Brain Serotonin Turnover Research Articles

Minocycline reduces neurobehavioral deficits evoked by chronic unpredictable stress in adult zebrafish

Chronic stress-related brain disorders are widespread and debilitating, and often cause lasting neurobehavioral deficits. Minocycline, a common antibiotic and an established inhibitor of microglia, emerges as potential treatment of these disorders. The zebrafish (Danio rerio) is an important emerging model organism in translational neuroscience and stress research. Here, we evaluated the potential of minocycline to correct microglia-mediated behavioral, genomic and neuroimmune responses induced by chronic unpredictable stress (CUS) in adult zebrafish. We demonstrated that CUS evoked overt behavioral deficits in the novel tank, light–dark box and shoaling tests, paralleled by elevated stress hormones (CRH, ACTH and cortisol), and upregulated brain expression of the ‘neurotoxic M1′ microglia-specific biomarker gene (MHC-2) and pro-inflammatory cytokine genes (IL-1β, IL-6 and IFN-γ). CUS also elevated peripheral (whole-body) pro-inflammatory (IL-1β, IFN-γ) and lowered anti-inflammatory cytokines (IL-4 and IL-10), as well as reduced whole-brain serotonin, dopamine and norepinephrine levels, and increased brain dopamine and serotonin turnover. In contrast, minocycline attenuated most of these effects, also reducing CUS-elevated peripheral levels of IL-6 and IFN-γ. Collectively, this implicates microglia in zebrafish responses to chronic stress, and suggests glial pathways as potential evolutionarily conserved drug targets for treating stress-evoked neuropathogenesis. Our findings also support the growing translational value of zebrafish models for understanding complex molecular mechanisms of brain pathogenesis and its therapy.

Acute behavioral and Neurochemical Effects of Novel N-Benzyl-2-Phenylethylamine Derivatives in Adult Zebrafish.

Hallucinogenic drugs potently affect brain and behavior and have also recently emerged as potentially promising agents in pharmacotherapy. Complementing laboratory rodents, the zebrafish (Danio rerio) is a powerful animal model organism for screening neuroactive drugs, including hallucinogens. Here, we test a battery of ten novel N-benzyl-2-phenylethylamine (NBPEA) derivatives with the 2,4- and 3,4-dimethoxy substitutions in the phenethylamine moiety and the -OCH3, -OCF3, -F, -Cl, and -Br substitutions in the ortho position of the phenyl ring of the N-benzyl moiety, assessing their acute behavioral and neurochemical effects in the adult zebrafish. Overall, substitutions in the Overall, substitutions in the N-benzyl moiety modulate locomotion, and substitutions in the phenethylamine moiety alter zebrafish anxiety-like behavior, also affecting the brain serotonin and/or dopamine turnover. The 24H-NBOMe(F) and 34H-NBOMe(F) treatment also reduced zebrafish despair-like behavior. Computational analyses of zebrafish behavioral data by artificial intelligence identified several distinct clusters for these agents, including anxiogenic/hypolocomotor (24H-NBF, 24H-NBOMe, and 34H-NBF), behaviorally inert (34H-NBBr, 34H-NBCl, and 34H-NBOMe), anxiogenic/hallucinogenic-like (24H-NBBr, 24H-NBCl, and 24H-NBOMe(F)), and anxiolytic/hallucinogenic-like (34H-NBOMe(F)) drugs. Our computational analyses also revealed phenotypic similarity of the behavioral activity of some NBPEAs to that of selected conventional serotonergic and antiglutamatergic hallucinogens. In silico functional molecular activity modeling further supported the overlap of the drug targets for NBPEAs tested here and the conventional serotonergic and antiglutamatergic hallucinogens. Overall, these findings suggest potent neuroactive properties of several novel synthetic NBPEAs, detected in a sensitive in vivo vertebrate model system, the zebrafish, raising the possibility of their potential clinical use and abuse.

Measurement of Noradrenaline and Serotonin Metabolites With Internal Jugular Vein Sampling: An Indicator of Brain Monoamine Turnover in Depressive Illness and Panic Disorder.

In research spanning three decades we have estimated brain monoamine turnover (approximately equating with synthesis rate) with sampling from the internal jugular veins and measurement of trans-cerebral plasma monoamine metabolite concentration gradients. Here we report indices of brain noradrenaline and serotonin turnover in patients with major depressive illness (MDD) and panic disorder (PD). Brain noradrenaline turnover was assessed from the combined flux into the internal jugular veins of the metabolites dihydroxyphenylglycol (DHPG) and 3-hydroxy-4-methoxyphenylglycol (MHPG), and brain serotonin turnover from the overflow of the primary metabolite, 5-hydroxyindole acetic acid (5HIAA). Comparison was made with matched healthy research participants. In both MD and PD the estimate of brain noradrenaline turnover provided by metabolite overflow was unremarkable. In contrast, in both patient groups the estimate of brain serotonin turnover provided by 5HIAA overflow was increased 3–4-fold (P < 0.01). This neurotransmitter abnormality was normalized in MDD and PD in clinical remission, during selective serotonin reuptake blocker (SSRI) dosing. We cannot be sure if the brain serotonergic abnormality we find in MDD and PD is causal or a correlate. Measurements in PD were not made during a panic attack. The increased estimated serotonin turnover here may possibly be a substrate for panic attacks; serotonergic raphe nuclei participate in anxiety responses in experimental animals. It is puzzling that the findings were identical in MDD and PD, although it may be pertinent that these psychiatric diagnoses are commonly comorbid. It is unlikely that activation of brain serotonergic neurons is driving the sympathetic nervous activation present, which contributes to cardiovascular risk, persistent sympathetic activation in MDD and episodic activation in PD during panic attacks. We have previously demonstrated that the mechanism of activation of human central sympathetic outflow in other contexts (hypertension, heart failure) is activation of noradrenergic brainstem neurons projecting to the hypothalamus and amygdala.

Neuromediators and defensive responses including tonic immobility (TI): Brain areas and circuits involved.

Serotonin, acetylcholine and GABA are the neuromediators most involved in tonic immobility (TI). TI duration, in fact, decreases in rabbits following systemic serotonin administration and in guinea pigs following serotonin microinjection administration into the amygdala owing to the activation of fear-related GABAergic inhibitory mechanisms. On the other hand, repeated TI inductions in rabbits and guinea pigs reduce brain serotonin turnover in several brain areas. Microinjections of the acetylcholine agonist carbachol into amygdala, hypothalamus and PAG increase TI duration and reduces other defensive responses to threatening stimuli in several animal species. The cholinergic and serotonergic systems exert different effects on TI in different regions of the PAG according to the receptors stimulated. Their combined action activates opioid-GABAergic neurons ultimately affecting TI duration. Mammals TI and human cataplexy are innate responses induced by different stimuli, although both characterized by deficiency in orexin, reduced muscle tone, normal jerk reflexes and preserved consciousness.

Integrated multi-biomarker responses of juvenile rainbow trout (Oncorhynchus mykiss) to an environmentally relevant pharmaceutical mixture

Pharmaceuticals are emerging pollutants of concern for aquatic ecosystems where they are occurring in complex mixtures. In the present study, the chronic toxicity of an environmentally relevant pharmaceutical mixture on juvenile rainbow trout (Oncorhynchus mykiss) was investigated. Five pharmaceuticals (paracetamol, carbamazepine, diclofenac, naproxen and irbesartan) were selected based on their detection frequency and concentration levels in the Meuse river (Belgium). Fish were exposed for 42 days to three different concentrations of the mixture, the median one detected in the Meuse river, 10-times and 100-times this concentration. Effects on the nervous, immune, antioxidant, and detoxification systems were evaluated throughout the exposure period and their response standardized using the Integrated Biomarker Response (IBRv2) index. IBRv2 scores increased over time in the fish exposed to the highest concentration. After 42 days, fish exposed to the highest concentration displayed significantly higher levels in lysozyme activity (p < 0.01). The mixture also caused significant changes in brain serotonin turnover (p < 0.05). In short, our results indicate that the subchronic waterborne exposure to a pharmaceutical mixture commonly occurring in freshwater ecosystems may affect the neuroendocrine and immune systems of juvenile rainbow trout.

Effects of oral administration of an aqueous ginger extract on anxiety behavior and tryptophan and serotonin metabolism in the rat

Background: Zingiber officinale (ginger) is used widely as a herb and medicine. It contains among its constituents 6-Gingerol (a phenol) and quercetin (a flavonoid) that possess anxiolytic and antidepressant properties, but the potential biochemical mechanism(s) of these effects has not been assessed, particularly in relation to serotonin synthesis and neurotransmission.&#x0D; Aims and Objectives: We investigated the anxiolytic-like activity of an aqueous ginger extract by evaluating its influence on behavior, and its effects on serotonin metabolism and on metabolism and disposition of the serotonin precursor tryptophan (Trp) in rats.&#x0D; Materials and Methods: An aqueous ginger extract was given orally in a single daily dose equivalent to 500 mg of ginger material per kg body weight for 3 weeks. The elevated plus maze test of anxiety and Trp metabolism and disposition and brain serotonin synthesis and turnover were assessed in Ginger-treated and control rats.&#x0D; Results: When compared with controls, ginger-treated rats showed a significant increase in the time spent in the open arm, indicative of decreased anxiety. However there was no effect on locomotor activity in open field test. The extract caused significant decreases in activities of liver Trp 2,3-dioxygenase and significant increases in concentrations of serum Trp and corticosterone and brain Trp, serotonin and the major serotonin metabolite 5-hydroxyindoleacetic acid.&#x0D; Conclusion: An aqueous ginger extract exerts an anxiolytic effect in a behavioral model of anxiety, which may be caused by increased serotonin synthesis, and influences tryptophan metabolism and disposition in a manner analogous to antidepressant drugs.

Oxidative Stress, Folate Receptor Autoimmunity, and CSF Findings in Severe Infantile Autism.

Background Biomarkers such as oxidative stress, folate receptor alpha (FRα) autoimmunity, and abnormal brain serotonin turnover are common in autism. Methods Oxidative stress biomarkers with pro- and antioxidants were measured in the severe form of infantile autism (n = 38) and controls (n = 24). Children and parents had repeated testing for serum FR autoantibodies, spinal fluid dopamine and serotonin metabolites, pterins, and N5-methyltetrahydrofolate (MTHF). Statistical analysis assessed correlations between variables. Genetic analysis included the SLC6A4 and SLC29A4 genes encoding synaptic serotonin reuptake proteins. Results Compared to controls, the autism group showed a significant increase in oxidative DNA damage in lymphocytes, plasma ceruloplasmin and copper levels with a high copper/zinc ratio, thiol proteins, and superoxide dismutase (SOD) activity. Vitamin C levels were significantly diminished. In most autistic patients, the vitamin A (64%) and D (70%) levels were low. Serum FR autoantibodies fluctuating over 5–7 week periods presented in 68% of all autistic children, 41% of parents vs. 3.3% of control children and their parents. CSF showed lowered serotonin 5-hydroxyindole acetic acid (5HIAA) metabolites in 13 (34%), a low 5HIAA to HVA (dopamine metabolite) ratio in 5 (13%), low 5HIAA and MTHF in 2 (5%), and low MTHF in 8 patients (21%). A known SLC6A4 mutation was identified only in 1 autistic child with low CSF 5HIAA and a novel SLC29A4 mutation was identified in identical twins. Low CSF MTHF levels among only 26% of subjects can be explained by the fluctuating FR antibody titers. Two or more aberrant pro-oxidant and/or antioxidant factors predisposed to low CSF serotonin metabolites. Three autistic children having low CSF 5HIAA and elevated oxidative stress received antioxidative supplements followed by CSF 5HIAA normalisation. Conclusion In autism, we found diverse combinations for FR autoimmunity and/or oxidative stress, both amenable to treatment. Parental and postnatal FR autoantibodies tend to block folate passage to the brain affecting folate-dependent pathways restored by folinic acid treatment, while an abnormal redox status tends to induce reduced serotonin turnover, corrected by antioxidant therapy. Trial Registration. The case-controlled study was approved in 2008 by the IRB at Liège University (Belgian Number: B70720083916). Lay Summary. Children with severe infantile autism frequently have serum folate receptor autoantibodies that block the transport of the essential vitamin folate across the blood-brain barrier to the brain. Parents are often asymptomatic carriers of these serum folate receptor autoantibodies, which in mothers can block folate passage across the placenta to their unborn child. This folate deficiency during the child's intrauterine development may predispose to neural tube defects and autism. Oxidative stress represents a condition with the presence of elevated toxic oxygen derivatives attributed to an imbalance between the formation and protection against these toxic reactive oxygen derivatives. Oxidative stress was found to be present in autistic children where these reactive oxygen derivatives can cause damage to DNA, which changes DNA function and regulation of gene expression. In addition, excessive amounts of these toxic oxygen derivatives are likely to damage the enzyme producing the neuromessenger serotonin in the brain, diminished in about 1/3 of the autistic children. Testing children with autism for oxidative stress and its origin, as well as testing for serum folate receptor autoantibodies, could open new approaches towards more effective treatments.

Zygotic Venlafaxine Exposure Impacts Behavioral Programming by Disrupting Brain Serotonin in Zebrafish.

The antidepressant venlafaxine, a selective serotonin and norepinephrine reuptake inhibitor, is present in surface waters downstream of wastewater treatment plants. We previously showed that zygotic venlafaxine deposition alters larval behavior in zebrafish (Danio rerio), but the mechanisms were unknown. Here we tested the hypothesis that venlafaxine disrupts central serotonergic development, leading to impaired behavioral responses in zebrafish larvae. This was tested by microinjecting embryos with venlafaxine immediately after fertilization and performing spatial distribution of serotonin immunoreactivity, as well as characterizing target genes involved in serotonin turnover in the zebrafish brain. We provide evidence that venlafaxine exposure reduces serotonin immunoreactivity and tyrosine hydroxylase-positive cell populations in specific larval brain regions, and this corresponded with reduced larval activity observed in the drug-exposed group. Lowered serotonin was not due to either reduced synthesis or increased breakdown capacity. However, co-injection of serotonin alongside venlafaxine in embryos recovered brain serotonin immunoreactivity, tyrosine hydroxylase-positive cell populations, and rescued venlafaxine-mediated behavioral changes. Overall, our results demonstrate for the first time that early life exposure to venlafaxine perturbs brain development, which may be due to reduced serotonin, leading to altered larval behavior in zebrafish.

The gut microbiota metabolite indole increases emotional responses and adrenal medulla activity in chronically stressed male mice

Background and aimsThe gut microbiota produces metabolites that are an integral part of the metabolome and, as such, of the host physiology. Changes in gut microbiota metabolism could therefore contribute to pathophysiological processes. We showed previously that a chronic and moderate overproduction of indole from tryptophan in male individuals of the highly stress-sensitive F344 rat strain induced anxiety-like and helplessness behaviors. The aim of the present study was to extend the scope of these findings by investigating whether emotional behaviors of male mice that are moderately stress-sensitive but chronically exposed to environmental stressors would also be affected by indole. MethodsWe colonized germ-free male C3H/HeN mice with a wild-type indole-producing Escherichia coli strain, or with the non-indole producing mutant. Gnotobiotic mice were subjected to an unpredictable chronic mild stress procedure, then to a set of tests aimed at assessing anxiety-like (novelty and elevated plus maze tests) and depression-like behaviors (coat state, splash, nesting, tail suspension and sucrose tests). Results of the individual tests were aggregated into a common z-score to estimate the overall emotional response to chronic mild stress and chronic indole production. We also carried out biochemical and molecular analyses in gut mucosa, plasma, brain hippocampus and striatum, and adrenal glands, to examine biological correlates that are usually associated with stress, anxiety and depression. ResultsChronic mild stress caused coat state degradation and anhedonia in both indole-producing and non-indole producing mice, but it did not influence behaviors in the other tests. Chronic indole production did not influence mice behavior when tests were considered individually, but it increased the overall emotionality z-score, specifically in mice under chronic mild stress. Interestingly, in the same mice, indole induced a dramatic increase of the expression of the adrenomedullary Pnmt gene, which is involved in catecholamine biosynthesis. By contrast, systemic tryptophan bioavailability, brain serotonin and dopamine levels and turnover, as well as expression of gut and brain genes involved in cytokine production and tryptophan metabolism along the serotonin and kynurenine pathways, remained similar in all mice. ConclusionsChronic indole production by the gut microbiota increased the vulnerability of male mice to the adverse effects of chronic mild stress on emotional behaviors. It also targeted catecholamine biosynthetic pathway of the adrenal medulla, which plays a pivotal role in body’s physiological adaptation to stressful events. Future studies will aim to investigate the action mechanisms responsible for these effects.

The Influence of Rearing on Behavior, Brain Monoamines, and Gene Expression in Three-Spined Sticklebacks

The causes of individual variation in behavior are often not well understood, and potential underlying mechanisms include both intrinsic and extrinsic factors, such as early environmental, physiological, and genetic differences. In an exploratory laboratory study, we raised three-spined sticklebacks (Gasterosteus aculeatus) under 4 different environmental conditions (simulated predator environment, complex environment, variable social environment, and control). We investigated how these manipulations related to behavior, brain physiology, and gene expression later in life, with focus on brain dopamine and serotonin levels, turnover rates, and gene expression. The different rearing environments influenced behavior and gene expression, but did not alter monoamine levels or metabolites. Specifically, compared to control fish, fish exposed to a simulated predator environment tended to be less aggressive, more exploratory, and more neophobic; and fish raised in both complex and variable social environments tended to be less neophobic. Exposure to a simulated predator environment tended to lower expression of dopamine receptor DRD4A, a complex environment increased expression of dopamine receptor DRD1B, while a variable social environment tended to increase serotonin receptor 5-HTR2B and serotonin transporter SLC6A4A expression. Despite both behavior and gene expression varying with early environment, there was no evidence that gene expression mediated the relationship between early environment and behavior. Our results confirm that environmental conditions early in life can affect phenotypic variation. However, the mechanistic pathway of the monoaminergic systems translating early environmental variation into observed behavioral responses was not detected.

Decreased brain serotonin turnover rate following administration of Sharbat-e-Ahmed Shah produces antidepressant and anxiolytic effect in rats.

Sharbat-e-Ahmed Shah (SAS) has usually been used in Traditional Unani Medicine (TUM) for depression and insomnia but still not evaluated for its anti-depressant and Neuropharmacological activity. In the present study, a Human dose of SAS (0.6ml/kg/d) was administered orally to the rats for 15 consecutive days. Antidepressant and anxiolytic were screened scientifically in rats by using Forced swim test and light and dark box test. At the end of study high-performance liquid chromatographic (HPLC) method with electrochemical (EC) detector was used for the measurement of blood and brain tryptophan and brain serotonin levels. The present reported results are according to what is known in TUM, where is prescribed as an antidepressant agent. After the administration, SAS (at a human dose for 15days) reduced the immobility time in rats analogous to Imipramine (positive control) indicating the antidepressant effect of SAS. In the present study, Diazepam or SAS (0.6ml/kg/day) treated rats stayed in the illuminated side of the light-dark box, as compare to control rats (Veh, 134.62±4.430s; SAS 0.6ml/kg, 192.2±8.11 s; DZP 1.0mg/kg, 205.21.20±10.26 s, p<0.05). It was also observed that SAS increased the availability of tryptophan in blood and brain and hence increases 5-hydroxytryptamine (Serotonin: 5HT) in the brain. At the end, it was concluded that SAS contains some active principles which increase the availability of neurochemical (tryptophan and 5HT) and decrease the 5HT turnover rate thus causes antidepressant and anxiolytic effects in experimental animals.

Effects of feather pecking phenotype (severe feather peckers, victims and non-peckers) on serotonergic and dopaminergic activity in four brain areas of laying hens (Gallus gallus domesticus)

Severe feather pecking (SFP) in laying hens is a detrimental behavior causing loss of feathers, skin damage and cannibalism. Previously, we have associated changes in frontal brain serotonin (5-HT) turnover and dopamine (DA) turnover with alterations in feather pecking behavior in young pullets (28–60days). Here, brain monoamine levels were measured in adult laying hens; focusing on four brain areas that are involved in emotional behavior or are part of the basal ganglia-thalamopallial circuit, which is involved in obsessive compulsive disorders. Three behavioral phenotypes were studied: Severe Feather Peckers (SFPs), Victims of SFP, and Non-Peckers (NPs). Hens (33weeks old) were sacrificed after a 5-min manual restraint test. SFPs had higher 5-HIAA levels and a higher serotonin turnover (5-HIAA/5-HT) in the dorsal thalamus than NPs, with intermediate levels in victims. NPs had higher 5-HT levels in the medial striatum than victims, with levels of SFPs in between. 5-HT turnover levels did not differ between phenotypes in medial striatum, arcopallium and hippocampus. DA turnover levels were not affected by feather pecking phenotype.These findings indicate that serotonergic neurotransmission in the dorsal thalamus and striatum of adult laying hens depends on differences in behavioral feather pecking phenotype, with, compared to non-pecking hens, changes in both SFP and their victims. Further identification of different SFP phenotypes is needed to elucidate the role of brain monoamines in SFP.

Antidepressant-like effect of 4-hydroxyisoleucine from Trigonella foenum graecum L. seeds in mice

Trigonella foenum graecum L. (Fabaceae), also known as fenugreek, is one of the oldest medicinal plants, and has a long history of medical use in traditional and modern literature. 4-hydroxyisoleucine (4-HI) constitutes about is 80% of the total content of free amino acids in Trigonella foenum graecum seeds. In present study, we report antidepressant-like effects of 4-HI in animal models of depression. The effects of 4-HI (10, 30 or 100mg/kg) in Forced swim test, 5-hydroxytryptophan (5-HTP)-induced head twitches, and spontaneous motor activity (SMA) scores were assessed in mice. Oral acute administration of 4-HI showed the dose-dependent reversal in forced swim induced increased immobility behavior in normal and reserpinized mice in dose range of 3 to 30mg/kg. The SMA scores were not affected by 4-HI in normal or reserpinized mice except for dose of 30mg/kg, showing central rather than peripheral mechanism of 4-HI. Further, significant increase in number of 5-HTP (precursor of serotonin) induced head twitches was shown by 4-HI. In conclusion, 4-HI showed antidepressant-like effects in animal models of depression by brain serotonin turnover enhancement.

D-amino acid oxidase activator gene (DAOA) variation affects cerebrospinal fluid homovanillic acid concentrations in healthy Caucasians

The d-amino acid oxidase activator (DAOA) protein regulates the function of d-amino oxidase (DAO), an enzyme that catalyzes the oxidative deamination of d-3,4-dihydroxyphenylalanine (D-DOPA) and d-serine. D-DOPA is converted to l-3,4-DOPA, a precursor of dopamine, whereas d-serine participates in glutamatergic transmission. We hypothesized that DAOA polymorphisms are associated with dopamine, serotonin and noradrenaline turnover in the human brain. Four single-nucleotide polymorphisms, previously reported to be associated with schizophrenia, were genotyped. Cerebrospinal fluid (CSF) samples were drawn by lumbar puncture, and the concentrations of the major dopamine metabolite homovanillic acid (HVA), the major serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) and the major noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) were measured. Two of the investigated polymorphisms, rs3918342 and rs1421292, were significantly associated with CSF HVA concentrations. Rs3918342 was found to be nominally associated with CSF 5-HIAA concentrations. None of the polymorphisms were significantly associated with MHPG concentrations. Our results indicate that DAOA gene variation affects dopamine turnover in healthy individuals, suggesting that disturbed dopamine turnover is a possible mechanism behind the observed associations between genetic variation in DAOA and behavioral phenotypes in humans.

An effective dietary method for chronic tryptophan depletion in two mouse strains illuminates a role for 5-HT in nesting behaviour

Physiological depletion of tryptophan, the precursor to serotonin has been shown to alter mood and cognition in both humans and rodents. Few studies have investigated the neurochemical and behavioural effects associated with tryptophan depletion in mice. Given that BALB/c and C57BL/6J mice differ in tryptophan hydroxylase (TPH) functionality, serotonin levels and behavioural phenotype, we hypothesised that a differential strain response to chronic dietary tryptophan manipulations would be observed. Therefore, the effects of four chronic dietary tryptophan manipulations were investigated, the diets include a depleted diet (0% tryptophan, TRP−), a deficient diet (0.25% tryptophan, TRP−/+), an enhanced diet (1.25% tryptophan, TRP+) and a control diet (0.7%). Diet-induced alterations in peripheral and central tryptophan levels and brain serotonin turnover were determined by high performance liquid chromatography. In addition, dietary-induced alterations in behaviour were assessed in several commonly used tasks. Peripheral and central tryptophan levels and consequently central serotonergic turnover were significantly decreased by the TRP− diet in both strains, however, no effect of tryptophan supplementation was observed on tryptophan or serotonin levels. Dietary tryptophan manipulation induced pronounced behavioural effects, particularly in nesting behaviour where a reduction in nesting was observed following depletion and an increase in nesting behaviour was observed with enhanced tryptophan in both strains. Additionally, depletion produces an anxiolytic-like effect and did not impede locomotion. This study demonstrates significant alterations in the levels of tryptophan, serotonin turnover and behaviour following chronic dietary tryptophan depletion.

Low-Dose-Rate, Low-Dose Irradiation Delays Neurodegeneration in a Model of Retinitis Pigmentosa

The existence of radiation hormesis is controversial. Several stimulatory effects of low-dose (LD) radiation have been reported to date; however, the effects on neural tissue or neurodegeneration remain unknown. Here, we show that LD radiation has a neuroprotective effect in mouse models of retinitis pigmentosa, a hereditary, progressive neurodegenerative disease that leads to blindness. Various LD radiation doses were administered to the eyes in a retinal degeneration mouse model, and their pathological and physiological effects were analyzed. LD gamma radiation in a low-dose-rate (LDR) condition rescues photoreceptor cell apoptosis both morphologically and functionally. The greatest effect was observed in a condition using 650 mGy irradiation and a 26 mGy/minute dose rate. Multiple rounds of irradiation strengthened this neuroprotective effect. A characteristic up-regulation (563%) of antioxidative gene peroxiredoxin-2 (Prdx2) in the LDR-LD-irradiated retina was observed compared to the sham-treated control retina. Silencing the Prdx2 using small-interfering RNA administration reduced the LDR-LD rescue effect on the photoreceptors. Our results demonstrate for the first time that LDR-LD irradiation has a biological effect in neural cells of living animals. The results support that radiation exhibits hormesis, and this effect may be applied as a novel therapeutic concept for retinitis pigmentosa and for other progressive neurodegenerative diseases regardless of the mechanism of degeneration involved.

Effects of genetic origin and social environment on behavioral response to manual restraint and monoamine functioning in laying hens

Purebred laying hen lines of White Leghorn (WL) origin have been found to be more flighty and to show more feather pecking than lines of Rhode Island Red (RIR) origin. It has been found, however, that when RIR birds were housed together with WL birds, RIR birds became more flighty and those mixed groups developed more feather damage than pure-line cage-housed groups. It is unknown, however, whether this effect of social environment is accompanied by changes in stress-related behavior and neurophysiological activity, which are assumed to be associated with increased feather damage. The objective of this study was therefore to investigate the effects of genetic origin (WL or RIR) and social environment (mixed or pure groups) on behavioral response to manual restraint and monoamine functioning. Monoamine functioning was measured by brain serotonin (5-HT) and dopamine turnover. Furthermore, correlations between 5-HT turnover in the brain and peripheral measures of 5-HT in the blood were calculated. Experimental birds, housed either with other birds from the same genetic origin (pure groups) or with both RIR and WL birds (mixed groups) from hatching onward, were subjected to a manual restraint test at 47 wk of age. The WL birds struggled less during restraint and had higher dopamine and 5-HT turnover levels after restraint than did RIR birds. The WL birds also showed higher levels of platelet 5-HT uptake than did RIR birds. No effects of social environment were found. Blood and brain 5-HT measures were found to be correlated, with correlations ranging from 0.34 to 0.57, which seems to offer opportunities for less invasive peripheral indicators of 5-HT activity. In conclusion, genetic origin, but not social environment, affected the behavioral response to manual restraint and monoamine functioning in laying hens.

Isolation, aggressiveness and brain 5-hydroxytryptamine turnover.

Isolation, aggressiveness and brain 5-hydroxytryptamine turnover.

Autism associated with low 5-hydroxyindolacetic acid in CSF and the heterozygous SLC6A4 gene Gly56Ala plus 5-HTTLPR L/L promoter variants

The known Gly56Ala mutation in the serotonin transporter SERT (or 5-HTT), encoded by the SLC6A4 gene, causes increased serotonin reuptake and has been associated with autism and rigid–compulsive behavior. We report a patient with macrocephaly from birth, followed by hypotonia, developmental delay, ataxia and a diagnosis of atypical autism (PDD-NOS) in retrospect at the age of 4½ years. Low levels of the serotonin end-metabolite 5-hydroxyindolacetic acid (5HIAA) in CSF were detected, and SLC6A4 gene analysis revealed the heterozygous Gly56Ala alteration and the homozygous 5-HTTLPR L/L promoter variant. These changes are reported to be responsible for elevated SERT activity and expression, suggesting that these alterations were responsible in our patient for low serotonin turnover in the central nervous system (CNS). Daily treatment with 5-hydroxytryptophan (and carbidopa) led to clinical improvement and normalization of 5HIAA, implying that brain serotonin turnover normalized. We speculate that the mutated 56Ala SERT transporter with elevated expression and basal activity for serotonin re-uptake is accompanied with serotonin accumulation within pre-synaptic axons and their vesicles in the CNS, resulting in a steady-state of lowered serotonin turnover and degradation by monoamine-oxidase (MAO) enzymes in pre-synaptic or neighboring cells.

Silver exposure in developing zebrafish produces persistent synaptic and behavioral changes

Environmental silver exposures are increasing due to the use of silver nanoparticles, which exert antimicrobial actions by releasing Ag +, a suspected developmental neurotoxicant. We evaluated the long-term neurochemical and behavioral effects of embryonic Ag + exposure in zebrafish at concentrations that had no overt effects on morphological development. Exposure to 0.03, 0.1 or 0.3 μM Ag + during the first five days post-fertilization caused elevations in both dopamine and serotonin turnover in the adult zebrafish brain without affecting basal neurotransmitter levels. Consistent with these synaptic effects, Ag +-exposed fish showed a faster acquisition of avoidance behavior in a three-chamber test apparatus, without any change in response latency or overall swimming ability. Our results indicate that Ag + is a developmental neurotoxicant that causes persistent neurobehavioral effects, reinforcing health concerns about Ag + released from silver nanoparticles.