Monoaminergic Neurotransmission Research Articles

Pharmacology of ketamine and esketamine as rapid-acting antidepressants

The lack of utter efficacy and fast action of commonly used antidepressants that selectively target the monoaminergic neurotransmission has led to the exploration of ketamine's actions. Ketamine's antidepressant effect was firstly described in 1973 and nowadays its therapeutic value as a fast- and long- lasting antidepressant has been extensively established. Ketamine is an antagonist of the N-Methyl-D-aspartate receptor (NMDAR) and its main mechanism of action via NMDAR inhibition expressed in GABAergic (gamma-Aminobutyric acid, GABA) interneurons may be relayed to its antidepressant effects. This review aims to describe the pharmacokinetic and pharmacodynamic profile of ketamine when used for treatment-resistant depression. Moreover, ketamine is a racemic mixture consisting of two enantiomers, R- and S- ketamine. We describe the pharmacology of esketamine, along with the guidelines for effective and safe intranasal administration of esketamine. Lastly, this review presents sex differences in preclinical and clinical studies of ketamine and esketamine administration.

The Potential of Hyperbaric Oxygen Therapy Against Codeine Addiction Reduction

Excessive opioid usage such as codeine can lead to anxiety, dose dependency, and addiction. Furthermore, drug addiction induce intoxication and in some case death. Several approach can be done to treat codein abuse. Hyberbaric oxygen is one of the therapy choices, considered that it can be used as main and supporting management. Related studies said increasing level of Nitric Oxide (NO) and Dopaminergic, main substances in drug addiction, can be inhibited by hyperbaric oxygen therapy thus it has the potential value to reduce narcotic addiction such as codeine. However, the review papers of previous research is rare. Therefore, this article discussed codeine, hyperbaric oxygen therapy (HBO), and its relation to decrease level of codein addiction, based on scientific literatures. In conclusion, HBO treatment has a potential correlation to minimize the effects of opioid withdrawal, since it can induce nitric oxide and involves the control of monoaminergic neurotransmitters that reduce withdrawal effects.

Role of Organic Cation Transporter 3 and Plasma Membrane Monoamine Transporter in the Rewarding Properties and Locomotor Sensitizing Effects of Amphetamine in Male andFemale Mice.

A lack of effective treatment and sex-based disparities in psychostimulant addiction and overdose warrant further investigation into mechanisms underlying the abuse-related effects of amphetamine-like stimulants. Uptake-2 transporters such as organic cation transporter 3 (OCT3) and plasma membrane monoamine transporter (PMAT), lesser studied potential targets for the actions of stimulant drugs, are known to play a role in monoaminergic neurotransmission. Our goal was to examine the roles of OCT3 and PMAT in mediating amphetamine (1 mg/kg)-induced conditioned place preference (CPP) and sensitization to its locomotor stimulant effects, in males and females, using pharmacological, decynium-22 (D22; 0.1 mg/kg, a blocker of OCT3 and PMAT) and genetic (constitutive OCT3 and PMAT knockout (−/−) mice) approaches. Our results show that OCT3 is necessary for the development of CPP to amphetamine in males, whereas in females, PMAT is necessary for the ability of D22 to prevent the development of CPP to amphetamine. Both OCT3 and PMAT appear to be important for development of sensitization to the locomotor stimulant effect of amphetamine in females, and PMAT in males. Taken together, these findings support an important, sex-dependent role of OCT3 and PMAT in the rewarding and locomotor stimulant effects of amphetamine.

The increasing importance of LNAA supplementation in phenylketonuria at higher plasma phenylalanine concentrations

BackgroundLarge neutral amino acid (LNAA) treatment has been suggested as alternative to the burdensome severe phenylalanine-restricted diet. While its working mechanisms and optimal composition have recently been further elucidated, the question whether LNAA treatment requires the natural protein-restricted diet, has still remained. ObjectiveFirstly, to determine whether an additional liberalized natural protein-restricted diet could further improve brain amino acid and monoamine concentrations in phenylketonuria mice on LNAA treatment. Secondly, to compare the effect between LNAA treatment (without natural protein) restriction and different levels of a phenylalanine-restricted diet (without LNAA treatment) on brain amino acid and monoamine concentrations in phenylketonuria mice. DesignBTBR Pah-enu2 mice were divided into two experimental groups that received LNAA treatment with either an unrestricted or semi phenylalanine-restricted diet. Control groups included Pah-enu2 mice on the AIN-93 M diet, a severe or semi phenylalanine-restricted diet without LNAA treatment, and wild-type mice receiving the AIN-93 M diet. After ten weeks, brain and plasma samples were collected to measure amino acid profiles and brain monoaminergic neurotransmitter concentrations. ResultsAdding a semi phenylalanine-restricted diet to LNAA treatment resulted in lower plasma phenylalanine but comparable brain amino acid and monoamine concentrations as compared to LNAA treatment (without phenylalanine restriction). LNAA treatment (without phenylalanine restriction) resulted in comparable brain monoamine but higher brain phenylalanine concentrations compared to the severe phenylalanine-restricted diet, and significantly higher brain monoamine but comparable phenylalanine concentrations as compared to the semi phenylalanine-restricted diet. ConclusionsPresent results in PKU mice suggest that LNAA treatment in PKU patients does not need the phenylalanine-restricted diet. In PKU mice, LNAA treatment (without phenylalanine restriction) was comparable to a severe phenylalanine-restricted diet with respect to brain monoamine concentrations, notwithstanding the higher plasma and brain phenylalanine concentrations, and resulted in comparable brain phenylalanine concentrations as on a semi phenylalanine-restricted diet.

Behavioural and neurochemical effects after repeated administration of N‐ethylpentylone (ephylone) in mice

N-ethyl-pentylone (NEP), also known as 'ephylone' and N-ethylnorpentylone, has been identified as one of the most recent novel psychostimulants to emerge into the illicit drug market and it has been associated with some intoxications and even fatalities. However, little is known about the consequences of its repeated consumption as well as the role of the monoaminergic system in such consequences. Thus, the aim of our study was to investigate the neurochemical profile and the behavioural effects after both acute and repeated NEP exposure. Male OF1mice were acutely (1, 3, 10mg/kg, i.p.) or repeatedly (1, 3, 10mg/kg, i.p., 5days, twice/day) exposed to NEP, and anxiety-like behaviour, aggressiveness, social interaction, depressive-like symptoms, body temperature, changes in monoaminergic enzymes and neurotransmitters levels as well as ΔFosB in striatum and prefrontal cortex (PFC) from post-mortem tissue were analysed short after drug-exposure or during drug-withdrawal. Acute administration of NEP induced anxiolytic effects but also an aggressive behaviour and social exploration deficits in mice, which persist during NEP-withdrawal. Moreover, NEP induced hyperthermia as well as depressive-like symptoms after repeated administrations that may be related to the decrease in serotonin and noradrenaline levels observed in striatum and PFC. Finally, the long-term increase in ΔFosB levels in striatum after NEP chronic exposure points to a high risk of dependence. Altogether indicates that NEP consumption induces different neurological and neuropsychiatric disorders accompanied by changes in the monoaminergic system, posing a threat to public health.

GCH1 Deficiency Activates Brain Innate Immune Response and Impairs Tyrosine Hydroxylase Homeostasis.

The Parkinson's disease (PD) risk gene GTP cyclohydrolase 1 (GCH1) catalyzes the rate-limiting step in tetrahydrobiopterin (BH4) synthesis, an essential cofactor in the synthesis of monoaminergic neurotransmitters. To investigate the mechanisms by which GCH1 deficiency may contribute to PD, we generated a loss of function zebrafish gch1 mutant (gch1-/-), using CRISPR/Cas technology. gch1-/- zebrafish develop marked monoaminergic neurotransmitter deficiencies by 5 d postfertilization (dpf), movement deficits by 8 dpf and lethality by 12 dpf. Tyrosine hydroxylase (Th) protein levels were markedly reduced without loss of ascending dopaminergic (DAergic) neurons. L-DOPA treatment of gch1-/- larvae improved survival without ameliorating the motor phenotype. RNAseq of gch1-/- larval brain tissue identified highly upregulated transcripts involved in innate immune response. Subsequent experiments provided morphologic and functional evidence of microglial activation in gch1-/- The results of our study suggest that GCH1 deficiency may unmask early, subclinical parkinsonism and only indirectly contribute to neuronal cell death via immune-mediated mechanisms. Our work highlights the importance of functional validation for genome-wide association studies (GWAS) risk factors and further emphasizes the important role of inflammation in the pathogenesis of PD.SIGNIFICANCE STATEMENT Genome-wide association studies have now identified at least 90 genetic risk factors for sporadic Parkinson's disease (PD). Zebrafish are an ideal tool to determine the mechanistic role of genome-wide association studies (GWAS) risk genes in a vertebrate animal model. The discovery of GTP cyclohydrolase 1 (GCH1) as a genetic risk factor for PD was counterintuitive, GCH1 is the rate-limiting enzyme in the synthesis of dopamine (DA), mutations had previously been described in the non-neurodegenerative movement disorder dopa-responsive dystonia (DRD). Rather than causing DAergic cell death (as previously hypothesized by others), we now demonstrate that GCH1 impairs tyrosine hydroxylase (Th) homeostasis and activates innate immune mechanisms in the brain and provide evidence of microglial activation and phagocytic activity.

Regulation of Mating-Induced Increase in Female Germline Stem Cells in the Fruit Fly Drosophila melanogaster

In many insect species, mating stimuli can lead to changes in various behavioral and physiological responses, including feeding, mating refusal, egg-laying behavior, energy demand, and organ remodeling, which are collectively known as the post-mating response. Recently, an increase in germline stem cells (GSCs) has been identified as a new post-mating response in both males and females of the fruit fly, Drosophila melanogaster. We have extensively studied mating-induced increase in female GSCs of D. melanogaster at the molecular, cellular, and systemic levels. After mating, the male seminal fluid peptide [e.g. sex peptide (SP)] is transferred to the female uterus. This is followed by binding to the sex peptide receptor (SPR), which evokes post-mating responses, including increase in number of female GSCs. Downstream of SP-SPR signaling, the following three hormones and neurotransmitters have been found to act on female GSC niche cells to regulate mating-induced increase in female GSCs: (1) neuropeptide F, a peptide hormone produced in enteroendocrine cells; (2) octopamine, a monoaminergic neurotransmitter synthesized in ovary-projecting neurons; and (3) ecdysone, a steroid hormone produced in ovarian follicular cells. These humoral factors are secreted from each organ and are received by ovarian somatic cells and regulate the strength of niche signaling in female GSCs. This review provides an overview of the latest findings on the inter-organ relationship to regulate mating-induced female GSC increase in D. melanogaster as a model. We also discuss the remaining issues that should be addressed in the future.

Dietary tryptophan, tyrosine, and phenylalanine depletion induce reduced food intake and behavioral alterations in mice

Important precursors of monoaminergic neurotransmitters, dietary tryptophan (TRP), tyrosine, and phenylalanine (all referred to as TTP), play crucial roles in a wide range of behavioral and emotional functions. In the current study, we investigated whether diets devoid of TTP or diets deficient in TRP alone can affect body weight, behavioral characteristics, and gut microbiota, by comparing mice fed on these amino acids-depleted diets to mice fed on diets containing regular levels of amino acids. Both dietary TTP- and TRP-deprived animals showed a reduction in food intake and body weight. In behavioral analyses, the mice fed TTP-deprived diets were more active than mice fed diets containing regular levels of amino acids. The TRP-deprived group exhibited a reduction in serum TRP levels, concomitant with a decrease in serotonin and 5-hydroxyindoleacetic acid levels in some regions of the brain. The TTP-deprived group showed a reduction in TTP levels in the serum, concomitant with decreases in both phenylalanine and tyrosine levels in the hippocampus, as well as serotonin, norepinephrine, and dopamine concentrations in some regions of the brain. Regarding the effects of TRP or TTP deprivation on gut microbial ecology, the relative abundance of genus Roseburia was significantly reduced in the TTP-deprived group than in the dietary restriction control group. Interestingly, TTP was found even in the feces of mice fed TTP- and TRP-deficient diets, suggesting that TTP is produced by microbial or enzymatic digestion of the host-derived proteins. However, microbe generated TTP did not compensate for the systemic TTP deficiency induced by the lack of dietary TTP intake. Collectively, these results indicate that chronic dietary TTP deprivation induces decreased monoamines and their metabolites in a brain region-specific manner. The altered activities of the monoaminergic systems may contribute to increased locomotor activity.

Monoamine oxidase A and B inhibitory activities of 3,5-diphenyl-1,2,4-triazole substituted [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives

Monoamine oxidase (EC 1.4.3.4, MAO) is a flavin adenine dinucleotide-containing flavoenzyme located on the outer mitochondrial membrane and catalyzes the oxidative deamination of monoaminergic neurotransmitters and dietary amines. MAO exists in humans as two isoenzymes, hMAO-A and hMAO-B, which are distinguished by their tertiary structures, preferred substrates and inhibitors, and selective inhibition of these isoenzymes are used in the treatment of different diseases such as Alzheimer's, Parkinson's and depression. In the present study, we report the design, synthesis and characterization of 3,5-diphenyl-1,2,4-triazole substituted [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives as novel and selective inhibitors of hMAO-B. Twenty one compounds (38, 39a-h, 41a-d, 42a-h) were screened for their inhibitory activity against hMAO-A and hMAO-B by using in vitro Amplex Red® reagent based fluorometric method and all compounds were found to be as selective h-MAO-B inhibitors to a different degree. The compound 42e and 42h displayed the highest inhibitory activity against hMAO-B with IC50 values of 2.51 and 2.81 µM, respectively, and more than 25-fold selectivity towards inhibition of hMAO-B. A further kinetic evaluation of the most potent derivative (42e) was also performed and a mixed mode of inhibition of hMAO-B by the compound 42e was determined (Ki = 0,26 µM). According to our findings the [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole emerged as a promising scaffold for the development of novel and selective hMAO-B inhibitors.

Correlations of blood and brain biochemistry in phenylketonuria: Results from the Pah-enu2 PKU mouse

BackgroundIn phenylketonuria (PKU), treatment monitoring is based on frequent blood phenylalanine (Phe) measurements, as this is the predictor of neurocognitive and behavioural outcome by reflecting brain Phe concentrations and brain biochemical changes. Despite clinical studies describing the relevance of blood Phe to outcome in PKU patients, blood Phe does not explain the variance in neurocognitive and behavioural outcome completely. MethodsIn a PKU mouse model we investigated 1) the relationship between plasma Phe and brain biochemistry (Brain Phe and monoaminergic neurotransmitter concentrations), and 2) whether blood non-Phe Large Neutral Amino Acids (LNAA) would be of additional value to blood Phe concentrations to explain brain biochemistry. To this purpose, we assessed blood amino acid concentrations and brain Phe as well as monoaminergic neurotransmitter levels in in 114 Pah-Enu2 mice on both B6 and BTBR backgrounds using (multiple) linear regression analyses. ResultsPlasma Phe concentrations were strongly correlated to brain Phe concentrations, significantly negatively correlated to brain serotonin and norepinephrine concentrations and only weakly correlated to brain dopamine concentrations. From all blood markers, Phe showed the strongest correlation to brain biochemistry in PKU mice. Including non-Phe LNAA concentrations to the multiple regression model, in addition to plasma Phe, did not help explain brain biochemistry. ConclusionThis study showed that blood Phe is still the best amino acid predictor of brain biochemistry in PKU. Nevertheless, neurocognitive and behavioural outcome cannot fully be explained by blood or brain Phe concentrations, necessitating a search for other additional parameters. Take-home messageBlood Phe is still the best amino acid predictor of brain biochemistry in PKU. Nevertheless, neurocognitive and behavioural outcome cannot fully be explained by blood or brain Phe concentrations, necessitating a search for other additional parameters.

Many Drugs of Abuse May Be Acutely Transformed to Dopamine, Norepinephrine and Epinephrine In Vivo.

It is well established that a wide range of drugs of abuse acutely boost the signaling of the sympathetic nervous system and the hypothalamic–pituitary–adrenal (HPA) axis, where norepinephrine and epinephrine are major output molecules. This stimulatory effect is accompanied by such symptoms as elevated heart rate and blood pressure, more rapid breathing, increased body temperature and sweating, and pupillary dilation, as well as the intoxicating or euphoric subjective properties of the drug. While many drugs of abuse are thought to achieve their intoxicating effects by modulating the monoaminergic neurotransmitter systems (i.e., serotonin, norepinephrine, dopamine) by binding to these receptors or otherwise affecting their synaptic signaling, this paper puts forth the hypothesis that many of these drugs are actually acutely converted to catecholamines (dopamine, norepinephrine, epinephrine) in vivo, in addition to transformation to their known metabolites. In this manner, a range of stimulants, opioids, and psychedelics (as well as alcohol) may partially achieve their intoxicating properties, as well as side effects, due to this putative transformation to catecholamines. If this hypothesis is correct, it would alter our understanding of the basic biosynthetic pathways for generating these important signaling molecules, while also modifying our view of the neural substrates underlying substance abuse and dependence, including psychological stress-induced relapse. Importantly, there is a direct way to test the overarching hypothesis: administer (either centrally or peripherally) stable isotope versions of these drugs to model organisms such as rodents (or even to humans) and then use liquid chromatography-mass spectrometry to determine if the labeled drug is converted to labeled catecholamines in brain, blood plasma, or urine samples.

Are Noradrenergic Transmission Reducing Drugs Antidepressants?

Major depressive disorder (MDD) remains a significant public health problem worldwide, and revised treatment strategies are therefore urgently needed, including the creation of novel antidepressant compounds or using existing molecular entities in new ways. Etiologic theories of MDD from decades ago have suggested that synaptic deficiencies of monoaminergic neurotransmitters play a causative role in this neuropsychiatric disorder, and that boosting monoamines with drugs such as SSRIs, SNRIs, TCAs, and MAOIs has antidepressant effects and in some individuals can even induce hypomania or mania. While other factors, such as various intracellular molecular pathways and hippocampal neurogenesis, undoubtedly also play a role in MDD, monoaminergic boosting drugs nonetheless have clearly demonstrated antidepressant properties. There is also, however, a body of studies in the preclinical literature suggesting that monoaminergic transmission reducing drugs, including noradrenergic ones, also have antidepressant-like behavioral properties in rodents. Given that there is increasing evidence that the monoamines have u-shaped or Janus-faced dose-response properties, in which a mid-range value is “optimal” in a variety of behavioral and physiological processes, it is plausible that either too much or too little synaptic norepinephrine in key circuits may exacerbate MDD in some individuals. Here we briefly review rodent depression-related behavioral data, focusing on the forced swim test, from three major classes of noradrenergic transmission reducing drugs (alpha2 agonists, beta blockers, alpha1 antagonists), and find much support for the hypothesis that they have antidepressant-like properties. Whether these drugs are antidepressants in human subjects remains to be determined.

Serotonin (5-hydroxytryptamine)-immunoreactive neurons in the brain of the viviparous fish Gambusia affinis

The monoaminergic neurotransmitter serotonin (5-HT) acts as a neuromodulator and is associated with a wide range of functions in fish. In this investigation, 5-HT immunoreactivity was studied in the central nervous system (CNS) of the viviparous mosquitofish Gambusia affinis. 5-HT-immunoreactive (5-HT-ir) cells/fibres were observed throughout the subdivisions of ventral and dorsal telencephalon including the olfactory bulb. Several intensely stained 5-HT-ir cells and/or fibres were detected in different areas of the hypothalamus as well as the proximal pars distalis of the pituitary gland. 5-HT-ir cells were restricted to the dorsal and ventral part of the pretectal diencephalic cluster, but only fibres were detected in the anterior, ventromedial and posterior subdivisions of the thalamic nucleus and in the preglomerular complex. In the mesencephalon, 5-HT-ir perikarya, and fibres were seen in the optic tectum, midbrain tegmentum and torus semicircularis. A cluster of prominently labelled 5-HT-ir neurons was observed in the superior raphe nucleus, whereas numerous 5-HT-ir fibres were distributed throughout the rhombencephalic divisions. In addition, a bundle of rostrocaudally running 5-HT-ir fibres was noticed in the spinal cord. This is the first detailed neuroanatomical study in a viviparous teleost, reporting a widespread distribution of 5-HT-ir somata and fibres in the CNS. The results of this study provide new insights into the evolutionarily well conserved nature of the monoaminergic system in the CNS of vertebrates and suggest a role for 5-HT in regulation of several physiological, behavioural and neuroendocrine functions in viviparous teleosts.

Dihydroergotamine affects spatial behavior and neurotransmission in the central nervous system of Wistar rats.

Dihydroergotamine (DHE) is a derivative of an ergot alkaloid used as an antimigraine medication. Nowadays, ergot alkaloids may still endanger the safety of humans and animals as food or medicine pollutants, but the outcomes of long-term DHE administration on the behaviour and neurotransmission remain undescribed. Adult male Wistar Albino Glaxo rats pre-treated orally with DHE for six weeks were investigated to assess the relationship between concentration of neurotransmitters and behavioural response. The behavioural effects of the drug administered at doses of either 30 µg/kg b.w. (group DHE30, n = 11) or 100 µg/kg b.w. per day (group DHE100, n = 10) were evaluated in the Morris Water Maze. It is known that monoaminergic neurotransmitters (serotonin, noradrenaline and dopamine) in some brain structures (prefrontal cortex, hippocampus, striatum, cerebellum, spinal cord) play a role in the control of cognitive and motor functions. The concentration of neurotransmitters was determined by High Performance Liquid Chromatography (HPLC). Administration of DHE influenced neither the learning processes nor memory in rats. Nevertheless, an increased motor activity of the DHE-administered animals was observed in both the cued and non-cued behavioural tasks. In HPLC examination, changes in the concentration of monoaminergic neurotransmitters and their metabolites were noted in all tested structures, except for the hippocampus. DHE is able to modulate noradrenergic, serotonergic and dopaminergic neurotransmission that may support the increase in locomotion.

Monoaminergic Multilocus Genetic Variants Interact with Stressful Life Events in Predicting Changes in Adolescent Anxiety Symptoms: A One-year Longitudinal Study

Research suggests that genetic variants linked to monoaminergic neurotransmitter function moderate the association between stress and anxiety symptoms, but examining gene-environment (G × E) interactions with individual genes limits power. As one of polygenetic approaches, the multilocus genetic profile score is derived theoretically from combining the effects of multiple candidate genes based on the "biological plausibility". Using this approach, the current study examined the interaction between monoaminergic multilocus genetic variants and stressful life events on the changes in adolescent anxiety symptoms across a one-year timespan. In a Chinese Han adolescent sample which was derived from three vocational high schools (N = 587; T1: Mage = 16.47 ± 1.53 years; 50.8%, girls), the monoaminergic multilocus genetic profile score was calculated using 5-HTR2C rs6318, TPH2 rs4570625 and DRD2 rs1800497 polymorphisms. Results showed that this monoaminergic multilocus genetic profile score interacted with stressful life events in predicting changes in anxiety symptoms. Consistent with the G×E hypothesis of differential susceptibility, adolescents with more monoaminergic plasticity alleles not only suffered more from high levels of stressful life events, which increased the risk for anxiety symptoms, but also benefited more from low levels of stressful life events, which decreased the risk for anxiety symptoms. There were no significant G × E interactions when individual polymorphisms were examined in isolation. The results highlight the importance of examining aggregated influences of multiple genes in G × E interactions underlying the longitudinal development of adolescent anxiety symptoms.

Kynurenine pathway in post-mortem prefrontal cortex and cerebellum in schizophrenia: relationship with monoamines and symptomatology

BackgroundThe cortico-cerebellar-thalamic-cortical circuit has been implicated in the emergence of psychotic symptoms in schizophrenia (SZ). The kynurenine pathway (KP) has been linked to alterations in glutamatergic and monoaminergic neurotransmission and to SZ symptomatology through the production of the metabolites quinolinic acid (QA) and kynurenic acid (KYNA).MethodsThis work describes alterations in KP in the post-mortem prefrontal cortex (PFC) and cerebellum (CB) of 15 chronic SZ patients and 14 control subjects in PFC and 13 control subjects in CB using immunoblot for protein levels and ELISA for interleukins and QA and KYNA determinations. Monoamine metabolites were analysed by high-performance liquid chromatography and SZ symptomatology was assessed by Positive and Negative Syndrome Scale (PANSS). The association of KP with inflammatory mediators, monoamine metabolism and SZ symptomatology was explored.ResultsIn the PFC, the presence of the anti-inflammatory cytokine IL-10 together with IDO2 and KATII enzymes decreased in SZ, while TDO and KMO enzyme expression increased. A network interaction analysis showed that in the PFC IL-10 was coupled to the QA branch of the kynurenine pathway (TDO-KMO-QA), whereas IL-10 associated with KMO in CB. KYNA in the CB inversely correlated with negative and general PANSS psychopathology. Although there were no changes in monoamine metabolite content in the PFC in SZ, a network interaction analysis showed associations between dopamine and methoxyhydroxyphenylglycol degradation metabolite. Direct correlations were found between general PANSS psychopathology and the serotonin degradation metabolite, 5-hydroxyindoleacetic acid. Interestingly, KYNA in the CB inversely correlated with 5-hydroxyindoleacetic acid in the PFC.ConclusionsThus, this work found alterations in KP in two brain areas belonging to the cortico-cerebellar-thalamic-cortical circuit associated with SZ symptomatology, with a possible impact across areas in 5-HT degradation.

Serotonergic and Dopaminergic Lesions Underlying Parkinsonian Neuropsychiatric Signs.

Parkinson's disease (PD) is characterized by heterogeneous motor and nonmotor manifestations related to alterations in monoaminergic neurotransmission systems. Nevertheless, the characterization of concomitant dopaminergic and serotonergic dysfunction after different durations of Parkinson's disease, as well as their respective involvement in the expression and severity of neuropsychiatric signs, has gained little attention so far. To fill this gap, we conducted a cross-sectional study combining clinical and dual-tracer positron emission tomography (PET) neuroimaging approaches, using radioligands of dopamine ([11 C]-N-(3-iodoprop-2E-enyl)-2-beta-carbomethoxy-3-beta-(4-methylphenyl)-nortropane) ([11 C]PE2I) and serotonin ([11 C]-N,N-dimethyl-2-(-2-amino-4-cyanophenylthio)-benzylamine) ([11 C]DASB) reuptake, after different durations of Parkinson's disease (ie, in short-disease duration drug-naive de novo (n=27, 0-2 years-duration), suffering from apathy (n=14) or not (n=13); intermediate-disease duration (n=15, 4-7 years-duration) and long-disease duration, non-demented (n=15, 8-10 years-duration) patients). Fifteen age-matched healthy subjects were also enrolled. The main findings are threefold: (1) both dopaminergic and serotonergic lesions worsen with the duration of Parkinson's disease, spreading from midbrain/subcortical to cortical regions; (2) the presence of apathy at PD onset is associated with more severe cortical and subcortical serotonergic and dopaminergic disruption, similar to the denervation pattern observed in intermediate-disease duration patients; and (3) the severity of parkinsonian apathy, depression, and trait-anxiety appears primarily related to serotonergic alteration within corticostriatal limbic areas. Altogether, these findings highlight the prominent role of serotonergic degeneration in the expression of several neuropsychiatric symptoms occurring after different durations of Parkinson's disease. © 2021 International Parkinson and Movement Disorder Society.

Genetic polymorphism of CYP2C19 and subcortical variability in the human adult brain

Pharmacogenetic studies have shown involvement of cytochrome P450 enzymes in the metabolism of psychotropic drugs. However, expression and activity on endogenous substrates in the brain may underlie a constitutive role of these enzymes beyond drug metabolism. CYP2C19, which is expressed in the human fetal brain during neurodevelopment, shows affinity for endogenous compounds including monoaminergic neurotransmitters, steroid hormones, and endocannabinoids. In this study (N = 608), we looked at the genetic polymorphism of CYP2C19 and its potential associations with structural phenotypes of subcortical brain volume with structural imaging. Using two independent volume estimation techniques, we found converging evidence for a positive association between CYP2C19 activity scores, as inferred from the genotype, and basal ganglia and hippocampal volume. This association was present only in female individuals, raising the possibility that effects on brain morphology may arise through a mechanism involving the metabolism of estrogen steroids.

Chronic adolescent stress increases exploratory behavior but does not appear to change the acute stress response in adult male C57BL/6 mice

Chronic stress exposure in adolescence can lead to a lasting change in stress responsiveness later in life and is associated with increased mental health issues in adulthood. Here we investigate whether the Chronic Social Instability (CSI) paradigm influences the behavioral and molecular responses to novel acute stressors in mice, and whether it alters physiological responses influenced by the noradrenergic system. Using large cohorts of mice, we show that CSI mice display a persistent increase in exploratory behaviors in the open field test alongside small but widespread transcriptional changes in the ventral hippocampus. However, both the transcriptomic and behavioral responses to novel acute stressors are indistinguishable between groups. In addition, the pupillometric response to a tail shock, known to be mediated by the noradrenergic system, remains unaltered in CSI mice. Ultra-high performance liquid chromatography analysis of monoaminergic neurotransmitter levels in the ventral hippocampus also shows no differences between control or CSI mice at baseline or in response to acute stress. We conclude that CSI exposure during adolescence leads to persistent changes in exploratory behavior and gene expression in the hippocampus, but it does not alter the response to acute stress in adulthood and is unlikely to alter the function of the noradrenergic system.

Antidepressant-like effect of Campomanesia xanthocarpa seeds in mice: Involvement of the monoaminergic system

Background and aimCampomanesia xanthocarpa Berg. (Myrtaceae) present several pharmacological actions, but there are no reports on its antidepressant-like potential. This study investigated the antidepressant-like effect and mechanism of action of Campomanesia xanthocarpa seeds extract obtained from supercritical CO2 (40 °C, 250 bar). Experimental procedureMice were orally treated with the extract 1 h before the TST. To investigate the involvement of the monoaminergic system in the antidepressant-like activity of the extract, pharmacological antagonists were administered prior to the acute oral administration of the extract (60 mg/kg). Also, the interaction of the extract with antidepressants was assessed in the tail suspension test (TST). The in vitro inhibitory potential of C. xanthocarpa seeds extract towards MAO A and MAO B enzymes was tested in vitro. Results and conclusionAnimals treated with Campomanesia xanthocarpa seeds extract showed a significant reduction in the immobility time in the TST. Mice pretreatment with SCH23390, sulpiride, prazosin, yohimbine, and p-chlorophenylalanine prevented the anti-immobility effect of the extract in the TST. The combined administration of sub-effective doses of the extract with imipramine, bupropion and fluoxetine significantly reduced mice immobility time in the TST. The extract showed MAO A inhibitory activity (IC50 = 151.10 ± 5.75 μg/mL), which was greater than that toward MAO B (IC50 > 400 μg/mL).The extract of Campomanesia xanthocarpa seeds obtained by supercritical CO2 shows antidepressant-like activity, which relies on the activation of the monoaminergic neurotransmission (serotoninergic, dopaminergic and noradrenergic), suggesting that this species might represent a resource for developing new antidepressants.