1,721,070 research outputs found
The current development of CNS drug research
Get PDFIn the past few years, several high profiled pharmaceutical companies have decided to shut down major
research activities within the central nervous system (CNS) area. For example, in December 2011
Novartis announced that the company is closing its neuroscience facility in Basel, Switzerland, where
Novartis is headquartered (Abbott, 2011). It follows similar moves by GlaxoSmithKline and
AstraZeneca, both based in the UK, which in 2010 announced the closure of major parts of their neuroscience
research divisions globally (Jack, Financial Times, 4 February 2010). Also companies primarily
based in the USA, Pfizer and Merck, as well as the French company Sanofi, have pulled back on research
into brain disorders. This development is still proceeding, as e.g. AstraZeneca closed their CNS/pain
centres (Fiercebiotech, press release, 2 February 2012). Several of the companies have launched smaller
new initiatives based on studies of genetics and biomarkers, but as mental disorders such as unipolar
depression impose the largest disease burden worldwide, e.g. 6.2% disability-adjusted life year of
total (WHO, 2008), and current treatments do not work particularly well for many patients, this has
obviously raised a number of concerns related to how the future developments should be carried out,
and whether the genetic approach may be sufficient. In June 2012, the International College of
Neuropsychopharmacology (http://www.cinp.org) hosted an international workshop in order to discuss
and consider the consequences and implications of the withdrawal of these research activities. This
paper presents the problem background together with a summary of the viewpoints of the invited speakers
and recommendations for future intervention
The Flinders sensitive line rat model of depression: 25 years and still producing
No full textApproximately 25 years have passed since the first publication suggesting the Flinders sensitive line (FSL) rat as an animal model of depression. At least 6 years of research on these rats was completed before that seminal paper, and there has been a steady stream of publications (130+) over the years. The present review will focus on several issues not previously covered in earlier reviews, summarize the several lines of ongoing investigations, and propose a novel mechanism that accounts for a number of previously unexplained observations. A key observation in the FSL rat relates to the antidepressant (AD)-like effects of known and putative antidepressants. The FSL rat typically exhibits an AD-like effect in behavioral tests for AD-like activity following chronic (14 days) treatment, although some studies have found AD-like effects after fewer days of treatment. In other observations, exaggerated swim test immobility in the FSL rat has been found to have a maternal influence, as shown by cross-fostering studies and observations of maternal behavior; the implications of this finding are still to be determined. Ongoing or recently completed studies have been performed in the laboratories of Marko Diksic of Canada, Aleksander Mathé of Sweden, Gregers Wegener of Denmark, Brian Harvey of South Africa, Paul Pilowsky and Rod Irvine of Australia, and Gal Yadid of Israel. Jennifer Loftis of Portland, Oregon, and Lynette Daws of San Antonio, Texas, have been working with the FSL rats in the United States. A puzzling feature of the FSL rat is its sensitivity to multiple chemicals, and its greater sensitivity to a variety of drugs with different mechanisms of action. It has been recently shown that each of these drugs feeds through G protein–coupled receptors to potassium-gated channels. Thus, an abnormality in the potassium channel could underlie the depressed-like behavior of the FSL rats.This research was supported by The Danish Medical Research Council (Grant 11-107897), the Lundbeck Foundation, and Aarhus
University Research Foundation (AU-IDEAS) (to G.W.)
Antidepressant efficacy of high and low frequency transcranial magnetic stimulation in the FSL/FRL genetic rat model of depression
No full textRepetitive Magnetic Stimulation (rTMS) has appeared to be a potential non-invasive antidepressant method, which implies non-convulsive focal stimulation of the brain through a time varying magnetic field. The antidepressant potential of rTMS has been supported by animal studies showing a number of interesting similarities between magnetic stimulation and electroconvulsive stimulation (ECS). Despite these positive results, this method still contains many unknown issues. Importantly, there are fundamental uncertainties concerning the optimal combination of stimulus parameters (frequency, intensity, duration, and number of pulses) to obtain an antidepressant effect. Therefore, the present study aimed to qualify the choice of rTMS stimulus frequency in a well-validated genetic animal model of depression, the FSL/FRL rats. We compared the antidepressant effect of low frequency, high frequency rTMS and ECS to sham treatment in FRL and FSL rats using 6 parallel groups. We used the Forced Swim Test and the Open Field Test to screen the depression-like state in rats. We found that both the high frequency and the low frequency rTMS resulted in a significant antidepressant effect. However, this effect was inferior to the effect of ECS. The low frequency and high frequency groups, which received the same total impulse load and stimulus intensity, did not differ with respect to antidepressant efficacy in this study. In conclusion, this study provides robust evidence that both rTMS interventions are efficacious, although not as efficient as EC
Discovery versus implementation research on mental disorders in low- and middle-income countries
No full textThe 10/90 research gap refers to the fact that only
10% of the world’s research resources are spent in lowand
middle-income countries (LMICs) although 90%
of preventable deaths occur in these regions: similar
disparities also exist in mental health research (1).
A number of efforts have been made to address the
mental health research gap, including establishment
of priorities and funding for global mental health
research (2)
A critical role of mitochondria in BDNF-associated synaptic plasticity after one-week vortioxetine treatment
Get PDFBackground
Preclinical studies have indicated that antidepressant effect of vortioxetine involves increased synaptic plasticity and promotion of spine maturation. Mitochondria dysfunction may contribute to the pathophysiological basis of major depressive disorder. Taking into consideration that vortioxetine increases spine number and dendritic branching in hippocampus CA1 faster than fluoxetine, we hypothesize that new spines induced by vortioxetine can rapidly form functional synapses by mitochondrial support, accompanied by increased brain-derived neurotrophic factor signaling.
Methods
Rats were treated for 1 week with vortioxetine or fluoxetine at pharmacologically relevant doses. Number of synapses and mitochondria in hippocampus CA1 were quantified by electron microscopy. Brain-derived neurotrophic factor protein levels were visualized with immunohistochemistry. Gene and protein expression of synapse and mitochondria-related markers were investigated with real-time quantitative polymerase chain reaction and immunoblotting.
Results
Vortioxetine increased number of synapses and mitochondria significantly, whereas fluoxetine had no effect after 1-week dosing. BDNF levels in hippocampus DG and CA1 were significantly higher after vortioxetine treatment. Gene expression levels of Rac1 after vortioxetine treatment were significantly increased. There was a tendency towards increased gene expression levels of Drp1 and protein levels of Rac1. However, both gene and protein levels of c-Fos were significantly decreased. Furthermore, there was a significant positive correlation between BDNF levels and mitochondria and synapse numbers.
Conclusion
Our results imply that mitochondria play a critical role in synaptic plasticity accompanied by increased BDNF levels. Rapid changes in BDNF levels and synaptic/mitochondria plasticity of hippocampus following vortioxetine compared with fluoxetine may be ascribed to vortioxetine’s modulation of serotonin receptor
GLP-1 receptor agonists have a sustained stimulatory effect on corticosterone release after chronic treatment
No full textObjective: Glucagon-like peptide 1 (GLP-1) receptor agonists are a new
group of antidiabetic medications quickly gaining popularity. We aimed to
examine behavioural and neuroendocrine changes following chronic
treatment with GLP-1 receptor agonists in animal models.
Methods: The effects of chronic treatment with GLP-1 receptor agonists
were determined on behavioural parameters [anxiety level in the light–dark
compartment test, the motor activity in automated activity cages,
immobility in the forced swimming test (FST)] and on corticosterone
release in mice. The possible antidepressant effect of chronic liraglutide
treatment was also studied in Flinders Sensitive Line (FSL) rats, a genetic
model of depression.
Results: Two weeks of treatment with exenatide (10 μg /kg twice daily) or
liraglutide (1200 μg/kg once daily) did not affect the anxiety level in a
light–dark compartment test nor induce an antidepressant-like effect in the
FST in mice. Moreover, chronic treatment with liraglutide had no effect on
depression-related behaviour in FSL rats. Interestingly, hypolocomotion
induced by the drugs in mice disappeared after chronic dosing. Both of the
GLP-1 receptor agonists induced robust increases in corticosterone levels
in mice under basal conditions as well as in the case of combination with
swimming stress. Remarkably, exenatide was as potent a stimulator of
corticosterone release after 2 weeks as after acute administration.
Conclusions: The increases in corticosterone release seen after acute
exenatide or liraglutide treatment do not abate after 2 weeks of treatment
demonstrating that tolerance does not develop towards this particular effect
of GLP-1 agonistsEstonian Science Foundation (grant 8324); Estonian
Ministry of Education and Research (SF 0180148s08);
Estonian Research Council (IUT-20-41); European Regional Development Fund; Aarhus University
Research Foundation and Danish Medical Research
Counci
Structural plasticity and molecular markers in hippocampus of male rats after acute stress
No full textStress plays a crucial role in the pathogenesis of psychiatric disorders and affects neuronal plasticity in different brain regions. We have previously found that acute foot-shock (FS) stress elicits fast and long-lasting functional and morphological remodeling of excitatory neurons in the prefrontal cortex (PFC), which were partly prevented by the pretreatment with antidepressants. Here we investigated, whether acute stress and pretreatment with desipramine (DMI) interfere in hippocampal dendritic remodeling. Male Sprague-Dawley rats were subjected to acute FS-stress, followed by measurement of time-dependent (1, 7 and 14 days) structural plasticity (dendritic arborization, spine number and morphology) in hippocampal CA1 pyramidal neurons and expression patterns of molecular markers implicated in neuronal plasticity. We found that acute stress significantly decreased spine number, dendritic length, and altered spine morphometric parameters at all time points evaluated after stress. This was paralleled by changes in the gene expression of Spinophilin and Cdc42, and protein expression of homer1. Pretreatment with DMI prevented the stress-induced dendritic atrophy and spine loss 14 days after acute FS. However, DMI treatment without stress differentially affected the expression patterns of spine-related genes and proteins. In conclusion, acute FS-stress and pretreatment with DMI significantly changed dendritic morphology, including number and morphology of spines, and the length of dendrites in hippocampal CA1 pyramidal cells as early as 1 day, and sustained up to 14 days after acute FS. The findings were paralleled by changes in gene and protein expression of actin binding and cytoskeletal proteins, Rho GTPases, and postsynaptic scaffolding protein
S-ketamine rapidly reverses synaptic and vascular deficits of hippocampus in genetic animal model of depression
Get PDFBackground:
The neurovascular plasticity of hippocampus is an important theory underlying major depression. Ketamine as a novel glutamatergic antidepressant drug can induce a rapid antidepressant effect within hours. In a mechanistic proof of this concept, we examined whether ketamine leads to an increase in synaptogenesis and vascularization within 24 hours after a single injection in a genetic rat model of depression.
Methods:
Flinders Sensitive Line and Flinders Resistant Line rats were given a single intraperitoneal injection of ketamine (15 mg/kg) or saline. One day later, their behavior was evaluated by a modified forced swim test. Microvessel length was evaluated with global spatial sampling and optical microscopy, whereas the number of asymmetric synapses was quantified through serial section electron microscopy by using physical disector method in the CA1.stratum radiatum area of hippocampus.
Results:
The immobility time in the forced swim test among Flinders Sensitive Line rats with ketamine treatment was significantly lower compared with Flinders Sensitive Line rats without treatment. The number of nonperforated and perforated synapses was significantly higher in the Flinders Sensitive Line-ketamine vs the Flinders Sensitive Line-vehicle group; however, ketamine did not induce a significant increase in the number of shaft synapses. Additionally, total length of microvessels was significantly increased 1 day after ketamine treatment in Flinders Sensitive Line rats in the hippocampal subregions, including the CA1.stratum radiatum.
Conclusion:
Our findings indicate that hippocampal vascularization and synaptogenesis is co-regulated rapidly after ketamine, and microvascular elongation may be a supportive factor for synaptic plasticity and neuronal activity. These findings go hand-in-hand with the behavioral observations, where ketamine acts as a potent antidepressan
Chronic mild stress induces anhedonic behavior and changes in glutamate release, BDNF trafficking and dendrite morphology only in stress vulnerable rats. The rapid restorative action of ketamine
Get PDFDepression is a debilitating mental disease, characterized by persistent low mood and anhedonia. Stress represents a major environmental risk factor for depression; the complex interaction of stress with genetic factors results in different individual vulnerability or resilience to the disorder. Dysfunctions of the glutamate system have a primary role in depression. Clinical neuroimaging studies have consistently reported alterations in volume and connectivity of cortico-limbic areas, where glutamate neurons and synapses predominate. This is confirmed by preclinical studies in rodents, showing that repeated stress induces morphological and functional maladaptive changes in the same brain regions altered in humans. Confirming the key role of glutamatergic transmission in depression, compelling evidence has shown that the non-competitive NMDA receptor antagonist, ketamine, induces, at sub-anesthetic dose, rapid and sustained antidepressant response in both humans and rodents.
We show here that the Chronic Mild Stress model of depression induces, only in stress-vulnerable rats, depressed-like anhedonic behavior, together with impairment of glutamate/GABA presynaptic release, BDNF mRNA trafficking in dendrites and dendritic morphology in hippocampus. Moreover, we show that a single administration of ketamine restores, in 24 h, normal behavior and most of the cellular/molecular maladaptive changes in vulnerable rats. Interestingly, ketamine treatment did not restore BDNF mRNA levels reduced by chronic stress but rescued dendritic trafficking of BDNF mRNA.
The present results are consistent with a mechanism of ketamine involving rapid restoration of synaptic homeostasis, through re-equilibration of glutamate/GABA release and dendritic BDNF for synaptic translation and reversal of synaptic and circuitry impairmen
Vortioxetine promotes early changes in dendritic morphology compared to fluoxetine in rat hippocampus
No full textPreclinical studies reveal that the multimodal antidepressant vortioxetine enhances long-term potentiation and dendritic branching compared to a selective serotonin reuptake inhibitor (SSRI). In the present study, we investigated vortioxetine׳s effects on spines and dendritic morphology in rat hippocampus at two time points compared to the SSRI, fluoxetine.
Rats were dosed for 1 and 4 weeks with vortioxetine and fluoxetine at doses relevant for antidepressant activity. Dendritic morphology of pyramidal neurons (i.e., dendritic length, dendritic branch, spine number and density, and Sholl analysis) was examined in Golgi-stained sections from hippocampal CA1.
After 1 week of treatment, vortioxetine significantly increased spine number (apical and basal dendrites), spine density (only basal), dendritic length (only apical), and dendritic branch number (apical and basal), whereas fluoxetine had no effect. After 4 weeks of treatment, vortioxetine significantly increased all measures of dendritic spine morphology as did fluoxetine except for spine density of basal dendrites. The number of intersections in the apical and basal dendrites was also significantly increased for both treatments after 4 weeks compared to control. In addition, 4 weeks of vortioxetine treatment, but not fluoxetine, promoted a decrease in spine neck length.
In conclusion, 1-week vortioxetine treatment induced changes in spine number and density and dendritic morphology, whereas an equivalent dose of fluoxetine had no effects. Decreased spine neck length following 4-week vortioxetine treatment suggests a transition to mature spine morphology. This implies that vortioxetine׳s effects on spine and dendritic morphology are mediated by mechanisms that go beyond serotonin reuptake inhibitio
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