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Bipolar (BD) and major depression (MDD) disorders are severe mental illnesses characterised by altered levels of immune/inflammatory markers and disrupted white matter (WM) microstructure. A pro-inflammatory state was suggested to activate indoleamine 2,3-dioxygenase which, in turn, increases the amount of tryptophan (Trp) converted into kynurenine (Kyn). We investigated whether plasma levels of Trp, Kyn and Kyn/Trp ratio are associated with peripheral levels of immune/inflammatory markers and whether they are related to WM integrity in 100 MDD and 66 BD patients. Patients also underwent MRI, and fractional anisotropy (FA) was estimated as a measure of WM microstructure. BD patients showed higher Kyn levels and Kyn/Trp ratio than MDD patients, and lower FA in several WM tracts, including the corpus callosum and the inferior fronto-occipital fasciculus (IFO). Lower Trp levels associated with a more severe depressive symptomatology irrespective of diagnosis and with lower FA in the corpus callosum (CC) and external capsule (EC). We found an association of immune/inflammatory markers with Kyn/Trp ratio selectively in BD patients: IL-1β and TNF-α showed a positive relationship and IL-2 and IL-9 a negative relationship; in addition, higher IL-4 correlated with lower Kyn levels; higher Kyn/Trp ratio and IL-1β correlated with lower FA in the CC and IFO. Notably, the detrimental effect of IL-1β on the IFO was moderated by the Kyn/Trp ratio. These data suggest that in BD, cytokines and the conversion of Trp into Kyn may affect WM microstructure and support the idea that distinct mechanisms underlie the pathophysiology of BD and MDD. [ABSTRACT FROM AUTHOR]

Aggressive behavior is one of the most challenging symptoms in psychiatry, and biological markers for aggression lack of large sample validations. Serotonin (5-HT) and other neuroactive compounds deriving from Tryptophan (Trp), including kynurenine (Kyn), have not yet been investigated in large cohorts of aggressive individuals to validate their potential as biomarkers of aggression. In 361 male inmates we measured serum levels of Trp, 5-hydroxytryptophan, 5-HT, Kyn, the ratios 5-HT/Trp ∗ 1000 and Kyn/Trp ∗ 1000, and performed Structured Clinical Interview for DSM-IV Axis-I and -II Disorders (SCID-I and -II), global assessment of functioning (GAF), and scales for aggressive behavior, impulsivity, adult attention-deficit/hyperactivity disorder (ADHD), and intelligent quotient (IQ). Aggressive compared to non-aggressive inmates exhibited lower Trp and Kyn serum levels but higher levels of 5-HT and 5-HT/Trp ∗ 1000, higher levels of impulsivity and ADHD indices, lower IQ and GAF, higher prevalence of mood disorders, drug abuse/dependence, and borderline, conduct and antisocial behaviors. Interestingly, Kyn/Trp ∗ 1000 was positively correlated to the number of severe aggressive acts (r = 0.593, P < 0.001). After adjusting for confounding factors, logistic regression analysis indicated that 5-HT/Trp ∗ 1000, antisocial behavior, and GAF were predictors of aggressive behavior. The model combining these three predictors had an area under the ROC curve of 0.851 (95% CI 0.806–0.895). This study indicates that while circulating Trp is reduced in aggressive individuals, the combination of biological (5-HT/Trp ratio) and psychopathological (antisocial behavior and GAF) markers discriminates between aggressive and non-aggressive behavior suggesting the potential of a multi-marker approach in psychiatry given the heterogenic nature of mental diseases. [ABSTRACT FROM AUTHOR]

Melatonin is a neurohormone involved in the regulation of both acute and chronic pain whose mechanism is still not completely understood. We have recently demonstrated that selective MT 2 melatonin receptor partial agonists have antiallodynic properties in animal models of chronic neuropathic pain by modulating ON/OFF cells of the descending antinociceptive system. Here, we examined the antinociceptive properties of the selective MT 2 melatonin receptor partial agonists N-{2-[(3-methoxyphenyl)phenylamino]ethyl}acetamide (UCM765) and N-{2-[(3-bromophenyl)-(4-fluorophenyl)amino]ethyl}acetamide (UCM924) in two animal models of acute and inflammatory pain: the hot-plate and formalin tests. UCM765 and UCM924 (5–40 mg/kg, s.c.) dose-dependently increased the temperature of the first hind paw lick in the hot-plate test, and decreased the total time spent licking the injected hind paw in the formalin test. Antinociceptive effects of UCM765 and UCM924 were maximal at the dose of 20 mg/kg. At this dose, the effects of UCM765 and UCM924 were similar to those produced by 200 mg/kg acetaminophen in the hot-plate test, and by 3 mg/kg ketorolac or 150 mg/kg MLT in the formalin test. Notably, antinociceptive effects of the two MT 2 partial agonists were blocked by the pre-treatment with the MT 2 antagonist 4-phenyl-2-propionamidotetralin (4P-PDOT, 10 mg/kg) in both paradigms. These results demonstrate the antinociceptive properties of UCM765 and UCM924 in acute and inflammatory pain models and corroborate the concept that MT 2 melatonin receptor may be a novel target for analgesic drug development. [ABSTRACT FROM AUTHOR]

Highlights: [•] Melatonin decreases the latency to NREM sleep. [•] Melatonin does not alter the duration of sleep during the 24-h light-dark cycle. [•] The non-selective MT1/MT2 receptor agonist UCM793 affects the number of episodes of wakefulness but not sleep. [•] MLT and the non-selective MT1/MT2 receptor agonist UCM793 differently influence quality of the three vigilance states. [•] Pharmacological activation of MT2 receptors increases NREMS. [ABSTRACT FROM AUTHOR]

Abstract: The neurohormone melatonin activates two G-protein coupled receptors, MT1 and MT2. Melatonin is implicated in circadian rhythms and sleep regulation, but the role of its receptors remains to be defined. We have therefore characterized the spontaneous vigilance states in wild-type (WT) mice and in three different types of transgenic mice: mice with genetic inactivation of MT1 (MT1 −/−), MT2 (MT2 −/−) and both MT1/MT2 (MT1 −/−/MT2 −/−) receptors. Electroencephalographic (EEG) and electromyographic sleep–wake patterns were recorded across the 24-h light–dark cycle. MT1 −/−mice displayed a decrease (−37.3%) of the 24-h rapid eye movement sleep (REMS) time whereas MT2 −/−mice showed a decrease (−17.3%) of the 24-h non rapid eye movement sleep (NREMS) time and an increase in wakefulness time (14.8%). These differences were the result of changes occurring in particular during the light/inactive phase. Surprisingly, MT1 −/−/MT2 −/− mice showed only an increase (8.9%) of the time spent awake during the 24-h. These changes were correlated to a decrease of the REMS EEG theta power in MT1 −/−mice, of the NREMS EEG delta power in MT2 −/−mice, and an increase of the REMS and wakefulness EEG theta power in MT1 −/−/MT2 −/− mice. Our results show that the genetic inactivation of both MT1 and MT2 receptors produces an increase of wakefulness, likely as a result of reduced NREMS due to the lack of MT2 receptors, and reduced REMS induced by the lack of MT1 receptors. Therefore, each melatonin receptor subtype differently regulates the vigilance states: MT2 receptors mainly NREMS, whereas MT1 receptors REMS. [Copyright &y& Elsevier]

Abstract: The contents of protein and non-protein (free and protein-bound) tryptophan and of proteins in cocoa beans of various origin were determined. Protein concentrations varied from 11.8g/100g in beans from the Dominican Republic to 15.7g/100g in roasted beans from the Ivory Coast. The highest protein tryptophan content was found in cocoa beans from Ecuador. Madagascar beans had the highest value of free tryptophan and Echeandia the lowest (17.26 and 6.39mg/100g, respectively). Tryptophan was bound to water-soluble proteins as well as to proteins soluble in buffer solution (pH 8.9) and in 70% ethanol. In particular, Dominican Republic cocoa contained the highest amount of tryptophan bound to water-soluble proteins. Very little tryptophan was linked to proteins soluble in alkaline or ethanol solutions, and values ranged from 0.96 to 3.04 and from 0.24 to 1.21mg/100g of dry defatted cocoa sample, respectively. [ABSTRACT FROM AUTHOR]

Abstract: The composition of the essential oil of Lindera neesiana Kurz fruit was examined by GC-MS, 1H, 13C and bidimensional NMR techniques (HMQC, HMBC, COSY, TOCSY). Forty compounds were identified, representing approximately 86% of the oil: Z-citral (15.08%), E-citral (11.89%), eucalyptol (8.75%), citronellal (6.72%), α-pinene (6.63%) and β-pinene (5.61%) were the major components. The essential oil of L. neesiana fruit showed significant antimicrobial activity against Staphylococcus aureus and Candida albicans at non-cytotoxic doses in human keratinocytes, suggesting possible topical applications. Graphical abstract: The essential oil of Lindera neesiana was investigated by GC-MS and NMR techniques. Its biological activities suggest possible topical applications. Display Omitted [Copyright &y& Elsevier]

Abstract: The contents of protein and non-protein (free and protein-bound) tryptophan and of proteins in the flours of nine legume seeds were determined. Lupins and soybeans showed the highest protein concentrations, followed by groundnuts, beans, broad beans, lentils, vetches, chick-peas, and peas. Protein tryptophan content is higher in soybeans and lower in peas (502 and 192mg/100g of dry flour, respectively) than in the other legumes, which also contain non-protein tryptophan. Chick-peas show the highest value of free tryptophan and groundnuts the lowest (58.2 and 2.24mg/100g of dry flour, respectively). Tryptophan appears to be bound to water-soluble proteins and to proteins soluble at pH 8.9. In particular, chick-peas contain a high amount of tryptophan bound to water-soluble proteins, followed by beans. The results are evaluated, considering the importance, not only of protein, but also non-protein tryptophan, for assessing the nutritive value of a protein in foods. [Copyright &y& Elsevier]

Abstract: The content of proteic and nonproteic (free and protein-bound) tryptophan and of proteins in quinoa, wheat, rice, maize, barley, oat, rye, spelt, sorghum and millet flours was determined. Protein content and proteic tryptophan of quinoa were similar to that of wheat and spelt, but higher than in other cereals. Free tryptophan in quinoa flour showed values similar to those of wheat, oat and sorghum Kalblank, lower than those of barley, spelt and pearl millet, but higher than in rice, maize, rye, sorghum DK 34 – Alabama hybrid. In addition, nonproteic tryptophan appears bound both to water soluble proteins and to proteins soluble at pH 8.9. The results are discussed regarding the importance of the nonprotein tryptophan fraction, the only one able to enter the brain, that is more easily absorbed, so guarantees a greater amount available for uptake by the central nervous system. [Copyright &y& Elsevier]

Abstract: Background: Quinolinic acid and other kynurenine metabolites of the oxidative metabolism of tryptophan play an important role in several pathophysiological conditions. We aimed to study the effect of age on the enzyme activities of tryptophan metabolism along the kynurenine pathway. Methods: Enzyme activity was investigated in liver, kidneys and small intestine obtained from Sprague–Dawley rats of various ages (1 week, 2–3, 12 and 18 months). Results: We found age-related differences in the liver tryptophan 2,3-dioxygenase, small intestine indole 2,3-dioxygenase, liver and kidney kynurenine 3-monooxygenase activities, which decreased significantly with age. Also liver kynureninase activity declined with age, while the activity in kidneys did not show an evident age-related pattern from 2–3 months to 18 months of age. Liver kynurenine oxoglutarate transaminase was quite similar through all considered age groups, while the activity in kidneys was significantly lower in newborn rats and progressively increased up to 12 months, then significantly decreased at 18 months of age. Liver and kidney 3-hydroxyanthranilate 3,4-dioxygenase progressively and significantly increased from newborns to 12 months of age; in the group of rats aged 18 months, the enzyme activity tended to diminish, although not significantly. The liver aminocarboxymuconate-semialdehyde decarboxylase activity increased up to 12 months of age, then tended to decrease at 18 months, while in the kidneys, in which the activity was higher than in the liver at all the considered ages, the activity remained constantly elevated from 2–3 months to 18 months of age. Conclusions: A progressive decline in the enzyme activities involved in tryptophan metabolism along the kynurenine pathway in rat tissues was found with age, except for aminocarboxymuconate-semialdehyde decarboxylase, which, on the contrary, was increased after 2–3 months to the other older groups of age. The altered metabolism of tryptophan with ageing can lead to a decreased biosynthesis of nicotinic acid, tryptophan being the major source of body stores of NAD coenzymes, which are involved in almost all biogenetic and biosynthetic pathways of the organism. [Copyright &y& Elsevier]

Two cardinal elements in the complex and multifaceted pathophysiology of schizophrenia (SCZ) are neuroinflammation and dysregulation of glutamatergic neurotransmission, with the latter being especially involved in treatment-resistant schizophrenia (TRS). Interestingly, the Kynurenine (KYN) pathway (KP) is at the crossroad between them, constituting a potential causal link and a therapeutic target. Although there is preclinical and clinical evidence indicating a dysregulation of KP associated with the clinical phenotype of SCZ, clinical studies investigating the possible relationship between changes in biomarkers of the KP and response to pharmacotherapy are still limited. Therefore, we have studied possible differences in the circulating levels of biomarkers of the metabolism of tryptophan along the KP in 43 responders to first-line treatments (FLR) and 32 TRS patients treated with clozapine, and their possible associations with psychopathology in the two subgroups. Plasma levels of KYN were significantly higher in TRS patients than in FLR patients, indicating a greater activation of KP. Furthermore, the levels of quinolinic (NMDA receptor agonist) and kynurenic acid (NMDA negative allosteric modulator) showed a negative and a positive correlation with several dimensions and the overall symptomatology in the whole sample and in FLR, but not in TRS, suggesting a putative modulating effect of clozapine elicited through the NMDA receptors. Despite the cross-sectional design of the study that prevents us from demonstrating causation, these findings show a significant relationship among circulating KP biomarkers, psychopathology, and response to pharmacotherapy in SCZ. Therefore, plasma KP biomarkers should be further investigated for developing personalized medicine approaches in SCZ. • Higher levels of KYN found in TRS point out a greater activation of the KP in TRS. • Levels of QUIN are negatively associated with the severity of symptoms only in FLRs. • KYNA/QUIN ratio shows a positive correlation with the symptomatology only in FLRs. • Clozapine probably nullifies the impact of QUINA and KYNA on symptoms in TRS. [ABSTRACT FROM AUTHOR]

Abstract: Melatonin (MLT) is a neurohormone known to be involved in the regulation of anxiety. Most of the physiological actions of MLT in the brain are mediated by two high-affinity G-protein-coupled receptors, denoted MT1 and MT2. However, the particular role of these receptors in anxiety remains to be defined. Here we used a novel MT2-selective partial agonist, UCM765 to evaluate the involvement of MT2 receptors in anxiety. Adult male rats were acutely injected with UCM765 (5–10–20mg/kg), MLT (20mg/kg) or diazepam (DZ, 1mg/kg). Anxiety-related behaviors were assessed in the elevated plus maze test (EPMT), novelty suppressed feeding test (NSFT) and open field test (OFT). UCM765 at the dose of 10mg/kg showed anxiolytic-like properties by increasing the time spent in the open arm of the EPMT, and by reducing the latency to eat in a novel environment in the NSFT. In the EPMT, animals treated with UCM765 (10mg/kg) or MLT (20mg/kg) spent more time in the open arms compared to vehicle-treated animals, but to a lesser extent compared to DZ (1mg/kg). In the NSFT, all treatments similarly decreased the latency to eat in a novel environment compared to vehicle. UCM765 and MLT did not affect the total time and the number of entries into the central area of the OFT, but unlike DZ, did not impair locomotion. The anxiolytic effects of UCM765 and MLT in the EPMT and the NSFT were blocked using a pre-treatment with the MT1/MT2 antagonist luzindole (10mg/kg) or the MT2 antagonist 4P-PDOT (10mg/kg). These results demonstrated, for the first time, the anxiolytic properties of UCM765 and suggest that MT2-receptors may be considered a novel target for the development of anxiolytic drugs. [Copyright &y& Elsevier]

Abstract: Centella asiatica (L.) Urban is widely used in traditional medicine in many countries and in the formulation of drugs and cosmetics, and is therefore suitable as a trade item for the development of medicinal plants for the population of Nepal. The aim of this work was to select plant populations of C. asiatica with high contents of secondary metabolites growing in various localities in Nepal, and to enhance knowledge of the cultivation of this plant. Quali-quantitative analysis of bioactive triterpenes (asiaticoside and asiatic acid) and phenol derivatives (flavonoids and caffeoyl esters) was performed by HPLC-DAD-ELSD. The highest quantities of triterpenes and phenols were found in samples from the Gorkha and Chitwan districts. Regarding cultivated plants, soil fertilisation is critical, since over-rich soils affect secondary metabolite content. Plants growing in sand-rich soils produce more terpenes. This work provides indications on how to select high-terpene producing germplasm and recommendations for plant cultivation. [Copyright &y& Elsevier]

Abstract: One new glycoside derivative from syringic acid and one new phenol glycoside, curculigoside E (1) and orchioside D (2), were isolated and characterized from the rootstock of Curculigo orchioides collected in the Nawalparasi District (Nepal). The structures of the new isolated compounds were elucidated by means of spectroscopic methods such as 1D, 2D NMR and MS. [Copyright &y& Elsevier]

Abstract: Since alterations of tryptophan metabolism have been reported in diabetes and atherosclerosis, it was thought of interest to investigate any role of cloricromene through the influence on the oxidative metabolism of the amino acid by using diabetic/hyperlipidemic rabbits. Male 4-month-old New Zealand white rabbits, fed a diet enriched with 1% cholesterol and 10% corn oil, were made diabetic with alloxan. During the hyperlipidemic diet, a group of rabbits was treated with cloricromene (10 mg/kg/day subcutaneously plus 1.5 mg/kg/day intravenously, for 5 weeks). The other group received saline. Normometabolic New Zealand rabbits fed standard diet, treated or not with cloricromene, were used as control. The specific activities of liver tryptophan 2,3-dioxygenase and small intestine indole 2,3-dioxygenase were not significantly changed by the drug treatment. Also the specific activities of other enzymes of the kynurenine pathway in the liver and kidneys, specifically kynurenine 3-monooxygenase, kynureninase and kynurenine-oxoglutarate transaminase, did not show any significant difference in both tissues between the two groups of rabbits. On the contrary, 3-hydroxyanthranilate 3,4-dioxygenase activity in the liver of diabetic/hyperlipidemic rabbits and control rabbits treated with cloricromene showed a slight increase in comparison with untreated animals. Conversely, the specific activity of the enzyme in kidneys was not affected by the drug treatment in diabetic/hyperlipidemic animals but was reduced in controls. Aminocarboxymuconate-semialdehyde decarboxylase specific activity remained unchanged in the liver following cloricromene treatment, instead the specific activity of the enzyme in the kidneys of the diabetic/hyperlipidemic rabbits was significantly increased by the drug, with a value more than double in comparison to untreated animals. The activity of the scavenger enzyme Cu/Zn superoxide dismutase (Cu/Zn SOD) in the small intestine was also determined and found significantly increased of about twice as much in the group of diabetic/hyperlipidemic rabbits treated with cloricromene. In conclusion, in diabetic/hyperlipidemic rabbits, cloricromene appeared to influence the enzymes involved in the last steps of tryptophan oxidative metabolism through the kynurenine pathway. This, together with the antioxidant action through the activation of Cu/Zn SOD, might deserve further investigation for evaluating any link between the observed experimental findings at the level of the kynurenine pathway and the clinical effect of the drug. [Copyright &y& Elsevier]

Background: Bipolar disorder (BD) is a severe mental illness characterised by reduced grey matter (GM) volumes and cortical thickness, and disrupted white matter (WM) microstructure. Activation of indoleamine 2,3-dioxygenase following a pro-inflammatory state could increase the amount of tryptophan (Trp) converted to kynurenine (Kyn) possibly leading to the production of detrimental catabolites of the Kyn pathway with neurotoxic effects. We investigated if peripheral levels of Trp-and Kyn and the breakdown of Trp-into Kyn (Kyn/Trp-ratio) are related to WM and GM integrity in BD.Methods: Peripheral levels of Trp-and Kyn were analysed in 72 patients with BD and 33 controls. Patients also underwent MRI in a Philips 3T scanner.Results: Patients showed higher Kyn levels and Kyn/Trp-ratio compared to controls. MRI analyses performed in patients with BD showed a negative association between the Kyn/Trp-ratio and the integrity of corpus callosum microstructure, the volume of the amygdala and cortical thickness in fronto-parietal regions.Limitation: The lack of information on the levels of downstream metabolites of Kyn prevent us to confirm the possible unbalance between quinolinic and kynurenic acids as well as their possible relationship with changes in GM and WM markers. The activation of the Kyn pathway as suggested by the increased Kyn/Trp-ratio may lead to an imbalance of the neurotoxic vs the neuroprotective arm of the biochemical pathway, resulting in significant changes in GM and WM regions of brain areas strongly implicated in the pathophysiology of BD, such as amygdala and corpus callosum. [ABSTRACT FROM AUTHOR]

The activity of nicotinic acid in hypercholesterolemia has been poorly understood. In man, nicotinic acid derives for the most part from tryptophan along the tryptophan–nicotinic acid pathway, also called the kynurenine pathway, kynurenine being the key metabolite in this process. In the present paper, we investigated if, in animals with hypercolesterolemia, degradation of tryptophan to nicotinic acid along the kynurenine pathway was perturbated.Liver, kidney and intestine enzyme activities of the tryptophan–nicotinic acid pathway in normolipidemic, diet-induced hyperlipidemic New Zealand and heritable hypercholesterolemic Watanabe (WHHL) rabbits were determined.Liver tryptophan 2,3-dioxygenase (TDO) activity was present only as a holoenzyme and was higher in the controls than in the hyperlipidemic and Watanabe rabbits, but no difference was present between the group fed an atherogenic hyperlipidic diet and the WHHL rabbits. Small intestine indole 2,3-dioxygenase (IDO) did not vary significantly among the three groups but was higher in comparison with liver TDO activity. In liver, kynurenine 3-monooxygenase and kynurenine-oxoglutarate transaminase activities did not show any significant difference among the three groups of rabbits. Kynureninase and 3-hydroxyanthranilate 3,4-dioxygenase activities per g of fresh tissue decreased significantly in the group of hyperlipidemic and in WHHL rabbits. In the kidneys, kynurenine 3-monooxygenase and kynureninase activity did not change significantly in the three groups of rabbits; kynurenine-oxoglutarate transaminase activity per g of fresh tissue decreased in both hyperlipidemic groups, but no significant difference was observed between hyperlipidemic and Watanabe rabbits. 3-Hydroxyanthranilate 3,4-dioxygenase activity in kidney was decreased markedly in hyperlipidemic and Watanabe rabbits, but there was no difference between the two hypercholesterolemic groups. Aminocarboxymuconate-semialdehyde decarboxylase activity did not change. Thus 3-hydroxyanthranilate 3,4-dioxygenase may be an important regulatory mechanism in the control of the flow of tryptophan along the kynurenine pathway to NAD in hypercholesterolemic rabbits.This study first demonstrates that in rabbits, hypercholesterolemia, both diet- or genetically induced, can influence the enzyme activities of the tryptophan–nicotinic acid pathway leading to a decreased formation of nicotinic acid, and thus NAD. [Copyright &y& Elsevier]

Synapsins (Syns) are a family of phosphoproteins associated with synaptic vesicles (SVs). Their main function is to regulate neurotransmitter release by maintaining a reserve pool of SVs at the presynaptic terminal. Previous studies reported that the deletion of one or more Syn genes in mice results in an epileptic phenotype and autism-related behavioral abnormalities. Here we aimed at characterizing the behavioral phenotype and neurobiological correlates of the deletion of Syns in a Syn triple knockout (TKO) mouse model. Wild type (WT) and TKO mice were tested in the open field, novelty suppressed feeding, light-dark box, forced swim, tail suspension and three-chamber sociability tests. Using in vivo electrophysiology, we recorded the spontaneous activity of dorsal raphe nucleus (DRN) serotonin (5-HT) and ventral tegmental area (VTA) dopamine (DA) neurons. Levels of 5-HT and DA in the frontal cortex and hippocampus of WT and TKO mice were also assessed using a High-Performance Liquid Chromatography. TKO mice displayed hyperactivity and impaired social and anxiety-like behavior. Behavioral dysfunctions were accompanied by reduced firing activity of DRN 5-HT, but not VTA DA, neurons. TKO mice also showed increased responsiveness of DRN 5-HT-1A autoreceptors, measured as a reduced dose of the 5-HT-1A agonist 8-OH-DPAT necessary to inhibit DRN 5-HT firing activity by 50%. Finally, hippocampal 5-HT levels were lower in TKO than in WT mice. Overall, Syns deletion in mice leads to a reduction in DRN 5-HT firing activity and hippocampal 5-HT levels along with behavioral alterations reminiscent of human neuropsychiatric conditions associated with Syn dysfunction. • Syn triple knockout (TKO) mice display hyperactivity and impaired social behavior. • TKO mice show reduced dorsal raphe serotonergic neuronal activity. • TKO mice have lower hippocampal serotonin levels. • TKO mice are a model of humans diseases associated with Syn dysfunctions. [ABSTRACT FROM AUTHOR]

Background: Antidepressants have a low rate of response paired with a delayed onset of action. Translational studies are thus seeking for novel targets for antidepressant drug development. Preclinical evidence has demonstrated that the endocannabinoid system plays an important role in mood and stress response, even if drugs targeting this system have not yet become available for clinical use. The dietary supplement N-Palmitoylethanolamide (PEA) is a fatty acid amide belonging to the endocannabinoid system with potential antidepressant properties.Methods: We performed a bibliographic search to review current knowledge on the potential antidepressant effects of PEA and its underlying mechanism of action.Results: PEA targets not only the peroxisome proliferator-activated receptor-alpha (PPAR-α), but also the endocannabinoid system, binding the G-protein-coupled receptor 55, a non-CB1/CB2 cannabinoid receptor, and also the CB1/CB2 receptors, although with a weak affinity. Preclinical studies have shown antidepressant activity of PEA in animal paradigms of depression and of depression associated with neuropathic pain and traumatic brain injury. In a translational perspective, PEA is increased in stress conditions, and a randomized, double-blind study in depressed patients indicated a fast-antidepressant action of PEA when associated with citalopram.Limitations: There are still limited preclinical and clinical studies investigating the effect of PEA upon the endocannabinoid system and its potential as antidepressant.Conclusions: PEA has potential antidepressant effects alone or in combinations with other classes of antidepressants. Future studies in depressed patients are needed to confirm the mood-modulating properties of PEA and its role as a biomarker of depression. [ABSTRACT FROM AUTHOR]