion alone' (10mg/kg), caffeine+duloxetine (5mg/kg, each), bupropion+caffeine (5mg/kg, each), and bupropion+duloxetine (5mg/kg, each) through the intra-peritoneal route. The immobility period was analyzed 30 min after the treatment in forced swim and tail suspension tests. Norepinephrine, dopamine, and serotonin levels were analyzed in hippocampus, cerebral cortex and whole brain using HPLC with fluorescence detector. Euthanasia was performed 1h after treatment. Comparison between vehicle treated group and other groups showed significant decrease in immobility in all drug treated groups in both antidepressant models. Caffeine plus duloxetine treated group was better among the combination treated groups in terms of decrease in immobility and increase in norepinephrine, dopamine, and serotonin levels in hippocampi, cerebral cortices, and whole brain when compared to their respective monotherapy treated groups. These combination approaches may help in reducing the dose of duloxetine/bupropion, and consequently lower the associated side/adverse effects.
Translation - Caffiene in combination with Cymbalta helps decrease fatique and sluggishness (side effects of Cymbalta). It also increased concentrations of norepinephrine, dopamine and seratonin in the hippocampus, cerebral cortex and the whole brain.
Document #11
https://www.ncbi.nlm...pubmed/23522402
J Psychiatr Res. 2013 Jun;47(6):802-8. doi: 10.1016/j.jpsychires.2013.02.013. Epub 2013 Mar 19.
Chronic administration of duloxetine and mirtazapine downregulates proapoptotic proteins and upregulates neurotrophin gene expression in the hippocampus and cerebral cortex of mice.
Engel D1, Zomkowski AD, Lieberknecht V, Rodrigues AL, Gabilan NH.
Abstract
Structural alterations in the limbic system, neuronal cell loss, and low levels of neurotrophins have been implicated in the pathogenesis of depression. While it is generally accepted that increasing monoamine levels in the brain can effectively alleviate depression, the precise neurobiological mechanisms involved are unclear. In the present study, we examined the effects of two antidepressants, duloxetine and mirtazapine, on the expression of apoptotic (natural cell deatah) and neurotrophic proteins (promotes growth, survival and specialize) in the cerebral cortex and hippocampus of mice. Duloxetine (10 mg/kg) and mirtazapine (3 mg/kg) were chronically administered for 21 days, and qRT-PCR analysis was carried for the following: neurotrophins (BDNF, NGF, FGF-2, and NT-3); anti-apoptotic proteins (Bcl-2 and Bcl-xL) and pro-apoptotic proteins (Bax, Bad, and p53). Both duloxetine and mirtazapine produced antidepressant activity in the forced swimming test and induced increased cortical and hippocampal mRNA expression of BDNF. Duloxetine also increased Bcl-2, Bcl-xL, FGF-2, and NT-3 expression in the cerebral cortex, and FGF-2 expression in the hippocampus. Moreover, duloxetine reduced Bax and p53 expression in the hippocampus, and Bad expression in the cerebral cortex. Mirtazapine decreased Bcl-xL and Bax expression in the hippocampus, and Bad and p53 expression in both the hippocampus and cerebral cortex. Mirtazapine also increased the expression of neurotrophins, NGF and NT-3, in the cerebral cortex. These results suggest that duloxetine and mirtazapine could elicit their therapeutic effect by modulating the activity of apoptotic and neurotrophic pathways, thus enhancing plasticity and cell survival in depressive patients.
Translation - Cymbalta increased production of BDNF (brain-derived neurotrophic factor). BDNF acts on certain neurons of the central nervous system and the peripheral nervous system, helping to support the survival of existing neurons, and encourage the growth and differentiation of new neurons and synapses. In the brain, it is active in the hippocampus, cortex, and basal forebrain—areas vital to learning, memory, and higher thinking. It is also expressed in the retina, motor neurons, the kidneys, saliva, and the prostate. Cymbalta increases the production of one protein for apotosis (cell death), 2 for cell growth and survival and one cell membrane protein in the cerebral cortex. In addition it increases the protein for cell membranes in the hippocampus. Cymbalta decreases a protein antigen used to fight cellular tumors and 2 proteins used to promote cell death.
Document #12
https://www.ncbi.nlm...pubmed/23010381
Pharmacol Biochem Behav. 2012 Dec;103(2):408-17. doi: 10.1016/j.pbb.2012.09.011. Epub 2012 Sep 23.
The role of the NMDA receptors and l-arginine-nitric oxide-cyclic guanosine monophosphate pathway in the antidepressant-like effect of duloxetine in the forced swimming test.
Zomkowski AD1, Engel D, Cunha MP, Gabilan NH, Rodrigues AL.
Abstract
Duloxetine is a selective serotonin and noradrenaline reuptake inhibitor used as antidepressant. However, its mechanisms of action are not fully understood. This study investigated the effect of duloxetine in the mouse forced swimming test (FST) and in the tail suspension test (TST) and the involvement of the NMDA receptors and the l-arginine-NO-cGMP pathway in its effect in the FST. Duloxetine reduced the immobility time both in the FST and in the TST (dose range of 1-30mg/kg, i.p.), without changing locomotion in an open-field. Duloxetine administered orally (1-30mg/kg) also reduced the immobility time in the FST. The effect of duloxetine (10mg/kg, p.o.) in the FST was prevented by pre-treatment with NMDA (0.1pmol/site, i.c.v.), d-serine (30μg/site, i.c.v.), (l-arginine (750mg/kg, i.p.), S-nitroso-N-acetyl-penicillamine (SNAP, 25μg/site, i.c.v) or sildenafil (5mg/kg, i.p.). The administration of MK-801 (0.001mg/kg, i.p.), 7-nitroindazole (50mg/kg, i.p.), methylene blue (20mg/kg, i.p.) or 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ) (30pmol/site i.c.v.) in combination with a sub-effective dose of duloxetine (0.3mg/kg, p.o.) reduced the immobility time in the FST. Moreover, the administration of duloxetine (10mg/kg) produced a reduction in NOx levels in the hippocampus and cerebral cortex. Altogether the results suggest that the effect of duloxetine in the FST is dependent on either a blockade of NMDA receptors or an inhibition of NO. In addition, our results further reinforce the role of NMDA receptors and l-arginine-NO-cGMP pathway, besides the monoaminergic systems, in the mechanism of action of current prescribed antidepressant agents.
Translation - Cymbalta reduces nitrous oxide levels in the hippocampua and cerebral cortex. Since it was first identified to play an important role in relaxation of blood vessels, nitric oxide has been demonstrated to regulate many biological processes, especially in the central nervous system. Of the three types of enzymes that produce nitric oxide in humans and rodents, neuronal type is found almost exclusively in the nervous system. This gaseous molecule is a nonclassical neurotransmitter, which maintains the activities of neural cells and regulates the normal functions of brain. It appears to play a role in promoting the transfer of nerve signals from one neuron to another, maintaining the synaptic strength. Meanwhile, nitric oxide is a unique regulator on neurogenesis (new nerve cell production) and synaptogenesis, producing the positive or negative effects upon different signal pathways or cellular origins and locations. Based on its significant roles in neural plasticity, nitric oxide is involved in a number of central nervous diseases, such as ischemia, depression, anxiety, and Alzheimer's disease.
Document #13
https://www.ncbi.nlm...pubmed/21820879
Psychiatry Res. 2011 Nov 30;194(2):157-62. doi: 10.1016/j.pscychresns.2011.03.011. Epub 2011 Aug 6.
Duloxetine's modest short-term influences in subcortical structures of first episode drug-naïve patients with major depressive disorder and panic disorder.
Lai CH1, Wu YT.
Abstract
We developed this study to follow up the hanges in subcortical structures after 6 weeks' treatment with therapy of duloxetine in first episode drug-naïve patients with major depressive disorder and panic disorder. Fifteen patients received duloxetine 60mg/d therapy for 6 weeks and achieved remission. They all underwent structural magnetic resonance imaging (MRI) of the brain at baseline and week 6. Fifteen healthy controls were also scanned twice at baseline and week 6 to exclude possible biases. Structural MRI data were preprocessed with FMRIB's Integrated Registration and Segmentation Tool function (FIRST version 1.2) of FSL (FMRIB Software Library; version 4.1.1) to perform subcortical segmentations of the brain using a shape and appearance model. Nonparametric corrections of these structural volumes in an F-test between pre- and post-treatment were used to identify the changes after duloxetine therapy. A false discovery correction of the F-test by FIRST was also performed. A paired t-test using SPSS was applied to confirm the changes in these structures. The patients had consistent changes of volumes in bilateral nucleus accumbens, left putamen, left hippocampus and brainstem after 6 weeks of treatment with duloxetine. There were no consistent changes in other subcortical structures. There were modest increases of the volumes of the above areas, which were not significant after false discovery correction by FIRST F-test comparisons. The volumetric increases were correlated with responses of clinical symptoms. The results suggested that duloxetine possibly contributed to modest increases in several subcortical areas of these patients with remission.
Translation - Consistent changes of volumes in bilateral nucleus accumbens, a region of the forebrain, (As a whole, the nucleus accumbens has a significant role in the cognitive processing of aversion, motivation, pleasure, reward and reinforcement learning; hence, it has a significant role in addiction. It plays a lesser role in processing fear (a form of aversion), impulsivity, and the placebo effect. It is involved in the encoding of new motor programs as well.), left putamen (located at the base of the forebrain it's main function is to regulate movements and influence various types of learning. It employs GABA, acetylcholine, and enkephalin to perform its functions. The putamen also plays a role in degenerative neurological disorders, such as Parkinson's disease.), left hippocampus and brainstem after 6 weeks of treatment with duloxetine.
Document #14
https://www.ncbi.nlm...pubmed/20381469
Brain Res. 2010 Jun 23;1341:93-9. doi: 10.1016/j.brainres.2010.03.086. Epub 2010 Apr 8.
Comparison of neurogenic effects of fluoxetine, duloxetine and running in mice.
Marlatt MW1, Lucassen PJ, van Praag H.
Abstract
Hippocampal neurogenesis can be regulated by extrinsic factors, such as exercise and antidepressants. While there is evidence that the selective serotonin reuptake inhibitor (SSRI) fluoxetine enhances neurogenesis, the new dual serotonergic-noradrenergic reuptake inhibitor (SNRI) duloxetine has not been evaluated in this context. In addition, it is unclear whether effects of antidepressants and running on cell genesis and behavior are of similar magnitude in mice. Here, we assessed neurogenesis and open-field behavior in 2-month-old female C57Bl/6 mice after 28days of treatment with either fluoxetine (18mg/kg), duloxetine (2, 6 or 18mg/kg) or exercise. New cell survival, as measured by 5-bromo-2'-deoxyuridine (BrdU)-labeled cells, was enhanced by 200% in the running group only. Both running and fluoxetine, but not duloxetine, increased the percentage of new cells that became neurons. In the open-field test, animals treated with either drug spent less time in the center than controls and runners. In addition, fluoxetine treatment resulted in reduced locomotor activity. Together, these data show that the neurogenic response to exercise is much stronger than to antidepressants and imply a low likelihood that anxiolytic effects of these drugs are mediated by adult neurogenesis in C57Bl/6 mice.
Document #15
https://www.ncbi.nlm...pubmed/20159945
Mol Pharmacol. 2010 May;77(5):846-53. doi: 10.1124/mol.109.063081. Epub 2010 Feb 16.
Long-Term duloxetine treatment normalizes altered brain-derived neurotrophic factor expression in serotonin transporter knockout rats through the modulation of specific neurotrophin isoforms.
Calabrese F1, Molteni R, Cattaneo A, Macchi F, Racagni G, Gennarelli M, Ellenbroek BA, Riva MA.
Abstract
Dysfunction of the serotonergic system is implicated in the etiology of many psychiatric disorders, including major depression. Major vulnerability genes for mood disorders are also related to the serotonergic system: one of these genes encodes for the serotonin transporter (SERT), which represent a major target for the action of antidepressant drugs. We have demonstrated recently that SERT knockout (KO) rats, generated by N-ethyl-N-nitrosourea-induced mutagenesis, show reduced expression of the neurotrophin brain-derived neurotrophic factor (BDNF) in the hippocampus and prefrontal cortex, suggesting that depression vulnerability can be associated with impaired neuronal plasticity. In the present study, we demonstrate that chronic treatment with the antidepressant duloxetine (DLX) was able to normalize the expression of BDNF mRNA-coding exon (IX) in the hippocampus and prefrontal cortex of SERT KO rats through the modulation of selected neurotrophin transcripts, whose expression was up-regulated by DLX only in SERT KO rats. On the other hand, the modulation of BDNF protein by DLX in frontal cortex was abolished in mutant rats. These data suggest that animals with a genetic defect of the serotonin transporter maintain the ability to show neuroplastic changes in response to antidepressant drugs. Because these animals show depression-like behavior, the region and isoform-specific increase of BDNF levels may be a mechanism activated by long-term antidepressant treatment to restore normal plasticity that is defective under genetic dysfunction of the serotonin transporter.
Translation - Cymbalta returns BDNF to proper levels and a return of neural plasticity (the ability of the brain to change and develop through it's life).
Document #16
https://www.ncbi.nlm...pubmed/18751896
Neurochem Res. 2009 Mar;34(3):542-55. doi: 10.1007/s11064-008-9818-2. Epub 2008 Aug 27.
Brain region-specific effects of short-term treatment with duloxetine, venlafaxine, milnacipran and sertraline on monoamine metabolism in rats.
Muneoka K1, Shirayama Y, Takigawa M, Shioda S.
Abstract
We examined brain region-specific changes in monoamines and metabolites, and their ratios, after short-term administration of antidepressants to rats. Serotonin noradrenaline reuptake inhibitors (SNRIs; duloxetine, venlafaxine, milnacipran) and a serotonin-selective reuptake inhibitor (SSRI; sertraline) elevated serotonin (5-HT) levels in the midbrain (MB). Duloxetine and venlafaxine increased 5-HT levels in the brainstem and 5-HT terminal areas, whereas milnacipran and sertraline increased levels in the brainstem only. Significant reductions in 5-HT turnover were observed in various forebrain regions, including the hippocampus and hypothalamus, after treatment with all of the tested drugs except for milnacipran. In addition, there was reduced 5-HT turnover in the dorsolateral frontal cortex (dlFC), the medial prefrontal cortex (mPFC), and both the dlFC and the mPFC after treatment with duloxetine, sertraline, and venlafaxine, respectively. Venlafaxine significantly increased dopamine (DA) levels in the nucleus accumbens (NAc) and the substantia nigra and decreased DA turnover in the NAc. Similar changes were observed after treatment with duloxetine and sertraline in the NAc, whereas milnacipran increased DA levels in the mPFC. Limited increases in noradrenaline levels were detected after treatment with duloxetine, venlafaxine, or sertraline, but not after treatment with milnacipran. These results show that SNRIs and SSRIs induced region-specific monoaminergic changes after short-term treatment.
Translation - Cymbalta initially increased seratonin in the brain stem, reduced reuptake (reuse) in the hippovampus, hypothalmus and frontal cortex. Also, Cymbalta icreased dopamine levels and decreased reuptake of dopamine in the nucleus accumbens and the substantia nigra(plays an important role in reward and movement). It also caused small increases in noradrenaline.
Document #17
https://www.ncbi.nlm...pubmed/17327885
Neuropsychopharmacology. 2007 Nov;32(11):2351-9. Epub 2007 Feb 28.
Chronic duloxetine treatment induces specific changes in the expression of BDNF transcripts and in the subcellular localization of the neurotrophin protein.
Calabrese F1, Molteni R, Maj PF, Cattaneo A, Gennarelli M, Racagni G, Riva MA.
Abstract
There is growing evidence that brain-derived neurotrophic factor (BDNF) can be relevant to mood disorders and that modulation of its biosynthesis following prolonged antidepressant treatment may contribute to neuroplastic changes required for clinical response. In the present study, we investigated the effects of the novel antidepressant duloxetine on BDNF in the rat brain. Duloxetine is a serotonin-norepinephrine reuptake inhibitor that differs from other antidepressants by virtue of its balanced potency on both neurotransmitter systems. We found that chronic, but not acute, treatment with duloxetine produces a robust increase of exon V BDNF mRNA levels in frontal cortex when the animals were killed 1 or 24 h after the last administration. The expression of the neurotrophin was also increased in other cortical subregions, but not in the hippocampus. We also found that the increased expression of BDNF in frontal cortex was mainly sustained by enhanced mRNA levels for exons I and III, whereas the expression of exon IV was reduced. Protein analysis in different subcellular fractions showed that chronic treatment with duloxetine, but not with the prototypical SSRI fluoxetine, reduced mature BDNF in the cytosol, but markedly increased its levels in the crude synaptosomal fraction. Our data suggest that chronic treatment with the novel antidepressant duloxetine not only produces a marked upregulation of BDNF mRNA and protein, but may also affect the subcellular redistribution of the neurotrophin. These changes might improve synaptic plasticity and cognitive function that are defective in depressed subjects.
Translation - Chronic treatment with Cymbalta not only produces a marked increase in the function of the BDNF mRNA but also the manufacturing of BDNF itself, and may also affect the subcellular redistribution of BDNF).
Document #18
https://www.ncbi.nlm.../pubmed/9686935
Naunyn Schmiedebergs Arch Pharmacol. 1998 Jun;357(6):600-10.
Effect of long-term administration of duloxetine on the function of serotonin and noradrenaline terminals in the rat brain.
Rueter LE1, Kasamo K, de Montigny C, Blier P.
Abstract
Duloxetine, an inhibitor of both 5-hydroxytryptamine (5-HT) and noradrenaline (NA) reuptake processes, has been developed as a potential antidepressant drug. The present study was initiated to investigate the functioning of multiple components of the 5-HT and NA systems following the long-term administration of duloxetine. In rats treated for 21 days with duloxetine (20 mg/kg/day), the recovery times of dorsal hippocampus CA3 pyramidal neurons from microiontophoretic applications of 5-HT and NA were significantly increased, indicating ongoing reuptake blockade with the minipump in place delivering the drug. The remaining experiments were performed following a 48-h washout. Electrically evoked release of [3H]5-HT from preloaded slices was enhanced in the midbrain, presumably due to a desensitization of the somatodendritic 5-HT1D and 5-HT1A autoreceptors. In addition, evoked release of [3H]5-HT was increased in the hippocampus, which could have been due to the desensitization of the alpha2-adrenergic heteroreceptors located on the 5-HT terminals. In contrast, there was no change in the evoked release of [3H]5-HT in the frontal cortex despite decreased functioning of the 5-HT transporter found in this brain region. Similar to changes in 5-HT release, electrically evoked release of [3H]NA was enhanced in the hippocampus and frontal cortex of rats treated chronically with duloxetine. These increases in [3H]NA release were most likely due to the desensitization of the alpha2-adrenergic autoreceptor in the hippocampus and to the desensitization of the NA transporter in the frontal cortex, respectively. These data suggest that long-term administration of duloxetine is able to induce changes in the 5-HT and NA systems that lead to enhanced release of both 5-HT and NA in some limbic brain areas. Duloxetine, therefore, may be a useful antidepressant compound.
Translation - Demonstrated the blocking of seratonin reuptake by Cymbalta. It also increased seratonin levels in the hippocampus. Although seratonin reuptake was blocked in the frontal cortex seratonin levels remained constant. Chronic use (21 days is chronic?) showed increase release of noradrenaline in the hippocampus and frontal cortex.
Document #19
https://www.ncbi.nlm.../pubmed/9580577
J Pharmacol Exp Ther. 1998 May;285(2):404-12.
Electrophysiological characterization of the effect of long-term duloxetine administration on the rat serotonergic and noradrenergic systems.
Rueter LE1, De Montigny C, Blier P.
Abstract
Duloxetine is a dual serotonin (5-HT)/norepinephrine (NE) re-uptake blocker with antidepressant potential. In the present in vivo electrophysiological study, the changes in the function of the rat 5-HT and NE systems after 2- and 21-day administration of duloxetine (20 mg/kg/day) were assessed in the dorsal hippocampus and the dorsal raphe nucleus (DRN). The firing rate of DRN neurons was decreased after 2 days of duloxetine, but returned to the control level after 21-day administration. This recovery of firing rate was presumably due to the desensitization of the DRN somatodendritic 5-HT1A autoreceptors found after long-term duloxetine administration. Overall serotonergic tone was assessed by examining the ability of the 5-HT1A antagonist WAY 100635 to alter hippocampal firing. WAY 100635 increased hippocampal firing rates in 21-day treated rats to a greater extent than in 2-day treated or control rats, suggesting that long-term administration induced an increase in endogenous levels of 5-HT in postsynaptic regions. This increase in 5-HT levels was accompanied by selective changes in the 5-HT and NE systems induced by long-term duloxetine administration, i.e., the desensitization of the alpha-2 adrenergic heteroreceptor on 5-HT terminals and the continued blockade of the 5-HT transporters. In contrast, the sensitivity of the alpha-2 adrenergic and terminal 5-HT1B autoreceptors, as well as that of the postsynaptic 5-HT1A receptor after 21-day treatment was unchanged. Therefore, this study demonstrates that duloxetine increases serotonergic tone in a limbic forebrain structure and may therefore be effective in the treatment of depression.
Translation - Cymbalta initially increased the firing of nerve cells in the dorsal raphe nucleus (The dorsal raphe nucleus is located on the midline of the brainstem The dorsal raphe nucleus have long been implicated in depression. Some studies have suggested that the dorsal raphe may be decreased in size in people with depression and, paradoxically, an increased cell density in those who commit suicide.) but firing rates returned to normal after 21 days due to fatique in the seratonin receptors. It also increased seratonin in the forebrain.
Document #20
https://www.ncbi.nlm.../pubmed/9105878
Eur J Pharmacol. 1997 Mar 26;323(1):69-73.
Electrophysiological effects of fluoxetine and duloxetine in the dorsal raphe nucleus and hippocampus.
Smith JE1, Lakoski JM.
Abstract
The cellular electrophysiological effects of duloxetine (LY248686), a dual serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine reuptake inhibitor, and the selective serotonin reuptake inhibitor fluoxetine were compared on spontaneously active neurons in the dorsal raphe nucleus and the hippocampus of chloral hydrate-anesthetized male rat. Systemic intravenous administration of duloxetine or fluoxetine inhibited dorsal raphe nucleus cell firing in a dose-dependent manner; duloxetine suppressed cell firing at significantly lower doses (ED100 1.4 +/- 0.3 mg/kg) than fluoxetine (ED100 10.0 +/- 2.0 mg/kg). In the hippocampus, microiontophoretic application of duloxetine or fluoxetine (0.01 M, pH 5.5; 5-40 nA) produced minimal inhibition of cell firing. When duloxetine was co-applied with 5-HT, the recovery response (RT50 values) of hippocampal pyramidal neurons to 5-HT application was not altered. In contrast, co-application of fluoxetine with 5-HT at the same iontophoretic currents significantly increased (59%) the RT50 values produced by 5-HT application alone. This physiological and pharmacological study contributes to understanding the cellular mechanisms of these agents which may be useful in the treatment of depression.
Translation - Cymbalta inhibited dorsal raphe nucleus cell firing. In the hippocampus little decrease was noted in cell firing.
Document #21
https://www.ncbi.nlm.../pubmed/8613930
J Pharmacol Exp Ther. 1996 Apr;277(1):278-86.
Blockade of the serotonin and norepinephrine uptake processes by duloxetine: in vitro and in vivo studies in the rat brain.
Kasamo K1, Blier P, De Montigny C.
Abstract
In in vitro uptake experiments, duloxetine inhibited [3H]5-hydroxytryptamine (5-HT) and [3H]norepinephrine (NE) uptake in hippocampus slices of control rats with IC50 values of 28 and 46 nM, respectively. The uptake of both[3H]5-HT and [3H]NE was equipotently inhibited in hippocampus slices prepared from rats treated for 2 days with different doses of duloxetine (5, 10, 15 and 20 mg/kg/day s.c.). In in vivo electrophysiological experiments in the hippocampus, the effects of duloxetine on the suppression of CA3 pyramidal neuronal firing activity by microiontophoretically applied 5-HT and NE were examined with two modes of administration. Five successive i.v. injections (2 mg/kg each) significantly and dose-dependently prolonged the recovery time of the firing activity of hippocampus CA3 pyramidal neurons from the 5-HT applications. A 2-day treatment (10, 15 and 20 mg/kg/day s.c.) also increased the recovery time in a dose-dependent manner. Whereas the recovery time from NE applications was unaffected by low doses of duloxetine (2 mg/kg i.v.; 10 mg/kg/day for 2 days), it was prolonged significantly by higher doses (8 and 1 0 mg/kg iv.; 20 mg/kg/day for 2 days). Acute i.v. injections of duloxetine suppressed the spontaneous firing activity of dorsal raphe 5-HT and locus ceruleus NE neurons with ED50 values of 99 and 475 microgram/kg, respectively. Taken together, the present results confirmed that duloxetine is a dual 5-HT/NE uptake inhibitor. Furthermore, the results obtained in in vivo experiments indicate that duloxetine has a preferential inhibitory effect on the 5-HT transporter.
Translation - Cymbalta inhibited the reuptake of both seratonin and noradrenaline in the hippocampus. It inhibited seratonin reuptake more than noradrenaline.
Document #22
https://www.ncbi.nlm...les/PMC3413810/
J Mol Neurosci. 2012 Sep; 48(1): 167–175.
Differential BDNF Responses of Triple Versus Dual Reuptake Inhibition in Neuronal and Astrocytoma Cells as well as in Rat Hippocampus and Prefrontal Cortex
,1,2,3 Gunter Kenis,1,2 Maria S. Quinton,3 Sharon Engel,3 Larry Melnick,3 and Rudy Schreiber3,4
Abstract
Monoamine reuptake inhibitors increase brain-derived neurotrophic factor (BDNF) activity, and this growth factor is regarded as an interesting target for developing new antidepressant drugs. The aims of this study were to evaluate whether monoaminergic reuptake inhibition increases BDNF in vivo and in vitro as predicted by the neurotrophic hypothesis of depression, and whether triple reuptake inhibition has a superior BDNF response compared to dual reuptake inhibition. Twenty-one days of oral treatment (30 mg/kg) with the dual serotonin/noradrenaline reuptake inhibitor duloxetine or the triple serotonin/noradrenaline/dopamine reuptake inhibitor DOV 216,303 restored BDNF protein levels in the rat hippocampus, which were initially decreased due to injection stress. The prefrontal cortex contained increased BDNF levels only after DOV 216,303 treatment. In vitro, neither duloxetine nor DOV 216,303 altered intracellular BDNF levels in murine HT22 neuronal cells. In contrast, BDNF release was more effectively decreased following treatment with DOV 216,303 in these cells. In rat C62B astrocytomas, both antidepressants increased intracellular BDNF levels at their highest nontoxic concentration. C62B astrocytomas did not release BDNF, even after antidepressant treatment. Increased BDNF levels support the neurotrophic hypothesis of depression, but our findings do not clearly evidence that the BDNF response after triple reuptake inhibitors is more effective than after dual reuptake inhibitors. Moreover, the data suggest that the role of BDNF in neurons and astrocytes is complex and likely depends on factors including specificity of cell types in different brain regions, cell–cell interactions, and different mechanisms of action of antidepressants used.
Translation - Cymbalta returned BDNF levels to normal in the hippocampus within 21 days.
Document #23
https://www.ncbi.nlm...les/PMC3176563/
Neuropsychopharmacology. 2011 Oct; 36(11): 2266–2275.
Short-Term Duloxetine Administration Affects Neural Correlates of Mood-Congruent Memory
Indira Tendolkar,1,2,3,* Guido van Wingen,1,4,5 Maren Urner,1,6 Robbert Jan Verkes,2 and Guillén Fernández1,4
Abstract
It is unknown how antidepressants reverse mood-congruent memory bias, a cognitive core factor causing and maintaining depression. Using a double-blind, placebo-controlled, cross-over design, we investigated the effect of a short-term treatment (14 days) with the dual reuptake inhibitor duloxetine on neural correlates of mood-congruent and mood-incongruent memory formation and retrieval in healthy volunteers who underwent a sad mood induction procedure. Duloxetine did not affect acute mood state or memory performance, but interacted with brain processes mediating mood-congruent memory. It decreased activity related to successful memory formation for mood-congruent and -incongruent items in a set of brain regions comprising the putamen and the middle frontal gyrus, as well as the middle and the anterior cingulate cortex. Duloxetine specifically increased amygdala activity related to successful memory retrieval for mood-incongruent items. Here we show that short-term administration of duloxetine affects the neural correlates of emotional memory formation and retrieval in a set of brain regions whose processing is related to affective state and its regulation. While duloxetine suppressed the neural correlates of emotional memory formation in general, it specifically enhanced amygdala processes associated with mood-incongruent memory retrieval. This pattern of results shows how an antidepressant may reduce emotional memory formation and reverse mood-congruent processing biases at retrieval.
Translation - A 14 day treatment with Cymbalta decreased activities related to memory formation in the putamen, frontal gyrus and anterior cingulate cortex. On the other hand it increased memory retrieval in the amygdala.
Document #24
https://www.ncbi.nlm...les/PMC4713700/
Int J Clin Exp Pathol. 2015; 8(11): 15454–15461.
Effects of duloxetine on microRNA expression profile in frontal lobe and hippocampus in a mouse model of depression
Bing Pan,1,* Yamei Liu2,*
Abstract
Depression is a major mood disorder affecting people worldwide. The posttranscriptional gene regulation mediated by microRNAs (miRNAs) which may have critical roles in the pathogenesis of depression. However, to date, little is known about the effects of the antidepressant drug duloxetine on miRNA expression profile in chronic unpredictable mild stress (CUMS)-induced depression model in mice. Healthy adult male Kunming mice were randomly divided into three groups: control group, model group and duloxetine group. Sucrose preference test and open field test were used to represent the behavioral change. MiRNAs levels in frontal lobe and hippocampus of mice were analyzed using miRNA microarrays assay. We observed that long-term treatment with duloxetine significantly ameliorated the CUMS procedure-induced sucrose preference decreases and mice treated with duloxetine demonstrated a reversal of the number of crossings, and rearings reduced by CUMS. A significant upregulation of miR-132 and miR-18a in hippocampus in the duloxetine treatment group compared with model group, whereas the levels of miR-134 and miR-124a were significantly downregulated. Furthermore, miR-18a showed significant upregulation in frontal lobe in the duloxetine treatment group relative to model group. Our data showed that miRNA expression profile in frontal lobe and hippocampus was affected by duloxetine in mice model of depression. The effect was especially pronounced in the hippocampus, suggesting that hippocampus might be the action site of duloxetine, which presumably worked by regulating the expression of miRNA levels.
Translation- Cymbalta increased the activity of two miRNA in the hippocampus (miRNA-132 which functions to regulate the expression levels of other genes by several mechanisms, generally reducing protein levels through the cleavage of mRNAs or the repression of their translation. Several targets for miR-132 have been described, including mediators of neurological development, synaptic transmission, inflammation and angiogenesis.; and miR-18a which triggers the function of other RNA) and decreases the function of two other miRNA (miR-134 is a brain-specific microRNA localised in hippocampal neurons and indirectly regulate synaptic development and is thought to mediate Creb protein giving it a role in higher brain functions such a memory formation; and miR-124a which has been found to be the most abundant microRNA expressed in nerve cells. It can change the structure of Glutamate receptors in the prefrontal cortex.)
Document #25
https://www.ncbi.nlm...les/PMC3055320/
Neuropsychopharmacology. 2010 Oct; 35(11): 2305–2317.
Effects of Duloxetine Treatment on Brain Response to Painful Stimulation in Major Depressive Disorder
Marina López-Solà,1,2 Jesus Pujol,1,3,* Rosa Hernández-Ribas,1,4,5 Ben J Harrison,1,6 Oren Contreras-Rodríguez,1,7 Carles Soriano-Mas,1,7 Joan Deus,1,8 Héctor Ortiz,1 José M Menchón,4,5 Julio Vallejo,2,5 and Narcís Cardoner1,4,5
Abstract
Major depressive disorder (MDD) is characterized by a constellation of affective, cognitive, and somatic symptoms associated with functional abnormalities in relevant brain systems. Painful stimuli are primarily stressful and can trigger consistent responses in brain regions highly overlapping with the regions altered in MDD patients. Duloxetine has proven to be effective in treating both core emotional symptoms and somatic complaints in depression. This study aimed to assess the effects of duloxetine treatment on brain response to painful stimulation in MDD patients. A total of 13 patients and a reference group of 20 healthy subjects were assessed on three occasions (baseline, treatment week 1, and week 8) with functional magnetic resonance imaging (fMRI) during local application of painful heat stimulation. Treatment with duloxetine was associated with a significant reduction in brain responses to painful stimulation in MDD patients in regions generally showing abnormally enhanced activation at baseline. Clinical improvement was associated with pain-related activation reductions in the pregenual anterior cingulate cortex, right prefrontal cortex, and pons. Pontine changes were specifically related to clinical remission. Increased baseline activations in the right prefrontal cortex and reduced deactivations in the subgenual anterior cingulate cortex predicted treatment responders at week 8. This is the first fMRI study addressed to assess the effect of duloxetine in MDD. As a novel approach, the application of painful stimulation as a basic neural stressor proved to be effective in mapping brain response changes associated with antidepressant treatment and brain correlates of symptom improvement in regions of special relevance to MDD pathophysiology.
Translation - Cymbalta reduced pain nerve signals in the pregenual anterior cingulate cortex (It plays a role in a wide variety of autonomic functions, such as regulating blood pressure and heart rate and is involved in certain higher-level functions, such as reward anticipation, decision-making, impulse control, and emotion.), right prefrontal cortex, and pons (The pons is part of the brainstem that conduct signals from the brain down to the cerebellum and medulla, and tracts that carry the sensory signals up into the thalamus.The pons contains nuclei that relay signals from the forebrain to the cerebellum, along with nuclei that deal primarily with sleep, respiration, swallowing, bladder control, hearing, equilibrium, taste, eye movement, facial expressions, facial sensation, and posture.).
Document #26
https://www.ncbi.nlm...pubmed/25880400
2015 Apr 14;15:82. doi: 10.1186/s12888-015-0457-2.
Multimodal functional and structural neuroimaging investigation of major depressive disorder following treatment with duloxetine.
Fu CH1,2, Costafreda SG3,4, Sankar A5, Adams TM6, Rasenick MM7,8, Liu P9, Donati R10,11, Maglanoc LA12, Horton P13, Marangell LB14.
Abstract
Participants were medication-free MDD patients (n = 32; mean age 40.2 years) in an acute depressive episode and healthy controls matched for age, gender, and IQ (n = 25; mean age 38.8 years). MDD patients received treatment with duloxetine 60 mg daily for 12 weeks with an optional dose increase to 120 mg daily after 8 weeks. All participants had serial imaging at weeks 0, 1, 8, and 12 on a 3 Tesla magnetic resonance imaging (MRI) scanner. Neuroimaging tasks included emotional facial processing, negative attentional bias (emotional Stroop), resting state functional MRI and structural MRI.
RESULTS: A significant group by time interaction was identified in the anterior default mode network in which MDD patients showed increased connectivity with treatment, while there were no significant changes in healthy participants. In the emotional Stroop task, increased posterior cingulate activation in MDD patients normalized following treatment. No significant group by time effects were observed for happy or sad facial processing, including in amygdala responsiveness, or in regional cerebral volumes. Reduced baseline resting state connectivity within the orbitofrontal component of the default mode network was predictive of clinical response. An early increase in hippocampal volume was predictive of clinical response.
CONCLUSIONS: Baseline resting state functional connectivity was predictive of subsequent clinical response. Complementary effects of treatment were observed from the functional neuroimaging correlates of affective facial expressions, negative attentional bias, and resting state. No significant effects were observed in affective facial processing, while the interaction effect in negative attentional bias and individual group effects in resting state connectivity could be related to the SNRI class of antidepressant medication. The specificity of the observed effects to SNRI pharmacological treatments requires further investigation.
Translation - Cymbalta normalized activation of the posterior cingulate. Imaging studies indicate a prominent role for the posterior cingulate cortex in pain and episodic memory retrieval. Increased size of posterior ventral cingulate cortex is related to working memory decline. The posterior cingulate cortex has been implicated as a key part of several control networks. The posterior cingulate cortex has also been firmly linked to prominent emotional experiences . Thus, it has been hypothesized that the emotional importance of personal memories may contribute to the strength and consistency of activity in the posterior cingulate cortex upon successful recollection of these memories. The posterior cingulate cortex is significantly activated by emotional stimuli.
Document #27
https://www.ncbi.nlm...pubmed/21195195
Neuroimage. 2011 Mar 15;55(2):825-31. doi: 10.1016/j.neuroimage.2010.12.051. Epub 2010 Dec 30.
Subchronic duloxetine administration alters the extended amygdala circuitry in healthy individuals.
van Marle HJ1, Tendolkar I, Urner M, Verkes RJ, Fernández G, van Wingen G.
Abstract
Neuroimaging studies have consistently linked depression to hyperactivation of a (para)limbic affective processing network centered around the amygdala. Recent studies have started to investigate how antidepressant drugs affect amygdala reactivity in healthy individuals, but the influence of their subchronic administration on the functional integrity of the affective neurocircuitry as a whole remains unknown. Therefore, we used functional magnetic resonance imaging in nineteen healthy volunteers to assess the effect of two weeks of administration of the combined serotonin and norepinephrine reuptake inhibitor duloxetine (60 mg) on reactivity and functional connectivity within the affective neurocircuitry in a double-blind, placebo-controlled, crossover design. Using an emotional face matching task we demonstrated that duloxetine reduced neural responses in affect processing regions including the amygdala, the anterior insula, the thalamus and the ventral aspect of the anterior cingulate cortex. Additionally, functional coupling between the amygdala and the anterior insula was enhanced by the drug. These results suggest that duloxetine attenuates the bottom-up processing of biologically salient information in an extended amygdala circuitry, while at the same time possibly potentiating the effective communication between its subparts. Since hyperactivation of the same affective neurocircuitry is thought to underlie emotional dysfunction in depression, these results suggest a putative neural mechanism through which duloxetine could normalize typical negativity biases in depression.
Translation - Cymbalta reduced nerve responses in the amygdala, anterior insula (The insulae are believed to be involved in consciousness and play a role in diverse functions usually linked to emotion or the regulation of the body's homeostasis. These functions include perception, motor control, self-awareness, cognitive functioning, and interpersonal experience. In relation to these, it is involved in psychopathology.), thalmus (Some of its functions are the relaying of sensory and motor signals to the cerebral cortex, and the regulation of consciousness, sleep, and alertness.) and cingulate cortex. Communication between the amygdala and the anterior insula were increased.
Document #28
https://www.ncbi.nlm...les/PMC3055320/
Neuropsychopharmacology. 2010 Oct; 35(11): 2305–2317.
Effects of Duloxetine Treatment on Brain Response to Painful Stimulation in Major Depressive Disorder
Marina López-Solà,1,2 Jesus Pujol,1,3,* Rosa Hernández-Ribas,1,4,5 Ben J Harrison,1,6 Oren Contreras-Rodríguez,1,7 Carles Soriano-Mas,1,7 Joan Deus,1,8 Héctor Ortiz,1 José M Menchón,4,5 Julio Vallejo,2,5 and Narcís Cardoner1,4,5
Abstract
Major depressive disorder (MDD) is characterized by a constellation of affective, cognitive, and somatic symptoms associated with functional abnormalities in relevant brain systems. Painful stimuli are primarily stressful and can trigger consistent responses in brain regions highly overlapping with the regions altered in MDD patients. Duloxetine has proven to be effective in treating both core emotional symptoms and somatic complaints in depression. This study aimed to assess the effects of duloxetine treatment on brain response to painful stimulation in MDD patients. A total of 13 patients and a reference group of 20 healthy subjects were assessed on three occasions (baseline, treatment week 1, and week 8) with functional magnetic resonance imaging (fMRI) during local application of painful heat stimulation. Treatment with duloxetine was associated with a significant reduction in brain responses to painful stimulation in MDD patients in regions generally showing abnormally enhanced activation at baseline. Clinical improvement was associated with pain-related activation reductions in the pregenual anterior cingulate cortex, right prefrontal cortex, and pons. Pontine changes were specifically related to clinical remission. Increased baseline activations in the right prefrontal cortex and reduced deactivations in the subgenual anterior cingulate cortex predicted treatment responders at week 8. This is the first fMRI study addressed to assess the effect of duloxetine in MDD. As a novel approach, the application of painful stimulation as a basic neural stressor proved to be effective in mapping brain response changes associated with antidepressant treatment and brain correlates of symptom improvement in regions of special relevance to MDD pathophysiology.
Translation - Cymblta reducted pain perception the pregenual anterior cingulate cortex, right prefrontal cortex, and pons.
Document #29
https://www.ncbi.nlm...pubmed/23507186
Psychoneuroendocrinology. 2013 Sep;38(9):1824-8. doi: 10.1016/j.psyneuen.2013.02.009. Epub 2013 Mar 16.
NGF serum levels variations in major depressed patients receiving duloxetine.
Martino M1, Rocchi G, Escelsior A, Contini P, Colicchio S, de Berardis D, Amore M, Fornaro P, Fornaro M.
Abstract
Nerve growth factor (NGF) is involved in the modulation of the neuro-endocrine-immune (NEI) system, whereas alterations in neuroplasticity and NEI homeostasis seem to play a role in the pathophysiology of major depressive disorder (MDD). Objective of the study was to investigate NGF levels variations in MDD patients during antidepressant treatment with duloxetine, a relatively newer SNRI.
METHODS: 30 MDD patients and 32 healthy controls were assessed using Hamilton depression scale (HAM-D) and monitored for NGF serum levels at baseline, week 6 and week 12 of duloxetine treatment (60 mg/day) and at baseline, respectively.
RESULTS: According to early clinical response to duloxetine (defined at week 6 by reduction >50% of baseline HAM-D score), MDD patients were distinguished in early responders (ER) and early non-responders (ENR), who overall reached clinical response at week 12. Laboratory analysis showed overall significant lower baseline NGF levels among depressed patients compared to healthy controls, not significantly in ER and significantly in ENR. During duloxetine treatment NGF levels further decreased in association with clinical response, reaching significantly lower values in ER at W6 compared to controls, and in ENR at W12 compared to baseline.
CONCLUSIONS: A decrease in NGF levels during duloxetine treatment in association to clinical response could be indicative of a relative restoring of NEI stress-adaptation system, since stressors, inducing neuronal instability due to neurotrophins activity changes, permits circuitry remodeling as background in the selection of alternative adaptive behaviors. However, the lower baseline NGF levels found in MDD patients that further decrease during the treatment could represent a lower neurotrophin set point, possibly reflecting a functional impairment in stress-adaptive neuroplasticity in depressive disorders.
Translation - Nerve growth factor concentrations were lower in depressed patients. Cymbalta further lowered nerve growth factor concentrations.
Document #30
https://www.ncbi.nlm...pubmed/20305306
Neuropsychopharmacol Hung. 2010 Mar;12(1):301-7.
[The effects of duloxetine on beta-actin stress response in rat brain].
Szücs S1, Pákáski M, Domokos A, Kálmán J Jr, Kálmán S, Garab D, Penke B, Szabó G, Janka Z, Kálmán J.
Abstract
Depression is a frequent prodromal symptom of Alzheimer's disease (AD). Stress factors play an important role in the etiopathology of both diseases, since increased corticosteroid levels caused by chronic stress indirectly induce neuronal damage. The aim of our experiments was to evaluate the changes induced by stress in the transcription of amyloid precursor protein (APP), mitogen activated protein kinase-1 (MAPK-1) and beta-actin, of which the latest plays a leading role in synaptic plasticity. Additionally we intended to examine how duloxetine - a serotonin-norepinephrin reuptake inhibitor type antidepressant - would modify the stress-induced changes. Wistar rats were exposed to immobilization stress for five hours daily through 21 days, while part of the animals received 45 mg/bwkg of duloxetine. At the end of the third week total RNA was purified from the cortex and hippocampus. The amount of beta-actin, APP and MAPK-1 mRNA was determined by real time PCR method. On protein level, semiquantitative measurement was performed by Western blot. The expression of beta-actin mRNA in the animals exposed to stress was four times as intense as in the control group. The increase in the beta-actin mRNA levels was repressed by the duloxetine treatment. In the case of APP and MAPK-1 no changes were detected. According to the Western blot results, the antidepressant treatment slightly, the drug along with the stress treatment strongly decreased the amount of the beta-actin protein. Our findings indicate that antidepressant treatment with duloxetine could play a protective role against the chronic stress-induced changes in the nervous system, such as disorders of synaptic plasticity, and the consequent cognitive dysfunctions in case of both affective disorders and AD.
Translation- Stress increases activity of the beta-actin mRNA (major part of muscle contractions) and Cymbalta decreased the activity of the beta-actin mRNA
Document #31
https://www.ncbi.nlm...pubmed/19020498
Neuropsychopharmacology. 2009 May;34(6):1523-32. doi: 10.1038/npp.2008.208. Epub 2008 Nov 19.
Acute stress responsiveness of the neurotrophin BDNF in the rat hippocampus is modulated by chronic treatment with the antidepressant duloxetine.
Molteni R1, Calabrese F, Cattaneo A, Mancini M, Gennarelli M, Racagni G, Riva MA.
Abstract
Compelling evidence suggests that mood disorders are characterized by reduced neuronal plasticity that might be normalized by pharmacological intervention. Our study aimed to establish whether chronic antidepressant treatment could alter the modulation of the neurotrophin brain-derived neurotrophic factor (BDNF) under a stressful condition. Therefore, adult male Sprague-Dawley rats were treated for 21 days with vehicle or with the SNRI duloxetine and, 24 h after the last injection, exposed to an acute swim stress (5 min) before being killed 15 min later. We found that chronic duloxetine treatment was able to modulate the rapid transcriptional changes of BDNF isoforms produced by an acute swim stress. Indeed whereas the mRNA levels of BDNF exon IV were upregulated by stress in vehicle as well as in duloxetine-treated rats, a significant increase of exon VI and exon IX was only found in rats that were pretreated with the antidepressant. These differential effects are in part because of selective changes in signaling pathways involved in the control of BDNF transcription. Moreover, the acute stressful episode significantly increased the levels of mature BDNF protein in the synaptosomal compartment in rats that were pretreated with the antidepressant, but not in control animals. Our results suggest that chronic antidepressant treatment might affect the responsiveness of BDNF under stressful conditions, suggesting that pharmacological intervention could 'prime' neuroprotective pathways and render them more responsive to preserve cell function and viability.
Translation - Stress increases BDNF concentration but Cymbalta treatment decreased the concentration. Pretreatment with Cymbalta had the opposite effect.
Document #32
https://www.ncbi.nlm...pubmed/18704370
Psychopharmacology (Berl). 2008 Dec;201(2):285-92. doi: 10.1007/s00213-008-1276-7. Epub 2008 Aug 14.
Basal and stress-induced modulation of activity-regulated cytoskeletal associated protein (Arc) in the rat brain following duloxetine treatment.
Molteni R1, Calabrese F, Mancini M, Racagni G, Riva MA.
Abstract
RATIONALE: Therapeutic efficacy of antidepressant drugs appears to be related to their ability in producing neuroadaptive changes that restore normal brain function. Activity-regulated cytoskeletal associated protein (Arc) is an effector immediate early gene that plays a fundamental role in activity-dependent neural plasticity in corticolimbic brain regions and has been implicated in the modulation of several functions known to be profoundly perturbed in depressive states.
OBJECTIVE: In the present study, we investigated transcriptional and translational changes of Arc in response to acute or chronic treatment with the novel antidepressant duloxetine.
RESULTS: Although a limited increase of Arc messenger RNA (mRNA) levels was found in some structures after acute antidepressant administration, a marked up-regulation of its gene expression was found after chronic treatment, primarily at the level of frontal cortex. The changes observed after prolonged duloxetine administration strongly correlates with those previously reported on brain-derived neurotrophic factor mRNA levels Calabrese et al. In addition, we found an anatomical-specific influence of chronic duloxetine on stress-dependent Arc modulation, which was limited to the frontal cortex.
CONCLUSIONS: We suggest that these neuroadaptive changes, among others, might contribute to the normalization of neuroplastic defects associated with mood disorders.
Translation - Chronic use of Cymbalta increases Arc concentrations in the frontal cortex (Arc is widely considered to be an important protein in neurobiology because of its activity regulation, localization, and utility as a marker for plastic changes in the brain. Dysfunctions in the production of Arc protein has been implicated as an important factor in understanding of various neurological conditions including: Amnesia; Alzheimer's disease; Autism spectrum disorders; and, Fragile X syndrome)
