Increased Serotonin Turnover Research Articles

Behavioral and Neurochemical Effects of Extra Virgin Olive Oil Total Phenolic Content and Sideritis Extract in Female Mice

The aim of this study was to determine the cognitive and behavioral effects of extra virgin olive oil total phenolic content (TPC) and Sideritis (SID) extracts in female mice, and identify the associated neurochemical changes in the hippocampus and the prefrontal cortex. All animals received intraperitoneal low or high doses of TPC, SID or vehicle treatment for 7 days and were subjected to the Open Field (OF), Novel Object Recognition (NOR) and Tail Suspension Test (TST). The prefrontal cortex and hippocampus were dissected for analysis of neurotransmitters and aminoacids with high performance liquid chromatography with electrochemical detection (HPLC-ED). Both TPC doses enhanced vertical activity and center entries in the OF, which could indicate an anxiolytic-like effect. In addition, TPC enhanced non-spatial working memory and, in high doses, exerted antidepressant effects. On the other hand, high SID doses remarkably decreased the animals’ overall activity. Locomotor and exploratory activities were closely associated with cortical increases in serotonin turnover induced by both treatments. Cognitive performance was linked to glutamate level changes. Furthermore, TPC reduced cortical taurine levels, while SID reduced cortical aspartate levels. TPC seems to have promising cognitive, anxiolytic and antidepressant effects, whereas SID has sedative effects in high doses. Both extracts act in the brain, but their specific actions and properties merit further exploration.

Sex-Specific Effects of Early Life Stress on Brain Mitochondrial Function, Monoamine Levels and Neuroinflammation.

Sex differences have been reported in the susceptibility to early life stress and its neurobiological correlates in humans and experimental animals. However, most of the current research with animal models of early stress has been performed mainly in males. In the present study, prolonged maternal separation (MS) paradigm was applied as an animal model to resemble the effects of adverse early experiences in male and female rats. Regional brain mitochondrial function, monoaminergic activity, and neuroinflammation were evaluated as adults. Mitochondrial energy metabolism was greatly decreased in MS females as compared with MS males in the prefrontal cortex, dorsal hippocampus, and the nucleus accumbens shell. In addition, MS males had lower serotonin levels and increased serotonin turnover in the prefrontal cortex and the hippocampus. However, MS females showed increased dopamine turnover in the prefrontal cortex and increased norepinephrine turnover in the striatum, but decreased dopamine turnover in the hippocampus. Sex differences were also found for pro-inflammatory cytokine levels, with increased levels of TNF-α and IL-6 in the prefrontal cortex and hippocampus of MS males, and increased IL-6 levels in the striatum of MS females. These results evidence the complex sex- and brain region-specific long-term consequences of early life stress.

Gut-brain axis serotonergic responses to acute stress exposure are microbiome-dependent.

Understanding the mechanisms underpinning the response to acute stress is critical for determining how this can be modulated in both health and disease and across sexes. Stress can markedly alter the microbiome and gut-brain axis signaling with the serotonergic system being particularly sensitive to acute stress. As the impact of acute stress on regional serotonergic dynamics in the gut-brain axis and the contribution of the microbiome to this are poorly appreciated, we used microbiota-deficient mice to assess whether the serotonergic response to acute stress exposure is microbiome dependent. Adult male and female conventional, germ-free, and colonized germ-free mice underwent a single acute stressor and samples were harvested immediately or 45minutes following stress. Serotonin and related metabolites and serotonergic gene expression were determined. Our data clearly show the microbiota influenced gastrointestinal serotonergic response to acute stress in a sex- and region-dependent manner. Male-specific poststress increases in colonic serotonin were absent in germ-free mice but normalized following colonization. mRNA serotonergic gene expression was differentially expressed in colon and ileum of germ-free mice on a sex-dependent basis. Within the frontal cortex, absence of the microbiome altered basal serotonin, its main metabolite 5-hydroxyindoleacetic acid, and prevented stress-induced increases in serotonin turnover. The gut microbiome influences the set points of the brain and gastrointestinal serotonergic systems and affected their response to acute stress in a sex- and region-dependent manner.

The zebrafish tail immobilization (ZTI) test as a new tool to assess stress-related behavior and a potential screen for drugs affecting despair-like states

BackgroundAffective disorders, especially depression and anxiety, are highly prevalent, debilitating mental illnesses. Animal experimental models are a valuable tool in translational affective neuroscience research. A hallmark phenotype of clinical and experimental depression, the learned helplessness, has become a key target for 'behavioral despair'-based animal models of depression. The zebrafish (Danio rerio) has recently emerged as a promising novel organism for affective disease modeling and CNS drug screening. Despite being widely used to assess stress and anxiety-like behaviors, there are presently no clear-cut despair-like models in zebrafish. New MethodHere, we introduce a novel behavioral paradigm, the zebrafish tail immobilization (ZTI) test, as a potential tool to assess zebrafish despair-like behavior. Conceptually similar to rodent 'despair' models, the ZTI protocol involves immobilizing the caudal half of the fish body for 5 min, leaving the cranial part to move freely, suspended vertically in a small beaker with water. ResultsTo validate this model, we used exposure to low-voltage electric shock, alarm pheromone, selected antidepressants (sertraline and amitriptyline) and an anxiolytic drug benzodiazepine (phenazepam), assessing the number of mobility episodes, time spent 'moving', total distance moved and other activity measures of the cranial part of the body, using video-tracking. Both electric shock and alarm pheromone decreased zebrafish activity in this test, antidepressants increased it, and phenazepam was inactive. Furthermore, a 5-min ZTI exposure increased serotonin turnover, elevating the 5-hydroxyindoleacetic acid/serotonin ratio in zebrafish brain, while electric shock prior to ZTI elevated both this and the 3,4-dihydroxyphenylacetic acid/dopamine ratios. In contrast, preexposure to antidepressants sertraline and amitriptyline lowered both ratios, compared to the ZTI test-exposed fish. Comparison with ExistingMethod(s)The ZTI test is the first despair-like experimental model in zebrafish. ConclusionsCollectively, this study suggests the ZTI test as a potentially useful protocol to assess stress-/despair-related behaviors, potentially relevant to CNS drug screening and behavioral phenotyping of zebrafish.

The new diagnostic test for dystonia

Dystonia is the debilitating movement disorder of central nervous system, often inherited, appearing as involuntary movements that occur due to deficiency or excess of neurotransmitters. The penetrance of dystonia is 30%, which means, that inherited dystonia is manifested only in 30% of mutating gene carriers, while the rest suffer from latent forms, so called forms frustes of this disorder. Until now only few mutations responsible for dystonia, had been unveiled, but we expect to exist up to 100 such mutations. Unless we uncover all mutations responsible for dystonia, we require reliable test for diagnosing latent forms of dystonia; and this necessity explains the importance of present study. The purpose of this research was to elaborate discrimination of dystonia on the basis of biogenic amines exchange peculiarities. The study presents the observational case control study. The control group was randomly composed of those patients, who were checked for neuroglial tumors. We checked catecholamines and serotonin metabolites in plasma and urine of 12 dystonia patients main group by means of chromatography method and compared the results obtained from these two groups by means of the decision tree method, discriminant analysis, and factor analysis. We revealed increased serotonin turnover in dystonia, and on the base of those increased metabolites in plasma, such as 5-hydroxytryptophane and 5-hydroxiindolacetic acid, by means of advanced statistical methods we eleborated sensitive and specific test for diagnosis of dystonia. We recommend introducing into clinical practice of diagnostic tests for dystonia on the base of analysis of diagnosing level in plasma of 5-hydroxytryptophane and 5-hydroxiindolacetic acid by means of discriminant analysis and classification tree method due to high sensitivity and high specifity of those methods.

Escalating low-dose Δ9 -tetrahydrocannabinol exposure during adolescence induces differential behavioral and neurochemical effects in male and female adult rats.

Cannabinoid administration during adolescence affects various physiological processes, such as motor and affective response, cognitive-related functions and modulates neurotransmitter activity. Literature remains scant concerning the parallel examination of the effects of adolescent escalating low-dose Δ9 -tetrahydrocannabinol (Δ9 -THC) on the behavioral and plasticity profile of adult rats in both sexes. Herein, we investigated the long-term behavioral, neurochemical and neurobiological effects of adolescent escalating low Δ9 -THC doses in adult male and female rats. In adult males, adolescent low-dose Δ9 -THC exposure led to increased spontaneous locomotor activity, impaired behavioral motor habituation and defective short-term spatial memory, paralleled with decreased BDNF protein levels in the prefrontal cortex. In this brain area, serotonergic activity was increased, as depicted by the increased serotonin turnover rate, while the opposite effect was observed in the hippocampus, a region where SERT levels were enhanced by Δ9 -THC, compared with vehicle. In adult females, adolescent Δ9 -THC treatment led to decreased spontaneous vertical activity and impaired short-term spatial memory, accompanied by increased BDNF protein levels in the prefrontal cortex. Present findings emphasize the key role of adolescent escalating low Δ9 -THC exposure in the long-term regulation of motor response, spatial-related cognitive functions and neuroplasticity indices in adulthood. In this framework, these changes could, at a translational level, contribute to clinical issues suggesting the development of psychopathology in a sex-differentiated manner following Δ9 -THC exposure during adolescence.

Immediate and long-term antidepressive-like effects of pre-pubertal escitalopram and omega-3 supplementation combination in young adult stress-sensitive rats

Major depressive disorder (MDD) affects a significant number of children and adolescents, yet treatment options for this population remain very limited. Escitalopram (ESC) is one of only two antidepressants approved as treatment for juvenile depression. Still, delayed onset of action, and immediate plus the risk of lasting side effects contribute to low patient adherence, and places the medical prescriber in a difficult situation weighing the potential long-term effects of juvenile treatment against the known consequences of untreated MDD. Research into alternative or augmentation strategies and their long-term effects are needed to improve clinical outcome and better our understanding of the long-term consequences of early-life treatment. We investigated the early-life (postnatal day 35 (PND35)) and lasting (PND60) bio-behavioural effects of pre-pubertal (PND21 to PND34) escitalopram (ESC) administration and/or ω-3 supplementation (OM3) in stress sensitive Flinders Sensitive Line rats. Only ESC treatment showed a strong trend to decrease depressive-like behaviour via significantly increased climbing behaviour on PND35. However, OM3 treatment reduced locomotor activity and increased hippocampal neuroplasticity on PND35, suggesting improved coping behaviour and masking of possible antidepressant-like effects. Reduced locomotor activity lasted into early-adulthood on PND60, despite a treatment-free period from PND35 to PND60. Regardless, early-adulthood antidepressive-like behaviour was only observed in the combination treatment (ESC + OM3) group, despite a significant increase in serotonin turnover, suggesting strong neurodevelopmental process to be involved. Taken together, the combination of ESC and OM3 might induce lasting beneficial neurodevelopmental effects in a stress-sensitive population, suggesting a possible role in current treatment strategies.

Acute effects of amitriptyline on adult zebrafish: Potential relevance to antidepressant drug screening and modeling human toxidromes

The need to develop novel antidepressants is an emerging problem in biomedicine. An aquatic vertebrate species, the zebrafish (Danio rerio) may serve as a useful in-vivo screen for CNS drugs, and displays high sensitivity to a wide range of antidepressants. Amitriptyline is a commonly used tricyclic antidepressant which acts primarily as a serotonin and noradrenaline reuptake inhibitor. Here, we characterize drug-induced behavioral and neurochemical responses in adult zebrafish following their acute exposure to amitriptyline. Overall, the drug at 1 and 5mg/L significantly increased time spent in top and shortened the latency to enter it, thereby paralleling recent reports on zebrafish ‘serotonin toxicity-like behavior’ caused by various serotonergic agents. The 10mg/L dose of the drug also significantly decreased top entries and maximal velocity and evoked overt ataxia, likely due to emerging non-specific toxic effects. Amitriptyline at 5 and 10mg/L also dose-dependently increased serotonin turnover, but not noradrenaline levels, in zebrafish whole-brain samples. Overall, zebrafish high sensitivity to acute effects of amitriptyline can help improve our understanding of psychopharmacological profiles of this compound and the related CNS drugs, and contributes further to the development of aquatic experimental models of human toxidromes.

Subchronic glucocorticoids, glutathione depletion and a postpartum model elevate monoamine oxidase a activity in the prefrontal cortex of rats

Recent human brain imaging studies implicate dysregulation of monoamine oxidase-A (MAO-A), in particular in the prefrontal cortex (PFC) and anterior cingulate cortex (ACC), in the development of major depressive disorder (MDD). This study investigates the influence of four alterations underlying important pathologies of MDD, namely, chronic elevation of glucocorticoid levels, glutathione depletion, changes in female gonadal sex hormones and serotonin concentration fluctuation, on MAO-A and MAO-B activities in rats. Young adult rats exposed chronically to the synthetic glucocorticoid dexamethasone at 0, 0.05, 0.5, and 2.0mg/kg/day (osmotic minipumps) for eight days showed significant dose-dependent increases in activities of MAO-A in PFC (+17%, p<0.001) and ACC (+9%, p<0.01) and MAO-B in PFC (+14%, p<0.001) and increased serotonin turnover in the PFC (+31%, p<0.01), not accounted for by dexamethasone-induced changes in serotonin levels, since neither serotonin depletion nor supplementation affected MAO-A activity. Sub-acute depletion of the major antioxidant glutathione by diethyl maleate (5mmol/kg, i.p.) for three days, which resulted in a 36% loss of glutathione in PFC (p=0.0005), modestly, but significantly, elevated activities of MAO-A in PFC and MAO-B in PFC, ACC and hippocampus (+6–9%, p<0.05). Changes in estrogen and progesterone representing pseudopregnancy were associated with significantly elevated MAO-A activity in the ACC day 4–7 postpartum (10–18%, p<0.05 to p<0.0001) but not the PFC or hippocampus. Hence, our study provides data in support of strategies targeting glucocorticoid and glutathione systems, as well as changes in female sex hormones for normalization of MAO-A activities and thus treatment of mood disorders.

Comments on Bozzatello et al. Supplementation with Omega-3 Fatty Acids in Psychiatric Disorders: A Review of Literature Data. J. Clin. Med. 2016, 5, 67.

Paola Bozzatello et al. [1] have done a comprehensive qualitative review of the potential use of long-chain polyunsaturated fatty acids in the prevention and treatment of mental disorders.[...].

Pharmacological Modulations of the Serotonergic System in a Cell-Model of Familial Alzheimer's Disease.

Serotonin (5-HT) plays a central role in the integrity of different brain functions. The 5-HT homeostasis is regulated by many factors, including serotonin transporter (SERT), monoamine oxidase enzyme (MAO), and several 5-HT receptors, including the 5-HT1B. There is little knowledge how the dynamics of this system is affected by the amyloid-β (Aβ) burden of Alzheimer's disease (AD) pathology. SH-SY5Y neuroblastoma cells transfected with the amyloid precursor protein (APP) gene containing the Swedish mutations causing familial AD (APPswe), were used as a model to explore the effect of Aβ pathology on 5-HT1B and related molecules including the receptor adaptor protein (p11), SERT and MAOA gene expression, and MAOA activity after treatment with selective serotonin reuptake inhibitor (SSRI) (sertraline), and a 5-HT1B receptor antagonist. Sertraline led more than 70 fold increase of 5-HT1B gene expression (p < 0.001), an increased serotonin turnover in both APPswe and control cells and reduced intracellular serotonin levels by 75% in APPswe cells but not in controls (p > 0.05). Treatment with the 5-HT1B receptor antagonist increased SERT gene-expression in control cells but not in the APPswe cells. 5-HT and 5-HT1B antagonist treatment resulted in different p11 expression patterns in APPswe cells compared to controls. Although MAOA gene expression was not changed by APPswe overexpression, adding 5-HT lead to a significant increase in MAOA gene expression in APPswe but not control cells. These findings suggest that the sensitivity of the 5-HT1B receptor and related systems is affected by APPswe overexpression, with potential relevance for pharmacologic intervention in AD. This may at least partly explain the lack of effect of SSRIs in patients with AD and depression.

Testing different paradigms to optimize antidepressant deep brain stimulation in different rat models of depression

Deep brain stimulation (DBS) of several targets induces beneficial responses in approximately 60% of patients suffering from treatment-resistant depression (TRD). The remaining 40% indicate that these stimulation sites do not bear therapeutic relevance for all TRD patients and consequently DBS-targets should be selected according to individual symptom profiles. We here used two animal models of depression known to have different genetic backgrounds and behavioral responses: the therapy-responsive Flinders sensitive line (FSL) and the therapy-refractory congenitally learned helpless rats (cLH) to study symptom-specific DBS effects i) of different brain sites ii) at different stimulation parameters, and iii) at different expressions of the disease. Sham-stimulation/DBS was applied chronic-intermittently or chronic-continuously to either the ventromedial prefrontal cortex (vmPFC, rodent equivalent to subgenual cingulate), nucleus accumbens (Nacc) or subthalamic nucleus (STN), and effects were studied on different depression-associated behaviors, i.e. anhedonia, immobility/behavioral despair and learned helplessness. Biochemical substrates of behaviorally effective versus ineffective DBS were analyzed using in-vivo microdialysis and post-mortem high-performance liquid chromatography (HPLC). We found that i) vmPFC-DBS outperforms Nacc-DBS, ii) STN-DBS increases depressive states, iii) chronic-continuous DBS does not add benefits compared to chronic-intermittent DBS, iv) DBS-efficacy depends on the disease expression modeled and iv) antidepressant DBS is associated with an increase in serotonin turnover alongside site-specific reductions in serotonin contents. The reported limited effectiveness of vmPFC DBS suggests that future research may consider the specific disease expression, investigation of different DBS-targets and alternative parameter settings.

Effects of HIV/TAT protein expression and chronic selegiline treatment on spatial memory, reversal learning and neurotransmitter levels in mice

Neurotoxic viral protein TAT may contribute to deficits in dopaminergic and cognitive function in individuals infected with human immunodeficiency virus. Transgenic mice with brain-specific doxycycline-induced TAT expression (TAT+, TAT- control) show impaired cognition. However, previously reported TAT-induced deficits in reversal learning may be compromised by initial learning deficits. We investigated the effects of TAT expression on memory retention/recall and reversal learning, and neurotransmitter function. We also investigated if TAT-induced effects can be reversed by improving dopamine function with selegiline, a monoamine oxidase inhibitor. Mice were tested in the Barnes maze and TAT expression was induced after the task acquisition. Selegiline treatment continued throughout behavioral testing. Dopamine, serotonin and glutamate tissue levels in the prefrontal/orbitofrontal cortex, hippocampus and caudate putamen were measured using high performance liquid chromatography. Neither TAT expression nor selegiline altered memory retention. On day 2 of reversal learning testing, TAT+ mice made fewer errors and used more efficient search strategies than TAT- mice. TAT expression decreased dopamine turnover in the caudate putamen, increased serotonin turnover in the hippocampus and tended to increase the conversion of glutamate to glutamine in all regions. Selegiline decreased dopamine and serotonin metabolism in all regions and increased glutamate levels in the caudate putamen. In the absence of impaired learning, TAT expression does not impair spatial memory retention/recall, and actually facilitates reversal learning. Selegiline-induced increases in dopamine metabolism did not affect cognitive function. These findings suggest that TAT-induced alterations in glutamate signaling, but not alterations in monoamine metabolism, may underlie the facilitation of reversal learning.

Prenatal nicotine changes the response to postnatal chlorpyrifos: Interactions targeting serotonergic synaptic function and cognition.

Nicotine and chlorpyrifos are developmental neurotoxicants that target serotonin systems. We examined whether prenatal nicotine exposure alters the subsequent response to chlorpyrifos given postnatally. Pregnant rats received nicotine throughout gestation at 3mg/kg/day, a regimen designed to achieve plasma levels seen in smokers; chlorpyrifos was given to pups on postnatal days (PN) 1-4 at 1mg/kg, just above the detection threshold for brain cholinesterase inhibition. We assessed long-term effects from adolescence (PN30) through full adulthood (PN150), measuring the expression of serotonin receptors and serotonin turnover (index of presynaptic impulse activity) in cerebrocortical brain regions encompassing the projections that are known targets for nicotine and chlorpyrifos. Nicotine or chlorpyrifos individually increased the expression of serotonin receptors, with greater effects on males than on females and with distinct temporal and regional patterns indicative of adaptive synaptic changes rather than simply an extension of initial injury. This interpretation was confirmed by our finding an increase in serotonin turnover, connoting presynaptic serotonergic hyperactivity. Animals receiving the combined treatment showed a reduction in these adaptive effects on receptor binding and turnover relative to the individual agents, or even an effect in the opposite direction; further, normal sex differences in serotonin receptor concentrations were dissipated or reversed, an effect that was confirmed by behavioral evaluations in the Novel Objection Recognition Test. In addition to the known liabilities associated with maternal smoking during pregnancy, our results point to additional costs in the form of heightened vulnerability to neurotoxic chemicals encountered later in life.

Nicotine administration in adolescence reprograms the subsequent response to nicotine treatment and withdrawal in adulthood: Sex-selective effects on cerebrocortical serotonergic function

Nicotine exposure in adolescence produces lasting changes in subsequent behavioral responses to addictive agents. We gave nicotine to adolescent rats (postnatal days PN30-47), simulating plasma levels in smokers, and then examined the subsequent effects of nicotine given again in adulthood (PN90-107), focusing on cerebrocortical serotonin levels and utilization (turnover) as an index of presynaptic activity of circuits involved in emotional state. Our evaluations encompassed responses during the period of adult nicotine treatment (PN105) and withdrawal (PN110, PN120, PN130), as well as long-term changes (PN180). In males, prior exposure to nicotine in adolescence greatly augmented the increase in serotonin turnover evoked by nicotine given in adulthood, an interaction that was further exacerbated during withdrawal. The effect was sufficiently large that it led to significant depletion of serotonin stores, an effect that was not seen with nicotine given alone in either adolescence or adulthood. In females, adolescent nicotine exposure blunted or delayed the spike in serotonin turnover evoked by withdrawal from adult nicotine treatment, a totally different effect from the interaction seen in males. Combined with earlier work showing persistent dysregulation of serotonin receptor expression and receptor coupling, the present results indicate that adolescent nicotine exposure reprograms future responses of 5HT systems to nicotine, changes that may contribute to life-long vulnerability to relapse and re-addiction.

Social status differences regulate the serotonergic system of a cichlid fish, Astatotilapia burtoni.

Serotonin (5-HT) inhibits aggression and modulates aspects of sexual behaviour in many species, but the mechanisms responsible are not well understood. Here, we exploited the social dominance hierarchy of Astatotilapia burtoni to understand the role of the serotonergic system in long-term maintenance of social status. We identified three populations of 5-HT cells in dorsal and ventral periventricular pretectal nuclei (PPd, PPv), the nucleus of the paraventricular organ (PVO) and raphe. Dominant males had more 5-HT cells than subordinates in the raphe, but the size of these cells did not differ between social groups. Subordinates had higher serotonergic turnover in the raphe and preoptic area (POA), a nucleus essential for hypothalamic-pituitary-gonadal (HPG) axis function. The relative abundance of mRNAs for 5-HT receptor (5-HTR) subtypes 1A and 2A (htr1a, htr2a) was higher in subordinates, a difference restricted to the telencephalon. Because social status is tightly linked to reproductive capacity, we asked whether serotonin turnover and the expression of its receptors correlated with testes size and circulating levels of 11-ketotestosterone (11-KT). We found negative correlations between both raphe and POA serotonin turnover and testes size, as well as between htr1a mRNA levels and circulating 11-KT. Thus, increased serotonin turnover in non-aggressive males is restricted to specific brain nuclei and is associated with increased expression of 5-HTR subtypes 1A and 2A exclusively in the telencephalon.

33. Neuroendocrine modulation of the immune system by repeated anticipation in domestic pigs

Emotional states may modulate immune functions. We used a model of repeated positive (food), negative (air-puff) or conflicting anticipation (food or air-puff) in domestic pigs in order to induce a change in mood over a treatment period of 4 weeks. Anticipation was triggered by a sound while controls received the same stimuli not preceded by a sound or no stimulus. Changes in heart rate and heart rate variability during the sound indicated repeated arousal involving the sympathetic nervous system only in the positively anticipating group. These animals also showed an increased serotonin turnover in the ventral tegmental area. Investigation of hypothalamic–pituitary–adrenal axis responses revealed a habituation of the animals to the experimental housing and procedure but no specific treatment effects. Also, gene expression of CRH and GR in limbic areas was not influenced by treatment indicating that the animals did not experience stress. However, immunological analyses revealed a reduced T-cell proliferation in response to the mitogen staphylococcal enterotoxin B and a less pronounced age-dependent increase of serum IgM concentrations in pigs with repeated positive anticipation. Our data suggest that repeated positive anticipation may induce a state of arousal that may slightly down-modulate immune functions without the induction of typical stress responses.

Behavioral and neurochemical changes in the zebrafish leopard strain

The zebrafish leopard phenotype (leo) displays abnormal pigmentation and shows increased anxiety-like behavior. The neurochemical changes associated with this anxious phenotype are not known. Here, we demonstrate that leo show increased anxiety-like behavior in the light/dark box and in the novel tank test. This anxious phenotype is rescued by acute treatment with a dose of a serotonin reuptake inhibitor, fluoxetine, that is inactive in wild-type animals. Moreover, leo show decreased tissue levels of serotonin, increased serotonin turnover and slightly increased monoamine oxidase activity. These results suggest that the anxious phenotype observed in leo zebrafish is caused by a decrease in serotonin uptake. This work could open an important avenue in defining the neurochemical underpinning of natural variation in anxiety disorders.

Does repeated anticipation induce neuroendocrine modulation of the immune system in domestic pigs?

To improve animal welfare in pig husbandry it is necessary to expand our knowledge of affective states and their physiological effects. In our study, we used a controlled setup to induce affective states and neuroendocrine immune modulation. For each trial, six female piglets were being housed in individual pens in the same room. Three of these piglets were conditioned six times a day to a sound that was followed by a positive stimulus (food), a negative stimulus (air-puff) or a random choice of food or air-puff. This was supposed to induce positive, negative or conflicting anticipation, respectively. The other three piglets obtained positive, negative or no stimuli without conditioning and served as controls. Within four weeks, we expected changes in mood and consequently physiological effects. Preliminary analyses showed an increase in heart rate and heart rate variability in positively anticipating pigs during the sound reflecting an activation of the sympathetic nervous system. These animals also showed an increased serotonin turnover in the ventral tegmental area and a significant decrease in SEB-induced T-cell proliferation. The immunoglobulin production showed an age-dependent increase which was less pronounced for IgM of positively anticipating pigs. While plasma ACTH and salivary cortisol concentrations decreased during the experiment indicating adaptation, there were no treatment-induced effects and in line with this no differences in CRH and GR gene expression in the brain. Our data indicate that a supposedly positive anticipation may be accompanied by a frequent arousal of the pigs with a potentially negative influence on immunocompetence.

Increased serotonergic neurotransmission is not responsible for the anticompulsive effect of berberine in a murine model of obsessive–compulsive disorder

Berberine, an isoquinoline alkaloid, is being extensively explored in several clinical trials for the treatment of metabolic disorder and cancer. It is also reported to be a potent inhibitor of prolyl oligopeptidase, which makes it a potential candidate for the treatment of neuropsychiatric disorders. We have previously shown the potential of berberine in the control of seizures in various murine models of epilepsy, diabetes-induced memory dysfunction, and ethanol-induced hyperexcitability. We have now examined the effects of acute and subchronic (7 days) administration of berberine on a murine model of obsessive-compulsive disorder - the marble-burying behavior of male mice, because berberine administration is reported to increase brain monoamine levels - a desirable endpoint in the treatment of obsessive-compulsive disorder. The studies showed that an acute administration of berberine [1-25 mg/kg, intraperitoneally (i.p.)] dose-dependently inhibited marble burying in male mice without altering locomotor activity. This effect was retained after its subchronic administration. Furthermore, coadministration of a subeffective dose of berberine (1 mg/kg) and fluoxetine (5 mg/kg, i.p.) significantly reduced marble burying in mice. Pretreatment with p-chlorophenylamine (300 mg/kg, i.p. ×3 days), a tryptophan hydroxylase inhibitor and serotonin-depleting agent, completely blocked the effect of fluoxetine on marble burying, whereas it failed to alter the effect of berberine. In conclusion, the findings of the present investigation indicate that the anticompulsive and/or anxiolytic effect of berberine observed in the present investigation may be attributed to its effect on other neurotransmitter systems, such as the nitrergic or the dopaminergic system rather than to increased serotonin turnover in the brain.