A comprehensive model for the biochemistry of ageing, senescence and longevity.

Various models for ageing, each focussing on different biochemical and/or cellular pathways have been proposed. This has resulted in a complex and non-coherent portrayal of ageing. Here, we describe a concise and comprehensive model for the biochemistry of ageing consisting of three interacting signalling hubs.

Toward a New Model of Understanding, Preventing, and Treating Adolescent Depression Focusing on Exhaustion and Stress.

Objective: Adolescent depression is a heterogeneous disorder, with a wide variety of symptoms and inconsistent treatment response, and is not completely understood. A dysregulated stress system is a consistent finding, however, and exhaustion is a consistent trait in adolescent patients. The aim of this paper is to critically assess current hypotheses in adolescent depression research and reframe causes and treatment approaches.

New drug-strategies to tackle viral-host interactions for the treatment of influenza virus infections.

The influenza virus (IV) is a highly contagious virus causing seasonal global outbreaks affecting annually up to 20% of the world's population and leading to 250,000-500,000 deaths worldwide. Current vaccines have variable effectiveness, and, in particular during a pandemic outbreak, they are probably not available in the amounts needed to protect the world population. Therefore we need effective small molecule drugs to combat an IV infection and that can be produced, in case of pandemic, rapidly and in large quantities.

Mast cells in neuroinflammation and brain disorders.

It is well recognized that neuroinflammation is involved in the pathogenesis of various neurodegenerative diseases. Microglia and astrocytes are major pathogenic components within this process and known to respond to proinflammatory mediators released from immune cells such as mast cells. Mast cells reside in the brain and are an important source of inflammatory molecules.

A study of time- and sex-dependent effects of vortioxetine on rat sexual behavior: Possible roles of direct receptor modulation.

Treatment-related sexual dysfunction is a common side effect of antidepressants and contributes to patient non-compliance or treatment cessation. However, the multimodal antidepressant, vortioxetine, demonstrates low sexual side effects in depressed patients. To investigate the mechanisms involved, sexual behavior was assessed in male and female rats after acute, and repeated (7 and 14 days) treatment with vortioxetine, flesinoxan (a 5-HT receptor agonist), CP-94253 (a 5-HT receptor agonist), or ondansetron (a 5-HT receptor antagonist).

Tramadol: Effects on sexual behavior in male rats are mainly caused by its 5-HT reuptake blocking effects.

Tramadol is a well-known and effective analgesic. Recently it was shown that tramadol is also effective in human premature ejaculation. The inhibitory effect of tramadol on the ejaculation latency is probably due to its mechanism of action as a μ-opioid receptor agonist and noradrenaline/serotonin (5-HT) reuptake inhibitor.

The 5-HT-receptor agonist eltoprazine increases both catecholamine release in the prefrontal cortex and dopamine release in the nucleus accumbens and decreases motivation for reward and "waiting" impulsivity, but increases "stopping" impulsivity.

The 5-HT-receptor agonist eltoprazine has a behavioral drug signature that resembles that of a variety of psychostimulant drugs, despite the differences in receptor binding profile. These psychostimulants are effective in treating impulsivity disorders, most likely because they increase norepinephrine (NE) and dopamine (DA) levels in the prefrontal cortex. Both amphetamine and methylphenidate, however, also increase dopamine levels in the nucleus accumbens (NAc), which has a significant role in motivation, pleasure, and reward.

Vilazodone does not inhibit sexual behavior in male rats in contrast to paroxetine: A role for 5-HT1A receptors?

Vilazodone (VLZ) is a selective serotonin reuptake inhibitor (SSRI) and 5-HT1A receptor partial agonist approved for the treatment of major depressive disorder in adults. In preclinical studies, VLZ had significantly lower sexual side effects than SSRIs and reduced serotonin transporter (SERT) levels in forebrain regions. In the current study, once-daily paroxetine (PAR, 10 mg/kg), VLZ (10 mg/kg), PAR + buspirone (BUS, 3 mg/kg; a 5-HT1A partial agonist), or vehicle (VEH) was administered to male rats for 2 weeks then switched for 7 days (eg, PAR switched to VLZ, PAR + BUS, or VEH).

Differential effects of vilazodone versus citalopram and paroxetine on sexual behaviors and serotonin transporter and receptors in male rats.

Rationale: Sexual side effects are commonly associated with selective serotonin reuptake inhibitor (SSRI) treatment. Some evidence suggest that activation of 5-HT1A receptors attenuates SSRI-induced sexual dysfunction.

Objective: This study in male rats compared the effects of vilazodone, an antidepressant with SSRI and 5-HT1A receptor partial agonist activity, with other prototypical SSRIs (citalopram and paroxetine) on sexual behaviors and 5-HT receptors (5-HT1A and 5-HT2A) and transporter (5-HTT) levels in select forebrain regions of the limbic system using quantitative autoradiography.

The many different faces of major depression: it is time for personalized medicine.

First line antidepressants are the so-called SSRIs (selective serotonin reuptake inhibitors), e.g. fluvoxamine, fluoxetine, sertraline, paroxetine and escitalopram.

Food restriction does not relieve PTSD-like anxiety.

We used the inescapable foot shock paradigm (IFS) in rats as an animal model for post-traumatic stress disorder (PTSD). Previously we showed that exercise reversed the enhanced stress sensitivity induced by IFS. From literature it is known that food restriction has antidepressant and anxiolytic effects.

The olfactory bulbectomy model in mice and rat: one story or two tails?

Olfactory bulbectomy (OBX), the surgical removal of the olfactory bulbs, lead, both in mice and rats, to a specific set of behavioral changes in social behavior, cognitive function and activity. The latter is often used as a readout measure to predict antidepressant effects of new compounds. More recently, the model is used to study neurodegeneration and the associated cognitive decline.

Dorsomedial Prefrontal Cortex Mediates the Impact of Serotonin Transporter Linked Polymorphic Region Genotype on Anticipatory Threat Reactions.

Background: Excessive anticipatory reactions to potential future adversity are observed across a range of anxiety disorders, but the neurogenetic mechanisms driving interindividual differences are largely unknown. We aimed to discover and validate a gene-brain-behavior pathway by linking presumed genetic risk for anxiety-related psychopathology, key neural activity involved in anxious anticipation, and resulting aversive emotional states.

Methods: The functional neuroanatomy of aversive anticipation was probed through functional magnetic resonance imaging in two independent samples of healthy subjects (n = 99 and n = 69), and we studied the influence of genetic variance in the serotonin transporter linked polymorphic region (5-HTTLPR).

From non-pharmacological treatments for post-traumatic stress disorder to novel therapeutic targets.

The development of new pharmacological therapies starts with target discovery. Finding new therapeutic targets for anxiety disorders is a difficult process. Most of the currently described drugs for post-traumatic stress disorder (PTSD) are based on the inhibition of serotonin reuptake.

Neuroprotective and cognitive enhancing effects of a multi-targeted food intervention in an animal model of neurodegeneration and depression.

Rising neurodegenerative and depressive disease prevalence combined with the lack of effective pharmaceutical treatments and dangerous side effects, has created an urgent need for the development of effective therapies. Considering that these disorders are multifactorial in origin, treatments designed to interfere at different mechanistic levels may be more effective than the traditional single-targeted pharmacological concepts. To that end, an experimental diet composed of zinc, melatonin, curcumin, piperine, eicosapentaenoic acid (EPA, 20:5, n-3), docosahexaenoic acid (DHA, 22:6, n-3), uridine, and choline was formulated.

Serotonin 1A receptors and sexual behavior in female rats: a review.

This review focuses on the role of serotonin and especially 5-HT₁A receptors in female rat sexual behavior. In addition, the differences and/or similarities with male rats are discussed. Overall, in both males and females 5-HT₁A receptors do not appear to be involved in sexual behavior under normal circumstances, but become very important under conditions of elevated serotonin levels.

Serotonin 1A receptors and sexual behavior in male rats: a review.

Serotonin plays an important role in male sexual behavior. Many studies have been performed on the pivotal role of 5-HT₁A receptors in sexual behavior. Overall, 5-HT₁A receptors do not appear to be involved under normal circumstances, but become very important under conditions of elevated serotonin levels in sexual behavior.

Sexual side effects of serotonergic antidepressants: mediated by inhibition of serotonin on central dopamine release?

Antidepressant-induced sexual dysfunction adversely affects the quality of life of antidepressant users and reduces compliance with treatment. Animal models provide an instructive approach for examining potential sexual side effects of novel drugs. This review discusses the stability and reproducibility of our standardized test procedure that assesses the acute, subchronic and chronic effects of psychoactive compounds in a 30 minute mating test.

Human fear acquisition deficits in relation to genetic variants of the corticotropin releasing hormone receptor 1 and the serotonin transporter.

The ability to identify predictors of aversive events allows organisms to appropriately respond to these events, and failure to acquire these fear contingencies can lead to maladaptive contextual anxiety. Recently, preclinical studies demonstrated that the corticotropin-releasing factor and serotonin systems are interactively involved in adaptive fear acquisition. Here, 150 healthy medication-free human subjects completed a cue and context fear conditioning procedure in a virtual reality environment.

Minocycline restores spatial but not fear memory in olfactory bulbectomized rats.

We investigated the effects of minocycline, a microglia suppressant, on olfactory bulbectomized (OBX) rats, a model of cognitive and behavioral impairments arising from neurodegenerative processes. Previously, we demonstrated that the major OBX-induced behavioral and cognitive impairments develop between day 3 and 7 following bulbectomy. Here we show that the onset of these cognitive changes parallel in time with signs of microglia activation (increased mRNA levels of IL-1β and CD68) in hippocampus.

Celecoxib delays cognitive decline in an animal model of neurodegeneration.

Cyclooxygenase-2 (COX-2) is thought to play a role in the pathogenesis of various neurodegenerative disorders. However, clinical trials with COX-2 inhibitors have yielded contradictory results. In the present study we investigated whether COX-2 plays a role in the behavioral and cognitive impairments seen in olfactory bulbectomized rats.

Re-exposure and environmental enrichment reveal NPY-Y1 as a possible target for post-traumatic stress disorder.

Exposure-based cognitive behavioral therapy in post-traumatic stress disorder (PTSD) patients relieves symptoms caused by fear association as well as symptoms that are not the result of associative learning. We used the inescapable foot shock model (IFS), an animal model for PTSD, to study the possible involvement of glutamate receptors, the corticotropin-releasing factor (CRF) system, and the neuropeptide Y (NPY) system in the reduction of stress sensitization following repeated re-exposure to the conditioning context. Starting one week after the IFS procedure, the rats were repeatedly re-exposed to the shock environment.

Memantine partly rescues behavioral and cognitive deficits in an animal model of neurodegeneration.

Memantine, a non-competitive NMDA receptor antagonist, is used for the treatment of Alzheimer's disease (AD) and off-label as an anti-depressant. Here we investigated possible anti-depressant, cognitive enhancing and neuroprotective effects of memantine in the olfactory bulbectomized (OBX) rat. OBX is used as a screening model for antidepressants and shows cognitive disturbances.