Serotonin Precursor 5-hydroxytryptophan Research Articles

Effects of rumen-protected 5-hydroxytryptophan on circulating serotonin concentration, behaviour, and mammary gland involution in goats

The risk of acquiring new intramammary infections is high at the end of lactation, especially for the high milk-producing dairy animals. Resistance to bacterial infection increases following the completion of mammary gland involution after milking cessation. The serotonin precursor 5-hydroxytryptophan (5-HTP) could accelerate involution by increasing circulating serotonin levels, but ruminal microbes may degrade 5-HTP if orally administered to adult ruminants. It is unclear whether rumen-protected 5-HTP could effectively mediate circulating serotonin (5-hydroxytryptamine, 5-HT) and therefore accelerate mammary gland involution in ruminants. Goats were used as a model in the current study to investigate the effects of rumen-protected 5-HTP on behaviour, 5-HT metabolism, and mammary involution in ruminants. In the first experiment, 16 female Dazu black goats were assigned to one of four groups in a randomised block design. The treatments included a basal diet plus 0, 4, 20, or 100 mg/kg BW of rumen-protected 5-HTP. Serum was collected at 0, 3, 6, 12, and 24 h after offering the rumen-protected 5-HTP in the morning feed, and the behaviours were monitored. In the second experiment, 12 female Dazu black goats (Somatic cell count < 250 000) were randomly assigned to the control (basal diet) or rumen-protected 5-HTP group (basal diet plus 20 mg/kg BW). Milk or mammary secretions were manually collected aseptically on d −1, 1, 2, 3, 4, and 5 around weaning. The results depicted that rumen-protected 5-HTP supplementation elevated circulating 5-HTP and 5-hydroxyindole acetic acid concentrations, while 20 mg/kg BW of rumen-protected 5-HTP supplementation lowered the goats’ locomotive activity. A high concentration of rumen-protected 5-HTP (100 mg/kg BW) increased serum alkaline phosphatase and gamma-glutamyl transpeptidase concentrations. Moreover, oral supplementation with 20 mg/kg BW of rumen-protected 5-HTP accelerated mammary gland involution and reduced feed intake in goats after weaning. These results demonstrate that oral supplementation with rumen-protected 5-HTP influences 5-HT metabolism and accelerates mammary gland involution after milking cessation in ruminants.

Beyond the Brain: Perinatal Exposure of Rats to Serotonin Enhancers Induces Long-Term Changes in the Jejunum and Liver.

Serotonin (5-hydroxytryptamine, 5HT) homeostasis is essential for many physiological processes in the central nervous system and peripheral tissues. Hyperserotonemia, a measurable sign of 5HT homeostasis disruption, can be caused by 5HT-directed treatment of psychiatric and gastrointestinal diseases. Its impact on the long-term balance and function of 5HT in the peripheral compartment remains unresolved and requires further research due to possible effects on human health. We explored the effects of perinatal 5HT imbalance on the peripheral organs responsible for serotonin metabolism-the jejunum, a synthesis site, and the liver, a catabolism site-in adult rats. Hyperserotonemia was induced by subchronic treatment with serotonin precursor 5-hydroxytryptophan (5HTP) or serotonin degradation inhibitor tranylcypromine (TCP). The jejunum and liver were collected on postnatal day 70 and analyzed histomorphometrically. Relative mRNA levels of 5HT-regulating proteins were determined using qRT-PCR. Compared to controls, 5HTP- and TCP-treated rats had a reduced number of 5HT-producing cells and expression of the 5HT-synthesising enzyme in the jejunum, and an increased expression of 5HT-transporter accompanied by karyomegaly in hepatocytes, with these differences being more pronounced in the TCP-treated animals. Here, we report that perinatal 5HT disbalance induced long-term cellular and molecular changes in organs regulating 5HT-metabolism, which may have a negative impact on 5HT availability and function in the periphery. Our rat model demonstrates a link between the developmental abnormalities of serotonin homeostasis and 5HT-related changes in adult life and may be suitable for exploring the neurobiological substrates of vulnerability to behavioral and metabolic disorders, as well as for modeling the adverse effects of the prenatal exposure to 5HT enhancers in the human population.

Intravenous infusion of 5-hydroxytryptophan to mid-lactation Holstein cows transiently affects milk production and circulating amino acid concentrations

In dairy cows, the lactating mammary glands synthesize serotonin, which acts in an autocrine-paracrine manner in the glands and is secreted into the periphery. Serotonin signaling during lactation modulates nutrient metabolism in peripheral tissues such as adipose and liver. We hypothesized that the elevation of circulating serotonin during lactation would increase nutrient partitioning to the mammary glands, thereby promoting milk production. Our objective was to elevate circulating serotonin via intravenous infusion of the serotonin precursor 5-hydroxytryptophan (5-HTP) to determine its effects on mammary supply and extraction efficiency of AA, and milk components production. Twenty-two multiparous mid-lactation Holstein cows were intravenously infused with 5-HTP (1 mg/kg body weight) or saline, in a crossover design with two 21-d periods. Treatments were infused via jugular catheters for 1 h/d, on d 1 to 3, 8 to 10, and 15 to 17 of each period, to maintain consistent elevation of peripheral serotonin throughout the period. Milk and blood samples were collected in the last 96 h of each period. Whole-blood serotonin concentration was elevated above saline control for 96 h after the last 5-HTP infusion. Dry matter intake was decreased for cows receiving 5-HTP, and on average they lost body weight over the 21-d period, in contrast to saline cows who gained body weight. Milk production and milk protein yield were lower in cows receiving 5-HTP during the 3 infusion days, but both recovered to saline cow yields in the days after. Although milk fat yield exhibited a day-by-treatment interaction, no significant difference occurred on any given day. Milk urea nitrogen concentration was lower in 5-HTP cows on the days following the end of infusions, but not different from saline cows on infusion days. Meanwhile, plasma urea nitrogen was not affected by 5-HTP infusion. Circulating concentrations of AA were overall transiently decreased by 5-HTP, with concentrations mostly returning to baseline within 7 h after the end of 5-HTP infusion. Mammary extraction efficiency of AA was unaffected by 5-HTP infusion. Overall, both lactation performance and circulating AA were transiently reduced in cows infused with 5-HTP, despite sustained elevation of circulating serotonin concentration.

Transcriptomic analysis of adipose, hepatic, and mammary gland tissues in lactating cows with elevated peripheral serotonin

Lactation is a highly energy intensive state, particularly for dairy cattle, which have been genetically selected for copious milk secretion. Blood serotonin content is greatly increased during lactation, at least in part because of increased production by the lactating mammary glands. We hypothesized that increasing peripheral serotonin in lactating cows, by infusion of the serotonin precursor 5-hydroxytryptophan (5-HTP), would alter gene expression in metabolically active tissues to support energy partitioning towards lactation.To test this hypothesis, multiparous midlactation Holstein cows (n=8/treatment) were intravenously infused with 5-HTP (1mg/kg bodyweight) or saline over two 10-day treatment periods. Treatments were infused via jugular catheters for 1h/day starting at 0700, on days 1–3 and 8–10, with no infusions on days 4–7. On day 10, 6h after the last infusion, biopsies of subcutaneous white adipose (WAT), hepatic, and mammary tissues were performed. Total RNAs were extracted from these tissues, and followed by whole transcriptome sequencing. Adapter-trimmed sequences were mapped to the cattle reference genome (ARS-UCD 1.2) using STAR. Differential gene expression analysis was done using DEseq2. A combinatory cutoff of mean read count≥5, fold-change≥2, and p-value&lt;0.01 was used to determine differentially expressed genes (DEG). Relative to saline-infused cows, 5-HTP cows had 152 genes downregulated and 38 upregulated in WAT, 117 genes downregulated and 141 upregulated in hepatic tissue, and 79 genes downregulated and 86 upregulated in mammary tissue.DEG from each tissue were then analyzed by QIAGEN Ingenuity Pathway Analysis (IPA) to identify enriched pathways and functions impacted by 5-HTP. In WAT, downregulated genes were enriched in triacylglycerol biosynthesis and upregulated genes were enriched in PPAR signaling, with upregulated gene enrichment in several apoptosis-related pathways as well. Decreased biological function categories in WAT included carbohydrate metabolism and lipid metabolism. In hepatic tissue, downregulated genes were enriched in superpathway of cholesterol biosynthesis while upregulated genes were enriched in cAMP-mediated signaling and citrulline biosynthesis. In mammary tissue, 5-HTP infusion exclusively upregulated genes involved in lipid metabolism, including functions in transport, export, flux and efflux of lipids and cholesterol. In conclusion, lactating cows with elevated peripheral serotonin developed a systemic response, altering the expression of genes in energy metabolic pathways, including reduced lipid synthesis and cell survival in WAT, reduced cholesterol synthesis in the liver, and increased lipid trafficking in the mammary tissue. Together, these changes may function to shift energy partitioning towards milk synthesis. This work was supported by USDA-NIFA Predoctoral Fellowship grant #2021-67034-35172 and research funding provided by Adisseo Bluestar Co. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Serotonin alters the response to a glucose challenge in lactating cows.

Energy partitioning in lactating cows affects milk production, feed efficiency, and body reserves, with the latter having health implications for the transition into the following lactation. One molecule likely involved in the regulation of energy partitioning is serotonin. The objective of this experiment was to explore how increasing circulating serotonin, by intravenous infusion of the serotonin precursor 5-hydroxytryptophan (5-HTP), affects metabolic responses to a glucose challenge in midlactation cows as a means to manipulate energy partitioning. We intravenously infused Holstein cows with 5-HTP (1 mg/kg bodyweight dissolved in saline, n = 11) or saline alone as control (n = 9) over 1 h/day for 3 days. Cows were fasted overnight on day 2. On day 3, fasted cows were given an intravenous bolus of glucose (0.092 g/kg bodyweight). Blood samples were collected for the following 120 min for metabolic and hormonal analysis. Infusion of 5-HTP elevated circulating concentrations of serotonin and free fatty acids, reduced the concentration of insulin and amino acids, and did not affect the concentration of glucose and glucagon before the glucose challenge. Surrogate insulin sensitivity indices indicated improved insulin sensitivity in 5-HTP cows, but due to the unique metabolism of lactating ruminants, these index changes may instead reflect effects in insulin-independent glucose disposal, like milk synthesis. Challenging 5-HTP-treated cows with a glucose bolus reduced the insulin spike and blunted the decrease in free fatty acids, compared to saline cows, without changing glucose dynamics. Overall, these results suggest that serotonin stimulates insulin-independent glucose disposal, requiring less insulin to maintain normoglycemia.

L‐DOPA and 5‐HTP modulation of air‐stepping in newborn rats

In newborn rats, L-DOPA increases the occurrence of air-stepping activity without affecting movement characteristics. L-DOPA administration increases the spinal content of dopamine in a dose-dependent manner. Injection of 5-HTP increases the spinal serotonin content but does not trigger air-stepping. 5-HTP counteracts the pro-locomotor action of L-DOPA. Less dopamine and serotonin are synthesized when L-DOPA and 5-HTP are administered as a cocktail. The catecholamine precursor, L-3,4-dihydroxyphenylalanine (L-DOPA), is a well-established pharmacological agent for promoting locomotor action in vertebrates, including triggering air-stepping activities in the neonatal rat. Serotonin is also a well-known neuromodulator of the rodent spinal locomotor networks. Here, using kinematic analysis, we compared locomotor-related activities expressed by newborn rats in response to varying doses of L-DOPA and the serotonin precursor 5-hydroxytryptophan (5-HTP) administered separately or in combination. L-DOPA alone triggered episodes of air-stepping in a dose-dependent manner (25-100mg/kg), notably determining the duration of locomotor episodes, but without affecting step cycle frequency or amplitude. In contrast, 5-HTP (25-150mg/kg) was ineffective in instigating air-stepping, but altered episode durations of L-DOPA-induced air-stepping, and decreased locomotor cycle frequency. High performance liquid chromatography revealed that L-DOPA, which was undetectable in control conditions, accumulated in a dose-dependent manner in the lumbar spinal cord 30min after its administration. This was paralleled by an increase in dopamine levels, whereas the spinal content of noradrenaline and serotonin remained unaffected. In the same way, the spinal levels of serotonin increased in parallel with the dose of 5-HTP without affecting the levels of dopamine and noradrenaline. When both precursors are administrated, they counteract each other for the production of serotonin and dopamine. Our data thus indicate for the first time that both L-DOPA and 5-HTP exert opposing neuromodulatory actions on air-stepping behaviour in the developing rat, and we speculate that competition for the production of dopamine and serotonin occurs when they are administered as a cocktail.

Cerebellin-2 regulates a serotonergic dorsal raphe circuit that controls compulsive behaviors.

Cerebellin-1 (Cbln1) and cerebellin-2 (Cbln2) are secreted glycoproteins that are expressed in distinct subsets of neurons throughout the brain. Cbln1 and Cbln2 simultaneously bind to presynaptic neurexins and postsynaptic GluD1 and GluD2, thereby forming trans-synaptic adhesion complexes. Genetic associations link cerebellins, neurexins and GluD’s to neuropsychiatric disorders involving compulsive behaviors, such as Tourette syndrome, attention-deficit hyperactivity disorder (ADHD), and obsessive-compulsive disorder (OCD). Extensive evidence implicates dysfunction of serotonergic signaling in these neuropsychiatric disorders. Here, we report that constitutive Cbln2 KO mice, but not Cbln1 KO mice, display robust compulsive behaviors, including stereotypic pattern running, marble burying, explosive jumping, and excessive nest building, and exhibit decreased brain serotonin levels. Strikingly, treatment of Cbln2 KO mice with the serotonin precursor 5-hydroxytryptophan or the serotonin reuptake-inhibitor fluoxetine alleviated compulsive behaviors. Conditional deletion of Cbln2 both from dorsal raphe neurons and from presynaptic neurons synapsing onto dorsal raphe neurons reproduced the compulsive behaviors of Cbln2 KO mice. Finally, injection of recombinant Cbln2 protein into the dorsal raphe of Cbln2 KO mice largely reversed their compulsive behaviors. Taken together, our results show that Cbln2 controls compulsive behaviors by regulating serotonergic circuits in the dorsal raphe.

Bioaminergic Responses in an In Vitro System Studying Human Gut Microbiota-Kiwifruit Interactions.

Whole kiwifruit (‘Hayward’ and ‘Zesy002’) were examined for their bioaminergic potential after being subjected to in vitro gastrointestinal digestion and colonic fermentation. Controls included the prebiotic inulin and water, a carbohydrate-free vehicle. The dopamine precursor l-dihydroxyphenylalanine (L-DOPA) and the serotonin precursor 5-hydroxytryptophan were increased in the kiwifruit gastrointestinal digesta (‘Hayward’ > ‘Zesy002’) in comparison to the water digesta. Fermentation of the digesta with human fecal bacteria for 18 h modulated the concentrations of bioamine metabolites. The most notable were the significant increases in L-DOPA (‘Zesy002’ > ‘Hayward’) and γ-aminobutyric acid (GABA) (‘Hayward’ > ‘Zesy002’). Kiwifruit increased Bifidobacterium spp. and Veillonellaceae (correlating with L-DOPA increase), and Lachnospira spp. (correlating with GABA). The digesta and fermenta were incubated with Caco-2 cells for 3 h followed by gene expression analysis. Effects were seen on genes related to serotonin synthesis/re-uptake/conversion to melatonin, gut tight junction, inflammation and circadian rhythm with different digesta and fermenta from the four treatments. These indicate potential effects of the substrates and the microbially generated organic acid and bioamine metabolites on intestinal functions that have physiological relevance. Further studies are required to confirm the potential bioaminergic effects of gut microbiota–kiwifruit interactions.

The Triple Combination Phentermine Plus 5-HTP/Carbidopa Leads to Greater Weight Loss, With Fewer Psychomotor Side Effects Than Each Drug Alone.

Obesity has become a serious public health problem. Although diet, surgery, and exercise are the primary treatments for obesity, these activities are often supplemented using appetite suppressants. A previous study reported that obesity specialists frequently prescribed a new drug combination for its treatment that includes phentermine (Phen; dopaminergic appetite suppressant), a serotonin (5-HT) precursor 5-hydroxytryptophan (5-HTP; an appetite suppressant that increases the 5-HT concentration), and carbidopa (CB; peripheral blocker of conversion of 5-HTP to 5-HT). Despite its widespread use, there is neither a preclinical study confirming the drug efficacy nor studies of its effects on the brain. To fill this gap, in rats for seven consecutive days, we administered Phen intraperitoneally at different doses either alone or in combination with a fixed dose of 5-HTP/CB. In a different group, we infused drugs via an intraperitoneal catheter while extracellular-recordings were performed in the nucleus accumbens shell (NAcSh), a brain region with dopamine-releasing effects that is involved in the action of appetite suppressants. We found that the triple-drug combination leads to greater weight-loss than each drug alone. Moreover, and as the treatment progresses, the triple drug combination partially reversed psychomotor side-effects induced by Phen. Electrophysiological results revealed that Phen alone evoked a net inhibitory imbalance in NAcSh population activity that correlated with the onset of psychomotor effects. In addition, and unlike the greater weight loss, the addition of 5-HTP/CB did not alter the Phen-evoked inhibitory imbalance in NAcSh responses. Subsequent experiments shed light on the underlying mechanism. That is the majority of NAcSh neurons modulated by 5-HTP/CB were suppressed by Phen. Notably, and despite acting via a different mechanism of action (DA for Phen vs. 5-HT for 5-HTP/CB), both drugs recruited largely overlapping NAcSh neuronal ensembles. These data suggest that the neural correlates of the greater weight loss could be located outside the NAcSh, in other brain circuits. Furthermore, we conclude that Phen + 5-HTP/CB is a potential treatment for overweight and obesity.

Increase in serotonin precursor levels reinstates the context memory during reconsolidation.

In the present study, we tested possible ways of modification of the context long-term memory using the reconsolidation as a tool. Recently, using a depletion of the serotonin content, it was shown that the reinforcing neurotransmitter serotonin is necessary for successful repeated reconsolidation of context memory in terrestrial snails Helix lucorum (Balaban et al. in Sci Rep 6:36933, 2016), and in the present study, we investigated effects of serotonin increase in memory maintenance by injection of the serotonin precursor 5-hydroxytryptophan (5-HTP). We studied reinstatement of the context memory after its impairment during reconsolidation with a protein synthesis blocker anisomycin (ANI) or with a specific inhibitor of protein-kinase Mζ (ZIP). It was observed that applications of 5-HTP alone, known to increase the release of serotonin, or reactivation of memory alone did not restore the ZIP- or ANI-impaired context memory, while combination of the 5-HTP + reactivation of memory effectively reinstated the context memory. The data obtained confirmed the assumption that serotonin/reinforcing transmitter is a part of successful reconsolidation necessary for memory maintenance, demonstrated possible ways of long-term memory regulation during the reconsolidation process.

Increasing serotonin bioavailability in preweaned dairy calves impacts hematology, growth, and behavior

Peripheral serotonin has been shown to regulate important physiological functions such as energy homeostasis and immunity, particularly in rodent and humans, but its role is poorly understood in livestock species. Herein, we tested the safety and effectiveness of increasing serotonin bioavailability in preweaned dairy calves by oral supplementation of a serotonin precursor (5-hydroxytryptophan, 5-HTP) or a serotonin reuptake inhibitor (fluoxetine, FLX). Bull Holstein calves (21 ± 2 d old; N = 24) were fed milk replacer (8 L/d) supplemented with either saline as control (CON, 8 mL/d, n = 8), FLX (40 mg/d, approx. 0.8 mg/kg; n = 8), or 5-HTP (90 mg/d, approx. 1.8 mg/kg; n = 8) for 10 consecutive days in a complete randomized block design. Heart rate (HR), respiration rate, rectal temperature, and health scores were recorded daily. Hip height and body weight were measured at d 1, 5, and 10 relative to initiation of supplementation. Blood samples were collected once before the supplementation period (d 1), during the 10-d supplementation period (daily), and during a 14-d withdrawal period (d 2, 3, 4, 7, and 14 relative to initiation of withdrawal). Cerebrospinal fluid and muscle tissue were collected from a subset of calves (n = 12) that were euthanized after the 10-d supplementation or 14-d withdrawal period. Whole blood serotonin concentrations increased in 5-HTP calves and decreased in FLX calves compared with CON (P < 0.001), indicating that serotonin bioavailability was increased in both groups. Whole blood serotonin concentrations of 5-HTP and FLX calves returned to CON levels after 7 d of withdrawal. All calves grew and were considered healthy throughout the study. In fact, calves fed 5-HTP had higher average daily gain compared with CON (0.87 vs 0.66 ± 0.12 kg/d, P = 0.05). Calves fed FLX had lower HR (P = 0.02) and greater red blood cells and hemoglobin counts on d 10 of supplementation compared with CON (P < 0.01). After the 14-d withdrawal period, FLX was not detected in circulation of FLX calves, but was still present in the muscle tissue. Our results demonstrate that manipulation of the serotonin pathway by supplementing FLX or 5-HTP is a feasible and safe approach in preweaned dairy calves; however, it takes more than 14 d for FLX to be completely withdrawn from the body.

Responses of Withdrawal Interneurons to Serotonin Applications in Naïve and Learned Snails Are Different.

Long-term changes in membrane potential after associative training were described previously in identified premotor interneurons for withdrawal of the terrestrial snail Helix. Serotonin was shown to be a major transmitter involved in triggering the long-term changes in mollusks. In the present study we compared the changes in electrophysiological characteristics of identifiable premotor interneurons for withdrawal in response to bath applications of serotonin (5-HT) or serotonin precursor 5-hydroxytryptophan (5-HTP) in preparations from naïve, neurotoxin-injected or associatively trained snails. It was found that 5-HT or 5-HTP applications caused a significant decrease of membrane potential in premotor interneurons of naïve snails, associatively trained snails and snails with impaired serotonergic system by injection of a selective neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) 1 week before the experiments. Applications of 5-HT or 5-HTP did not cause significant changes in the action potential (AP) threshold potential of these neurons in naïve snails. Conversely, applications of 5-HT or 5-HTP to the premotor interneurons of previously trained or 5,7-DHT-injected snails caused a significant increase in the firing threshold potential in spite of a depolarizing shift of the resting membrane potential. Results demonstrate that responsiveness of premotor interneurons to extracellularly applied 5-HT or 5-HTP changes for days after the associative training or serotonin depletion. Similarity of the effects in trained and 5,7-DHT-injected animals may be due to massive release of serotonin elicited by 5,7-DHT injection. Our results suggest that serotonin release due to aversive conditionining or elicited by the neurotoxin administration triggers similar changes in resting membrane potential and AP threshold in response to bath applications of 5-HT or its precursor 5-HTP.

Passive Membrane Penetration of the Serotonin Precursor 5-Hydroxytryptophan is Controlled by Its Zwitterion.

Species-specific partition coefficients in the octanol/water system were determined for the neurotransmitter serotonin (5-HT) and its precursor 5-hydroxytryptophan (5-HTP). The pH-independent partition coefficients (p) of the individual microspecies were determined by combination of experimentally measured distribution constants and a custom-tailored evaluation method, using highly similar auxiliary compounds. Experimental microscopic partition coefficients for triprotic molecules have only been reported before for thyroxine and its derivatives. The parabolic pH-distribution profile of 5-HT shows the dominance of the lipophilic non-charged microspecies, with a log p of 0.66. However, the most lipophilic non-charged form of 5-HTP, with a log p of 0.31, has no significant contribution to the distribution coefficient at any pH value. Instead, the less lipophilic zwitterionic protonation isomer dominates the distribution in the pH range 2.10-11.11. Although the non-charged microspecies of 5-HTP is 151 times more lipophilic than its zwitterionic protonation isomer, the overwhelming dominance of the zwitterionic form ensures that its contribution to the overall lipophilicity exceeds 1320 times that of the non-charged one. This fact is another counter-example of the widespread belief that passive diffusion into lipophilic media is predominated by the non-charged species. The lipophilicity profile of 5-HT and 5-HTP is depicted in terms of species-specific lipophilicities.

DOPA Decarboxylase Modulates Tau Toxicity

BackgroundThe microtubule-associated protein tau accumulates into toxic aggregates in multiple neurodegenerative diseases. We found previously that loss of D2-family dopamine receptors ameliorated tauopathy in multiple models including a Caenorhabditis elegans model of tauopathy. MethodsTo better understand how loss of D2-family dopamine receptors can ameliorate tau toxicity, we screened a collection of C. elegans mutations in dopamine-related genes (n = 45) for changes in tau transgene–induced behavioral defects. These included many genes responsible for dopamine synthesis, metabolism, and signaling downstream of the D2 receptors. ResultsWe identified one dopamine synthesis gene, DOPA decarboxylase (DDC), as a suppressor of tau toxicity in tau transgenic worms. Loss of the C. elegans DDC gene, bas-1, ameliorated the behavioral deficits of tau transgenic worms, reduced phosphorylated and detergent-insoluble tau accumulation, and reduced tau-mediated neuron loss. Loss of function in other genes in the dopamine and serotonin synthesis pathways did not alter tau-induced toxicity; however, their function is required for the suppression of tau toxicity by bas-1. Additional loss of D2-family dopamine receptors did not synergize with bas-1 suppression of tauopathy phenotypes. ConclusionsLoss of the DDC bas-1 reduced tau-induced toxicity in a C. elegans model of tauopathy, while loss of no other dopamine or serotonin synthesis genes tested had this effect. Because loss of activity upstream of DDC could reduce suppression of tau by DDC, this suggests the possibility that loss of DDC suppresses tau via the combined accumulation of dopamine precursor levodopa and serotonin precursor 5-hydroxytryptophan.

Oral 5-Hydroxytryptophan (5-HTP) Does not Affect Grooved Pegboard Test Performance

Abstract: There is limited knowledge of the neurocognitive effects of the serotonin precursor 5-hydroxytryptophan (5-HTP), which is sold over-the-counter as a nutritional supplement. Animal studies have demonstrated that exogenous 5-HTP promotes the production of ectopic serotonin in dopaminergic neurons—an effect that may reduce dopamine output in these cells. Behavioral studies in humans have demonstrated specific 5-HTP induced cognitive deficits on the Iowa Gambling Task and the Tower of London task that are likely the result of reduced forebrain dopamine. However, it remains unclear if 5-HTP induced performance decrements observed on the Tower of London task were the result of a motor or cognitive impairment. The objective of this double-blind, placebo-controlled study was to clarify this point by determining if oral administration of 150 mg of 5-HTP disrupts fine motor control, as measured by the Grooved Pegboard Test. Seventy five university undergraduates received either a placebo or 5-HTP and completed the Grooved Pegboard Test. The groups did not differ in the amount of time needed to complete the place (p = 0.67) and remove (p = 0.48) components of the Grooved Pegboard Test. Therefore, 5-HTP induced reductions in performance on the Tower of London task appear to be cognitive in nature, and are unlikely to be the result of fine motor impairment (as measured by the Grooved Pegboard Test). These results also provide important safety information for 5-HTP by demonstrating that a 150 mg oral dose does not generally alter fine motor function.

Perturbation of Serotonin Homeostasis during Adulthood Affects Serotonergic Neuronal Circuitry.

Growing evidence shows that the neurotransmitter serotonin (5-HT) modulates the fine-tuning of neuron development and the establishment of wiring patterns in the brain. However, whether serotonin is involved in the maintenance of neuronal circuitry in the adult brain remains elusive. Here, we use a Tph2fl°x conditional knockout (cKO) mouse line to assess the impact of serotonin depletion during adulthood on serotonergic system organization. Data show that the density of serotonergic fibers is increased in the hippocampus and decreased in the thalamic paraventricular nucleus (PVN) as a consequence of brain serotonin depletion. Strikingly, these defects are rescued following reestablishment of brain 5-HT signaling via administration of the serotonin precursor 5-hydroxytryptophan (5-HTP). Finally, 3D reconstruction of serotonergic fibers reveals that changes in serotonin homeostasis affect axonal branching complexity. These data demonstrate that maintaining proper serotonin homeostasis in the adult brain is crucial to preserve the correct serotonergic axonal wiring.

Activation of brain serotonergic system by repeated intracerebral administration of 5-hydroxytryptophan (5-HTP) decreases the expression and activity of liver cytochrome P450

Our recent studies suggest that brain serotonergic system may be involved in the neuroendocrine regulation of cytochrome P450 expression. Intracerebral injection of the serotonergic neurotoxin 5,7-dihydroxytryptamine affected serum hormone concentration and increased the expression and activity of the hormone-dependent isoforms CYP1A1/2, CYP2C11 and CYP3A1. Therefore, the aim of the present study was to investigate the effect of stimulation of brain serotonergic system on cytochrome P450 expression in the liver. The serotonin precursor 5-hydroxytryptophan (5-HTP) was injected for 5 days to the lateral ventricles of rat brain. Afterwards, the brain concentrations of serotonin and its metabolite 5-hydroxyindoleacetic acid 5-HIAA, serum hormone levels and liver cytochrome P450 expression and activity were measured. 5-HTP potently increased the concentration of serotonin and its metabolite 5-HIAA in all the brain structures studied including the hypothalamus. The brain concentrations of noradrenaline or dopamine and its metabolites were not changed in that structure. At the same time, a significant decrease in the serum concentration of the growth hormone and an increase in that of thyroxine were observed. In the liver, the activity of CYP1A, CYP2A, CYP2B, CYP2C11 and CYP3A was diminished, which positively correlated with a decrease in the respective CYP protein levels and a reduction in the mRNA levels of CYP1A2, CYP2A2, CYP2C11, CYP3A1 and CYP3A2. The obtained results provide evidence to prove that brain serotonergic system negatively regulates liver cytochrome P450 expression via endocrine system and suggest mechanisms by which this enzyme may be regulated by drugs with a serotonergic profile such as antidepressants.

Effects of Serotonergic Activation on Respiratory Motor Recovery following Chronic Cervical Spinal Cord Injury

Unilateral cervical spinal cord hemisection (i.e., C2Hx) usually interrupts the bulbospinal respiratory pathways and results in attenuation of the phrenic motor output. It has been shown that activation of serotonergic system can induce partial recovery of phrenic activity after acute C2Hx. The purpose of present study was to examine whether manipulation of the serotonin system can still improve respiratory function during the chronic injury phase. Bilateral diaphragm electromyogram (EMG) and tidal volume were measured in anesthetized and spontaneously breathing adult rats at 8 weeks post‐C2Hx or C2 laminectomy. A bolus intravenous injection of a serotonin precursor (5‐Hydroxytryptophan; 5‐HTP, 10 mg/kg) or a potent agonist for serotonin 2A receptor agonist (TCB‐2, 0.05 mg/kg) was used to activate serotonergic system. Current results demonstrated that both 5‐HTP and TCB‐2 significantly induced a persistent increase in activity of the diaphragm EMG ipsilateral to the lesion but not contralateral diaphragm in C2Hx animals or bilateral diaphragm in uninjured animals. However, the tidal volume was not changed after administration of 5‐HTP or TCB‐2, indicating the enhancement of ipsilateral diaphragm activity is not associated with improvement of the tidal volume. These results suggest that activation of the serotonergic system can specifically increase the ipsilateral diaphragmatic motor output, but it is not sufficient to improve respiratory functional recovery following chronic cervical spinal injury.

Platelet-derived serotonin: Translational implications for liver regeneration

Platelet-derived serotonin: Translational implications for liver regeneration

Influence of temporal relationships between serotonergic and dopaminergic precursors on the regulation of gonadal development in birds

This article is focused on the effect of specific phase relation of serotonergic and dopaminergic oscillations on the gonadal responses of different avian species. These species include (i) summer breeding birds – Red headed bunting (exhibiting post-reproductive absolute photorefractoriness) and Indian Weaver bird (which lacks absolute photorefractoriness), (ii) autumn breeding – Spotted munia and Lal munia (photoperiodic responses of which are distinctly different from that of any long day birds described thus far) and (iii) domesticated Japanese quail (which under natural day length breeds in summer, exhibits relative photorefractoriness, but breeds continuously if maintained in long photoperiod).Previous experiments have shown that daily administration of serotonin precursor 5-hydroxytryptophan and dopamine precursor L-dihydroxyphenylalanine given 8h apart during progressive phase of gonadal cycle can lead to a significant decrease in gonadal activity. However, if given at an interval of 12h it leads to an increase in gonadal activity and the effect of other intervals (0-, 4-, 16- and 20-h) were not different from control. Similar effects were observed during regressive phase of the gonadal cycle of above species except in those which display absolute photorefractory phase in their breeding cycle. This shows that, gonad of such species not only develop post-reproductive photorefractoriness but also becomes insensitive to the stimulatory effects of 5-HTP and L-DOPA when given at the interval of 12h. It is suggested that, temporal phase relation of circadian serotonergic and dopaminergic oscillations is the basis of seasonality in birds and may alter the activity of neuroendocrine-gonadal axis not only under natural day length but also under experimental/different photoperiodic conditions. These results are in agreement with the internal coincidence model of photoperiodic time measurement and indicate that birds can detect specific phase relationship between the two neural oscillations for their reproductive regulations and circadian organization is intricately involved in the regulation of seasonality.