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Parkinson's disease (PD) and carbon monoxide (CO) poisoning demonstrate parkinsonian features related to presynaptic dopaminergic deficits. However, their clinical features and treatment responses are different, indicating other roles of neurotransmitters in symptomatic modulation. In this study, we used 18F-FP-(+)-DTBZ PET to explore vesicular monoamine transporter type 2 (VMAT2) distributions in 31 patients with PD, 39 patients with CO poisoning and parkinsonian features (n = 39), and 24 age-matched controls. In addition to the disease-specific VMAT2 topographies in PD and CO poisoning, we also constructed feature-specific functional networks. The cardinal features included tremor, rigidity, akinesia, and rapid alternating movements (RAM), and the overall motor severity was scored using Unified Parkinson Disease Rating Scale (UPDRS) and modified Hoehn-Yahr (mH-Y) Scale scores. Our results suggested that a reduction in VMAT2 signals in the caudate, amygdala, and hippocampus were more specific to CO poisoning, while low uptake in the putamen and substantia nigra was more specific to PD. UPDRS and mH-Y scores were related to striatum signals in both groups and hippocampus and raphe in the CO poisoning group. With regards to the cardinal features, the putamen was related to akinesia in both groups. The substantia nigra was related to rigidity in PD, and the caudate and nucleus accumbens were related to akinesia, RAM and rigidity in CO poisoning. Our study enhances the current understanding of different patterns of monoaminergic terminal deficits in patients with CO poisoning and PD.

This review aims to elucidate environmental and genetic factors, as well as their epigenetic and neuroendocrine moderators, that may underlie the association between early childhood experiences and Substance Use Disorders (SUD), through the lens of parental attachment. Here we review those attachment-related studies that examined the monoaminergic systems, the hypothalamic pituitary adrenal stress response system, the oxytoninergic system, and the endogenous opioid system from a genetic, epigenetic, and neuroendocrine perspective. Overall, the selected studies point to a moderating effect of insecure attachment between genetic vulnerability and SUD, reasonably through epigenetic modifications. Preliminary evidence suggests that vulnerability to SUDs is related with hypo-methylation (e.g. hyper-expression) of high-risk polymorphisms on the monoaminergic and hypothalamic pituitary adrenal system and hyper-methylation (e.g. hypo-expressions) of protective polymorphisms on the opioid and oxytocin system. These epigenetic modifications may induce a cascade of neuroendocrine changes contributing to the subclinical and behavioural manifestations that precede the clinical onset of SUD. Protective and supportive parenting could hence represent a key therapeutic target to prevent addiction and moderate insecure attachment.

Agitation is a common neuropsychiatric symptom of Alzheimer’s disease (AD) that greatly impacts quality of life and amplifies caregiver burden. Agitation in AD may be associated with volume loss in the anterior cingulate cortex, posterior cingulate cortex, insula, amygdala, and frontal cortex, as well as with degeneration of monoaminergic neurotransmission, disrupted circadian rhythms, and frailty. Current pharmacological options have troubling safety concerns and only modest efficacy. There is increasing interest in cannabinoids as promising agents due to pre-clinical and early clinical research that suggest cannabinoids can elicit anxiolytic, antidepressant, and/or anti-inflammatory effects. Cannabinoids may relieve agitation by regulating neurotransmitters, improving comorbidities and circadian rhythms, and increasing cerebral circulation. Here we discuss the possible contributory mechanisms for agitation in AD and the therapeutic relevance of cannabinoids, including CBD and THC.

Trace amines, including β-phenylethylamine (β-PEA), p-tyramine (TYR), tryptamine (TRP) and p-octopamine (OCT), represent a group of amines expressed at low levels in the mammalian brain. Given the close structural similarities to traditional monoamines, the links between trace amines and the monoaminergic system have long been established. Trace amine associated receptor 1 (TAAR1), the most well characterized receptor in the TAARs family, has been shown to be potently activated by trace amines like TYR and PEA. Meanwhile, catecholamine metabolites and amphetamine analogs are also potent agonists of TAAR1, implicating its role in mediating the monoaminergic system and substance use disorders. In the central nervous system, TAAR1 is expressed in brain regions involved in dopaminergic, serotonergic and glutamatergic transmission. Genetic animal models and electrophysiological studies have revealed that TAAR1 is a potent modulator of the monoaminergic system, and TAAR1 agonists may be potential pharmacotherapies for the treatment of substance use disorders. Selective and potent engineered TAAR1 ligands, including full (RO5166017 and RO5256390) and partial (RO5203648, RO5263397 and RO5073012) agonists and the antagonist EPPTB (N-(3-ethoxyphenyl)-4-(1-pyrrolidinyl)-3-(trifluoromethyl)benzamide, RO5212773), serve as invaluable tools for the investigation of TAAR1 functions and display high potential for the development of TAAR1-based pharmacotherapies for the treatment of substance use disorders. Despite a number of advances that have been made, more clinical studies are warranted in order to test the potential and efficacy of TAAR1 ligands in the treatment of psychiatric disorders, especially substance use disorders.

Aim: Stress-related disorders like depression and anxiety represent one of the greatest therapeutic challenges globally. Although previous studies have revealed the antidepressant-like potentials of naringin, the neurotransmitter receptor interaction mechanisms of action have not been studied, hence, this study was carried out to evaluate the role of neurotransmitter-receptor antagonists in the antidepressant-like effects of naringin in mice. Method: Male Swiss mice were subjected to chronic unpredictable mild stress (CUMS) apart from mice in the control group. The mice were then pretreated with different neurotransmitter antagonists; metergoline (4 mg /kg i.p.), a 5-HT1 - and 5-HT2 -receptor antagonist; propranolol; (0.2 mg/kg i.p.), β1,2-noradrenoceptor antagonist or haloperidol (0.2 mg/kg i.p.), D 2 -dopaminergic receptor antagonists prior to the administration of naringin or vehicle (10 mL/kg). The antidepressant-like and anxiolytic effects of naringin were evaluated 30 min later using the tail suspension test (TST), open-field test (OFT), sucrose preference test (SPT) and elevated plus maze (EPM) tests paradigms. Results: Administration of naringin following CUMS significantly decrease immobility time and locomotion activity in TST and OFT respectively, relative to control while increasing preference to sucrose in SPT, open arm entries as well as time spent in open arm in EPM, relative to control suggesting antidepressant-like property. Pretreatment with metergoline, propranolol, and haloperidol following CUMS increased immobility time in TST, locomotor activity in OFT and IOAA in the EPM. Reduced preference for sucrose in SPT, open arm entry and duration in EPM relative to control (p < 0.05), however, these effects were attenuated by naringin. Conclusion: These findings suggest that the antidepressant-like activity exhibited by naringin might be mediated via interactions with 5-HTergic, noradrenergic, and dopaminergic receptors, while the anxiolytic effect might involve interaction with both 5-HTergic and noradrenergic receptors.

Major depressive disorder (MDD) is a brain disorder often characterized by recurrent episode and remission phases. The molecular correlates of MDD have been investigated in case-control comparisons, but the biological alterations associated with illness trait (regardless of clinical phase) or current state (symptomatic and remitted phases) remain largely unknown, limiting targeted drug discovery. To characterize MDD trait- and state-dependent changes, in single or recurrent depressive episode or remission, we generated transcriptomic profiles of subgenual anterior cingulate cortex of postmortem subjects in first MDD episode (n = 20), in remission after a single episode (n = 15), in recurrent episode (n = 20), in remission after recurring episodes (n = 15) and control subject (n = 20). We analyzed the data at the gene, biological pathway, and cell-specific molecular levels, investigated putative causal events and therapeutic leads. MDD-trait was associated with genes involved in inflammation, immune activation, and reduced bioenergetics (q

Introduction 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. Material and methods 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). Results 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. Conclusions DHE is able to modulate noradrenergic, serotonergic and dopaminergic neurotransmission that may support the increase in locomotion.

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.

Parkinson’s disease (PD) is a neurodegenerative disorder mainly diagnosed in elderly patients, which is now considered incurable. To date, there are no effective neuroprotectors suitable to treat PD patients. We have previously demonstrated that U133 therapy, which induces the synthesis of Hsp70 and Hsp40 heat shock proteins in the brain, prevents the development of neurodegeneration in the nigrostriatal system and eliminates sleep disorders in an animal model of PD. In the present study, we assessed the antidepressant properties of preventive U133 therapy, as well as its neuroprotective effect on monoaminergic emotiogenic brain structures in a preclinical model of PD in aged (20-month-old) Wistar rats, created by intranasal administration of the proteasome inhibitor lactacystin. It was found that intraperitoneal U133 administration in aged animals led to a delayed (after 3–7 days) elevation of the Hsp70 (HSPA1) level in the midbrain ventral tegmental area and locus coeruleus. Preventive U133 therapy eliminated the manifestations of depression-like behavior in the form of anhedonia, which develops during the preclinical stage of PD in aged rats. It was established that the antidepressant-like effect of the chaperone inducer U133 is due to the ability of the Hsp70 chaperone to attenuate neurodegeneration and neuroinflammation in the dopaminergic mesolimbic reward system and locus coeruleus noradrenergic system. The data obtained may serve as a fundamental basis for the development of a novel chaperone inducer-based molecular technology for preventive therapy of polyetiological PD and concomitant anhedonia.

Translational Psychiatry 11(1), 467 (2021). doi:10.1038/s41398-021-01591-5, Published by Nature Publishing Group, London

Methcathinone (MCAT) is a psychostimulant of abuse that can cause both persistent striatal dopaminergic and serotonergic, as well as hippocampal serotonergic, deficits. Evidence suggests that the rapid effects of stimulants that are structurally and mechanistically similar to MCAT on monoamine transporter function may contribute to the abuse liability and/or persistent monoaminergic deficits caused by these agents. Thus, effects of MCAT on 1) striatal dopamine (DA) transporter (DAT); and 2) striatal and hippocampal serotonin transporter (SERT) function, as determined in tissues from adult male rats, were assessed. As reported previously, a single administration of MCAT rapidly (within 1 hr) decreases striatal [3 H]DA uptake. Similarly, incubation of rat synaptosomes with MCAT at 37℃ (but not 4˚C) decreased striatal [3 H]DA uptake. Incubation with MCAT likewise decreased [3 H]5HT but not vesicular [3 H]DA uptake. MCAT incubation in vitro was without effect on [3 H]DA uptake in striatal synaptosomes prepared from MCAT-treated rats. The decrease in [3 H]DA uptake caused by MCAT incubation: (a) reflected a decrease in Vmax , with minimal change in Km , and (b) was attenuated by co-incubation with the cell-permeable calcium chelator, N,N'-[1,2-ethanediylbis(oxy-2,1-phenylene)]bis[N-[2-[(acetyloxy)methoxy]-2-oxoethyl]-1,1'-bis[(acetyloxy)methyl] ester-glycine (BAPTA-AM), as well as the non-selective protein kinase-C (PKC) inhibitors bisindolylmaleimide-1 (BIM-1) and 2-[1-3(Aminopropyl)indol-3-yl]-3(1-methyl-1H-indol-3-yl)maleimide (or Bisindolylmaleimide VIII; Ro-31-7549). Taken together, these results suggest that in vitro MCAT incubation may model important aspects of MCAT administration in vivo, and that calcium and PKC contribute to the in vitro effects of MCAT on DAT.

Although monoaminergic antidepressants are effective for some depressed patients, at least a third remain treatment refractory even after multiple treatment trials. Investigation into novel antidepressant approaches targeted to specific mechanisms implicated in the pathophysiology of treatment-resistant depression (TRD) has significant potential to improve treatment response rates. This review highlights emerging novel antidepressant approaches for TRD, bridging neuromodulation and novel pharmacotherapeutics. We discuss how these new approaches target depression neurobiology via modulation of neurotrophic factors, cellular metabolic machinery, neurotransmitter systems, and inflammatory activity. Since a significant number of depressed patients do not respond to classic monoaminergic-based antidepressants, research focus has shifted to novel approaches that have been providing promising results in TRD. Recent studies detail plenty of new technologies in the field of electrical stimulation, antidepressant medications, and novel mechanisms that are hypothesized to provide antidepressant effects through modulating neurobiological pathways implicated in the neurocircuitry of depression. Some factors known to impair therapeutic efficacy of current front-line treatments include circadian disruption, inflammation, and metabolic disturbances. Dysregulation of these systems can be readily identified using peripheral markers, implying that biologically directed treatment stratification is possible. However, more work is needed to understand how to best align such biomarkers with emerging novel treatments. Nevertheless, this represents an exciting time in the development of novel treatment approaches for psychiatry. Understanding the neurobiology of novel therapies that have demonstrated potential antidepressant efficacy is a key factor for research in TRD. Improved alignment of these emerging novel treatments with the pathophysiological targets on which they act will move us a step closer to precision medicine approaches for psychiatry, which in turn, is likely to close the current “response failure” gap and overall levels of TRD.

The early social environment an animal experiences may have pervasive effects on its behaviour. The social decision-making network (SDMN), consisting of interconnected brain nuclei from the forebrain and midbrain, is involved in the regulation of behaviours during social interactions. In species with advanced sociality such as cooperative breeders, offspring are exposed to a large number and a great diversity of social interactions every day of their early life. This diverse social environment may have life-long consequences on the development of several neurophysiological systems within the SDMN, although these effects are largely unknown. We studied these life-long effects in a cooperatively breeding fish, Neolamprologus pulcher, focusing on the expression of genes involved in the monoaminergic and stress response systems in the SDMN. N. pulcher fry were raised until an age of 2 months either with their parents, subordinate helpers and same-clutch siblings (+F), or with same-clutch siblings only (-F). Analysis of the expression of glucocorticoid receptor, mineralocorticoid receptor, corticotropin releasing factor, dopamine receptors 1 and 2, serotonin transporter and DNA methyltransferase 1 genes showed that early social experiences altered the neurogenomic profile of the preoptic area. Moreover, the dopamine receptor 1 gene was up-regulated in the preoptic area of -F fish compared to +F fish. -F fish also showed up-regulation of GR1 expression in the dorsal medial telencephalon (functional equivalent to the basolateral amygdala), and in the dorsolateral telencephalon (functional equivalent to the hippocampus). Our results suggest that early social environment has life-long effects on the development of several neurophysiological systems within the SDMN. info:eu-repo/semantics/acceptedVersion

The discovery of the rapid-acting antidepressant effects of ketamine has 1) led to a paradigm shift in our perception of what is possible in treating severe depression; 2) spurred a wave of basic, translation, and clinical research; and 3) provided an unprecedented investigational tool to conduct longitudinal mechanistic studies that may capture behavioral changes as complex as clinical remission and relapse within hours and days of treatment. Unfortunately, these advances did not yet translate into clinical biomarkers or novel treatments, beyond ketamine. In contrast to slow-acting antidepressants, in which targeting monoaminergic receptors identified several efficacious drugs with comparable mechanisms, the focus on the receptor targets of ketamine has failed in several clinical trials over the past decade. Thus, it is becoming increasingly crucial that we concentrate our effort on the downstream molecular mechanisms of ketamine and their effects on the brain circuitry and networks. Honoring the legacy of our mentor, friend, and colleague Ron Duman, we provide a historical note on the discovery of ketamine and its putative mechanisms. We then detail the molecular and circuits effect of ketamine based on preclinical findings, followed by a summary of the impact of this work on our understanding of chronic stress pathology across psychiatric disorders, with particular emphasis on the role of synaptic connectivity and its brain network effects in the pathology and treatment of clinical depression.

International audience; Limited studies in humans and in animal models have investigated the neurotoxic risks related to a gestational exposure to diesel exhaust particles (DEP) on the embryonic brain, especially those regarding monoaminergic systems linked to neurocognitive disorders. We previously showed that exposure to DEP alters monoaminergic neurotransmission in fetal olfactory bulbs and modifies tissue morphology along with behavioral consequences at birth in a rabbit model. Given the anatomical and functional connections between olfactory and central brain structures, we further characterized their impacts in brain regions associated with monoaminergic neurotransmission. At gestational day 28 (GD28), fetal rabbit brains were collected from dams exposed by nose-only to either a clean air or filtered DEP for 2 h/day, 5 days/week, from GD3 to GD27. HPLC dosage and histochemical analyses of the main monoaminergic systems, i.e., dopamine (DA), noradrenaline (NA), and serotonin (5-HT) and their metabolites were conducted in microdissected fetal brain regions. DEP exposure increased the level of DA and decreased the dopaminergic metabolites ratios in the prefrontal cortex (PFC), together with sex-specific alterations in the hippocampus (Hp). In addition, HVA level was increased in the temporal cortex (TCx). Serotonin and 5-HIAA levels were decreased in the fetal Hp. However, DEP exposure did not significantly modify NA levels, tyrosine hydroxylase, tryptophan hydroxylase or AChE enzymatic activity in fetal brain. Exposure to DEP during fetal life results in dopaminergic and serotonergic changes in critical brain regions that might lead to detrimental potential short-term neural disturbances as precursors of long-term neurocognitive consequences.

Depression is a common mental disorder and one of the leading causes of disability around the world. Monoaminergic antidepressants often take weeks to months to work and are not effective for all patients. This has led to a search for a better understanding of the pathogenesis of depression as well as to the development of novel antidepressants. One such novel antidepressant is ketamine, which has demonstrated both clinically promising results and contributed to new explanatory models of depression, including the potential role of neuroplasticity in depression. Early clinical trials are now showing promising results of serotonergic psychedelics for depression; however, their mechanism of action remains poorly understood. This paper seeks to review the effect of depression, classic antidepressants, ketamine, and serotonergic psychedelics on markers of neuroplasticity at a cellular, molecular, electrophysiological, functional, structural, and psychological level to explore the potential role that neuroplasticity plays in the treatment response of serotonergic psychedelics.

The desmin-associated protein myospryn, encoded by the cardiomyopathy-associated gene 5 (CMYA5), is a TRIM-like protein associated to the BLOC-1 (Biogenesis of Lysosomes Related Organelles Complex 1) protein dysbindin. Human myospryn mutations are linked to both cardiomyopathy and schizophrenia; however, there is no evidence of a direct causative link of myospryn to these diseases. Therefore, we sought to unveil the role of myospryn in heart and brain. We have genetically inactivated the myospryn gene by homologous recombination and demonstrated that myospryn null hearts have dilated phenotype and compromised cardiac function. Ultrastructural analyses revealed that the sarcomere organization is not obviously affected; however, intercalated disk (ID) integrity is impaired, along with mislocalization of ID and sarcoplasmic reticulum (SR) protein components. Importantly, cardiac and skeletal muscles of myospryn null mice have severe mitochondrial defects with abnormal internal vacuoles and extensive cristolysis. In addition, swollen SR and T-tubules often accompany the mitochondrial defects, strongly implying a potential link of myospryn together with desmin to SR- mitochondrial physical and functional cross-talk. Furthermore, given the reported link of human myospryn mutations to schizophrenia, we performed behavioral studies, which demonstrated that myospryn-deficient male mice display disrupted startle reactivity and prepulse inhibition, asocial behavior, decreased exploratory behavior, and anhedonia. Brain neurochemical and ultrastructural analyses revealed prefrontal-striatal monoaminergic neurotransmitter defects and ultrastructural degenerative aberrations in cerebellar cytoarchitecture, respectively, in myospryn-deficient mice. In conclusion, myospryn is essential for both cardiac and brain structure and function and its deficiency leads to cardiomyopathy and schizophrenia-associated symptoms.

BACKGROUND AND PURPOSE Functional brain imaging using genetically encoded Ca2+ sensors in larval zebrafish is being developed for studying seizures and epilepsy as a more ethical alternative to rodent models. Despite this, few data have been generated on pharmacological mechanisms of action other than GABAA antagonism. Assessing larval responsiveness across multiple mechanisms is vital to test the translational power of this approach, as well as assessing its validity for detecting unwanted drug-induced seizures and testing antiepileptic drug efficacy. EXPERIMENTAL APPROACH Using light-sheet imaging, we systematically analysed the responsiveness of 4 days post fertilisation (dpf; which are not considered protected under European animal experiment legislation) transgenic larval zebrafish to treatment with 57 compounds spanning more than 12 drug classes with a link to seizure generation in mammals, alongside eight compounds with no such link. KEY RESULTS We show 4dpf zebrafish are responsive to a wide range of mechanisms implicated in seizure generation, with cerebellar circuitry activated regardless of the initiating pharmacology. Analysis of functional connectivity revealed compounds targeting cholinergic and monoaminergic reuptake, in particular, showed phenotypic consistency broadly mapping onto what is known about neurotransmitter-specific circuitry in the larval zebrafish brain. Many seizure-associated compounds also exhibited altered whole brain functional connectivity compared with controls. CONCLUSIONS AND IMPLICATIONS This work represents a significant step forward in understanding the translational power of 4dpf larval zebrafish for use in neuropharmacological studies and for studying the events driving transition from small-scale pharmacological activation of local circuits, to the large network-wide abnormal synchronous activity associated with seizures.

Depression is a highly prevalent mood disorder and one of the major health concerns in modern society. Moreover, it is characterized by a high prevalence of coexistence with many other diseases including metabolic disorders such as type 2 diabetes mellitus (T2DM) and obesity. Currently used antidepressant drugs, which mostly target brain monoaminergic neurotransmission, have limited clinical efficacy. Although the etiology of depression has not been fully elucidated, current scientific data emphasize the role of neurotrophic factors deficiencies, disturbed homeostasis between the nervous system and the immune and endocrine systems, as well as disturbances in brain energy metabolism and dysfunctions in the gut-brain axis as important factors in the pathogenesis of this neuropsychiatric disorder. Therefore, therapeutic options that could work in a way other than classic antidepressants are being sought to increase the effectiveness of the treatment. Interestingly, glucagon-like peptide-1 receptor agonists (GLP-1RAs), used in the treatment of T2DM and obesity, are known to show pro-cognitive and neuroprotective properties, and exert modulatory effects on immune, endocrine and metabolic processes in the central nervous system. This review article discusses the potential antidepressant effects of GLP-1RAs, especially in the context of their action on the processes related to neuroprotection, inflammation, stress response, energy metabolism, gut-brain crosstalk and the stability of the gut microbiota. Graphic abstract

The monoaminergic neurotransmitters dopamine, noradrenaline, and serotonin are pivotal actors of the interplay between the nervous and the immune system due to their ability of binding to cell-receptors of both systems, crucially regulating their function within the central nervous system and the periphery. As monoamines are dysfunctional in many neurological and psychiatric diseases, they have been successfully used as pharmacological targets. Multiple sclerosis (MS) is one of the best examples of neurological disease caused by an altered interaction between the nervous and immune system and emerging evidence supports a dysregulation of monoaminergic systems in the pathogenesis of MS, secondary to both inflammation-induced reduction of monoamines' synthesis and structural damage to monoaminergic pathways within the brain. Here we review the evidence for monoamines being key mediators of neuroimmune interaction, affecting MS pathogenesis and course. Moreover, we discuss how the reduction/dysfunction of monoamines in MS may contribute to some clinical features typical of the disease, particularly fatigue and depression. Finally, we summarize different drugs targeting monoamines that are currently under evaluation for their potential efficacy to treat MS, as well as to alleviate fatigue and depression in MS.

BACKGROUND Altered monoamine (i.e., serotonin, dopamine, and norepinephrine) activity following episodes of alcohol abuse plays key roles not only in the motivation to ingest ethanol, but also physiological dysfunction related to its misuse. Although monoamine activity is essential for physiological processes that require coordinated communication across the gut-brain axis (GBA), relatively little is known about how alcohol misuse may affect monoamine levels across the GBA. Therefore, we evaluated monoamine activity across the mouse gut and brain following episodes of binge-patterned ethanol drinking. METHODS Monoamine and select metabolite neurochemical concentrations were analyzed by ultra-high-performance liquid chromatography in gut and brain regions of female and male C57BL/6J mice following "Drinking in the Dark" (DID), a binge-patterned ethanol ingestion paradigm. RESULTS First, we found that alcohol access had an overall small effect on gut monoamine-related neurochemical concentrations, primarily influencing dopamine activity. Second, neurochemical patterns between the small intestine and the striatum were correlated, adding to recent evidence of modulatory activity between these areas. Third, although alcohol access robustly influenced activity in brain areas in the mesolimbic dopamine system, binge exposure also influenced monoaminergic activity in the hypothalamic region. Finally, sex differences were observed in the concentrations of neurochemicals within the gut, which was particularly pronounced in the small intestine. CONCLUSION Together, these data provide insights into the influence of alcohol abuse and biological sex on monoamine-related neurochemical changes across the GBA, which could have important implications for GBA function and dysfunction.

Why individuals differ in behavioral responses has received intense research attention (particularly in the context of animal personality), and has typically focused on describing variation in boldness, activity, and exploration. Nevertheless, the mechanisms underlying this behavioral variation remain largely unknown. Variation in these behaviors is likely influenced by genetic differences between individuals, with genes in the monoaminergic systems commonly implicated. When examining the link between variation in boldness, activity and exploration and genes, studies have focused on different monoaminergic systems (mainly serotonergic and dopaminergic), and predominantly on mammals and passerine birds. Therefore, to replicate this general approach and examine if genes from these systems are linked to boldness, activity, and exploration, we exposed red junglefowl chicks (Gallus gallus) to behavioral assays (measuring boldness, activity, exploration) before analyzing prefrontal cortex gene expression of several dopaminergic (DRD1, DRD2) and serotonergic genes (TPH, 5HT2A, 5HT2B, 5HT2C, 5HT1B). We observed no relationships between our measured behaviors and gene expression. Together with previous studies, our results suggest that a clear link between boldness, activity and exploration and monoaminergic gene variation is lacking. We, therefore, suggest that this is due to differences among studies (e.g., methodological differences), or that the nature of the relationship between these behaviors and monoaminergic systems is more species-specific, and/or more complex than so far assumed.

Depression is a common and highly disabling condition in older adults. It is a heterogenous disorder and there is emerging evidence of a link between inflammation and depression in older patients, with a possible inflammatory subtype of depression. Persistent low-level inflammation, from several sources including psychological distress and chronic disease, can disrupt monoaminergic and glutaminergic systems to create dysfunctional brain networks. Despite the evidence for the role of inflammation in depression, there is insufficient evidence to recommend use of any putative anti-inflammatory agent in the treatment of depression in older adults at this stage. Further characterisation of markers of inflammation and stratification of participants with elevated rates of inflammatory markers in treatment trials is needed.

The prefrontal cortex (PFC) serves as the chief executive officer of the brain, controlling the highest level cognitive and emotional processes. Its local circuits among glutamatergic principal neurons and GABAergic interneurons, as well as its long-range connections with other brain regions, have been functionally linked to specific behaviors, ranging from working memory to reward seeking. The efficacy of synaptic signaling in the PFC network is profundedly influenced by monoaminergic inputs via the activation of dopamine, adrenergic, or serotonin receptors. Stress hormones and neuropeptides also exert complex effects on the synaptic structure and function of PFC neurons. Dysregulation of PFC synaptic transmission is strongly linked to social deficits, affective disturbance, and memory loss in brain disorders, including autism, schizophrenia, depression, and Alzheimer's disease. Critical neural circuits, biological pathways, and molecular players that go awry in these mental illnesses have been revealed by integrated electrophysiological, optogenetic, biochemical, and transcriptomic studies of PFC. Novel epigenetic mechanism-based strategies are proposed as potential avenues of therapeutic intervention for PFC-involved diseases. This review provides an overview of PFC network organization and synaptic modulation, as well as the mechanisms linking PFC dysfunction to the pathophysiology of neurodevelopmental, neuropsychiatric, and neurodegenerative diseases. Insights from the preclinical studies offer the potential for discovering new medical treatments for human patients with these brain disorders.

The efficacy of depressive disorders treatment is insufficient. It is explained by an incomplete understanding of both pathogenesis of depression and antidepressants mechanism action. An improvement of the treatment efficacy of depression disorders is closely associated with complete knowledge of the pathogenesis of disorders and antidepressant mechanism of action. The effect produced by the first line of antidepressants prescribed currently in the clinical practice includes the accumulation of monoamines and prolonged activation of their membrane receptors. However, a decrease in the membrane receptors density evoked by prolonged activation of monoaminergic receptors is counteracted by the second line of antidepressant activity. It is associated with the expression of inducible regulatory protein S100A10 (p11) and its partners. In this review, the authors examined the structure and function of protein p11, its interaction with such proteins as annexin A2, Ahnak, chromatinremodeling factor SMARCA3. The authors analyzed the influence of p11 on the membrane density of serotonin 5-HT1B and 5-HT4 receptors, metabotropic glutamate receptors 5, voltage-dependent potassium Kv3, and calcium Cav1.2 and 1.3 channels, that play an important role in both the effect of antidepressants and the pathogenesis of depression disorders. A systematic literature search was conducted in Scopus, Web of Science, MedLine, elibrary, and other databases.

The nucleus accumbens shell (NAcSh) receives extensive monoaminergic input from multiple midbrain structures. However, little is known how norepinephrine (NE) modulates NAc circuit dynamics. Using a dynamic electrophysiological approach with optogenetics, pharmacology, and drugs acutely restricted by tethering (DART), we explored microcircuit-specific neuromodulatory mechanisms recruited by NE signaling in the NAcSh of parvalbumin (PV)-specific reporter mice. Surprisingly, NE had little direct effect on modulation of synaptic input at medium spiny projection neurons (MSNs). In contrast, we report that NE transmission selectively modulates glutamatergic synapses onto PV-expressing fast-spiking interneurons (PV-INs) by recruiting postsynaptically-localized α2-adrenergic receptors (ARs). The synaptic effects of α2-AR activity decrease PV-IN-dependent feedforward inhibition onto MSNs evoked via optogenetic stimulation of cortical afferents to the NAcSh. These findings provide insight into a new circuit motif in which NE has a privileged line of communication to tune feedforward inhibition in the NAcSh.SIGNIFICANCE STATEMENTThe nucleus accumbens (NAc) directs reward-related motivational output by integrating glutamatergic input with diverse neuromodulatory input from monoamine centers. The present study reveals a synapse-specific regulatory mechanism recruited by norepinephrine (NE) signaling within parvalbumin-expressing interneuron (PV-IN) feedforward inhibitory microcircuits. PV-IN-mediated feedforward inhibition in the NAc is instrumental in coordinating NAc output by synchronizing the activity of medium spiny projection neurons (MSNs). By negatively regulating glutamatergic transmission onto PV-INs via α2-adrenergic receptors (ARs), NE diminishes feedforward inhibition onto MSNs to promote NAc output. These findings elucidate previously unknown microcircuit mechanisms recruited by the historically overlooked NE system in the NAc.

Background Dominant-submissive relationships depend upon functionality of the neural circuits involving monoaminergic neurotransmission. Behavioral profiles of selectively bred dominant (Dom) and submissive (Sub) mice have been proposed to mimic hyperthymic- or depressive-like temperaments observed in patients with affective disorders. These mice differentially respond to psychotropic agents and stressful stimuli, however, the mechanisms underlying these differences remain unclear. To address these mechanisms, we analyzed the brain monoamine content and responses to paroxetine (PXT) in Dom and Sub mice. Methods The behavioral effects of PXT (3 mg/kg, single injection) were assessed with the Elevated Plus Maze (EPM) and Forced Swim Test (FST). Monoamine tissue content was analyzed by HPLC-ECD. Results Compared to Dom, Sub mice had decreased levels of serotonin (5-HT) in the brainstem (BS), reduced levels of norepinephrine (NE) in the prefrontal cortex (PFC), hippocampus (HPC), and striatum (STR) and elevated levels of dopamine (DA) in PFC, HPC, STR and BS. In EPM, PXT administration increased locomotion and exploration in Dom mice, with no effect in Sub mice. In FST, PXT disrupted immobility in Dom mice only. The PXT-produced differences in regional monoamine content were strain-dependent and consistent with the behavioral alterations. Limitations Chronic PXT treatment, in vivo monoamine assays and sex-dependent analysis were out of the scope of this study and will be performed in the future in order to provide an in-depth evaluation of the neurochemical mechanisms underlying temperament-dependent responses to SSRIs. Conclusions Our findings suggest neurochemical mechanisms that underlie temperament-based response to antidepressant treatment.

Hypothalamic orexinergic neurons are involved in controlling various body functions, particularly energy balance, feeding behavior, wakefulness, and awakening. The direct effects of brain dopamine and serotonin on orexinergic neurons in the hypothalamus are mediated via various subtypes of the corresponding receptors, whose expression has previously been demonstrated in the bodies of orexinergic neurons. Studies were performed on 18-day rat embryos to assess the possibility that these interactions form during the embryonic period of development. Western blotting was used to demonstrate expression of dopamine D1 and serotonin 2C receptor proteins in the developing hypothalamus. Studies using double fluorescence immunolabeling and confocal microscopy confirmed the expression of dopamine D1 and serotonin 2C receptors in the bodies of developing orexin-immunopositive cells in rat embryos. These results provide evidence that the development of morphofunctional interactions between the monoaminergic systems and the orexinergic system occur during the embryonic period of development.

Serotonin (5-HT) and dopamine (DA) are involved in the regulation of social behaviors. However, the effects of their interactions on social behavior are not well understood. In this study, rats received a serotonergic neurotoxin injection into the raphe nuclei and/or systemic administration of L-3, 4-dihydroxyphenylalanine (L-DOPA), and their agonistic behaviors were investigated using the resident-intruder (RI) paradigm. Rats in the DA + /5-HT-group, which were administered both monoaminergic treatments, exhibited intense jump and flight responses to intruders. These behaviors were not observed in rats that received either 5-HT lesions or L-DOPA treatment only. To address the neural basis of these aberrant behaviors, we compared c-Fos immunoreactivity in the brain among the different groups. The DA + /5-HT-group had c-Fos activation in areas related to anti-predatory defensive behaviors, such as the ventromedial hypothalamic nucleus, premammillary nucleus, and periaqueductal gray. Moreover, this group had increased c-Fos expression in the ventroposterior part of the anterior olfactory nucleus (AOVP). To test the involvement of this area in the aberrant behaviors, cytotoxic lesions were performed in the AOVP prior to the monoaminergic treatments, and subsequent behaviors were examined using the RI test. The AOVP-lesioned DA + /5-HT-rats had attenuation of the aberrant behaviors. Together, these results suggest that the AOVP is involved in the generation of the aberrant defensive behaviors, and that 5-HT/DA balance is important in the regulation of social behaviors.

Os antidepressivos surgiram empiricamente através de observações em pacientes esquizofrênicos e com tuberculose. No caso dos pacientes esquizofrênicos, a imipramina surgira como sendo uma nova proposta da classe dos neurolépticos devido a semelhança estrutural à clorpormazina, entretanto não houve êxito algum, exceto a melhora no humor em pacientes deprimidos. Já no caso da tuberculose, a iproniazida era usada no tratamento da tuberculose e que também pôde ser observada elevação de humor em pacientes deprimidos. Em 1960, surge a primeira hipótese que tenta esclarecer a causa da depressão: a hipótese monoaminérgica, que dizia que a depressão era uma condição patológica onde o indivíduo apresentava depleção de serotonina, dopamina e noradrenalina e que os antidepressivos deveriam reestabelecer seus níveis em homeostase. Desde o surgimento da psicoterapia até os avanços atuais, ainda não é esclarecido totalmente as vias de neurotransmissores, receptores onde atuam ou mecanismo de ação de fármacos de ação central e isso pode estar relacionado com a sua estrutura, ao qual se denomina relação estrutura-atividade ou com seus receptores. Principalmente através do entendimento farmacodinâmico dos fármacos, é possível evitar interações medicamentosas ou justificar e evitar alguns efeitos colaterais. Com isso, o objetivo deste trabalho é apresentar através da análise das moléculas e padronizar com seus efeitos ou afinidades por determinados receptores, quando for possível estabelecer relação estrutura-atividade e justificar os efeitos colaterais através das interações com receptores para que se possa evitar interações ou potencializações de efeito, uma vez que este pode ser fatal.

To reveal the effect and mechanism of Jiaotai Pill (交泰丸, JTP) on insomniac rats. The insomniac model was established by intraperitoneal injection of p-chlorophenylalanine (PCPA). In behavioral experiments, rats were divided into control, insomniac model, JTP [3.3 g/(kg•d)], and diazepam [4 mg/(kg•d)] groups. The treatment effect of JTP was evaluated by weight measurement (increasement of body weight), open field test (number of crossings) and forced swimming test (immobility time). A high performance liquid chromatography-electrochemical detection (HPLC-ECD) method was built to determine the concentration of monoamine transmitters in hypothalamus and peripheral organs from normal, model, JTP, citalopram [30 mg/(kg•d)], maprotiline [40 mg/(kg•d)] and bupropion [40 mg/(kg•d)] groups. Expressions of serotonin transporter (SERT), dopamine transporter (DAT), and norepinephrine transporter (NET) were analyzed by quantitative polymerase chain reaction (qPCR) and Western blot in normal, model and JTP groups. A high performance liquid chromatography-electrospray ionization mass spectrometry (HPLC-ESI-MS/MS) method was established to determine the pharmacokinetics, urine cumulative excretion of metformin in vivo, and tissue slice uptake in vitro, which were applied to assess the activity of organic cation transporters (OCTs) in hypothalamus and peripheral organs. Compared with the insomniac model group, the body weight and spontaneous locomotor were increased, and the immobility time was decreased after treatment with JTP (P

—We studied the dopamine-, serotonin-, and norepinephrinergic systems in various brain structures of BALB/c male mice on days 15, 42, and 64 of postnatal development (PND) in the model of autism spectrum disorder induced by sodium valproate administration (400 mg/kg, s/c) to pregnant females. It was found that the level of both catechol- and indolamines in the brain structures of control 15-day-old mice is considerably lower than in 64-day-old adult animals. Prenatal administration of sodium valproate (SV) caused a decrease in all parameters of monoaminergic neurotransmission in the striatum of mouse offspring aged 15 days but did not lead to neurochemical changes in other studied brain structures. By PND 42, the general pattern of changes in neurotransmitter concentrations did not differ from the developmental dynamics of neurotransmitter system maturation in the control group. The level of DA kept increasing and by PND 64, did not differ from controls. The parameters of serotonergic system changed similarly, with the peak serotonin concentration by PND 42 and a significant decrease by PND 64, whereas the level of 5-HIAA in the striatum increased gradually with maximum differences observed by PND 64. Thus, the data obtained suggest that administration of SV to pregnant females affects the activity of the dopamine- and serotonergic brain systems in the progeny, inducing its decrease in the striatum by PND 15 followed by recovery to control level by PND 64.

Introduction: Hausa people of north-western Nigeria were reported to utilize the plant Adansonia digitata for the management of depressive illnesses in an ethnobotanical survey. Thus, this study aimed to establish the mechanism(s) via which methanol stem bark extract of A. digitata (MEAD) exhibits antidepressant activity in mice. Methods: Antidepressant activity of MEAD was evaluated using tail suspension test (TST) at doses of 250, 500 and 1000 mg/kg. For the mechanistic studies, mice were pre-treated with sulpiride (50 mg/kg), prazosin (1 mg/kg), yohimbine (1 mg/kg), metergoline (1 mg/kg), cyproheptadine (3 mg/kg), L-arginine (50 mg/kg), N omega-nitro-L-arginine (L-NNA; 50 mg/kg), atropine (1 mg/kg) and naloxone (2 mg/kg) 15 minutes prior to MEAD (1000 mg/kg) administration, then antidepressant activity was assessed using TST one hour later. Data were analyzed using one-way ANOVA followed by Bonferroni post hoc test. Results: The extract (at doses of 250, 500 and 1000 mg/kg) significantly (P < 0.05) and dose-dependently decreased the duration of immobility in the TST. Sulpiride (D2 receptor antagonist), prazosin and yohimbine (α1 and α2 receptor antagonists, respectively), metergoline and cyproheptadine (5-HT1 and 5-HT2 receptor antagonists, respectively) significantly (P < 0.05) reversed the antidepressant effect of MEAD. On the other hand, L-NNA (NOS inhibitor) augmented the antidepressant effect of MEAD while L-arginine (nitric oxide substrate) had no effect on MEAD. However, atropine (muscarinic receptor antagonist) significantly (P < 0.01) augmented the antidepressant effect of MEAD. Conclusion: The antidepressant activity of methanol stem bark extract of A. digitata was established to be via the monoaminergic, nitric oxide and cholinergic pathways.

Monoamine oxidase B (MAO-B) is an important enzyme regulating the levels of monoaminergic neurotransmitters. Selective MAO-B inhibitors have been labeled with carbon-11 or fluorine-18 to visualize the localization of MAO-B in vivo by positron emission tomography (PET) and thereby have been useful for studying neurodegenerative diseases. The aim of this study was to develop promising fluorine-18 labeled reversible MAO-B PET radioligands and their biological evaluation in vitro by autoradiography. Radiolabeling was achieved by classical one-step fluorine-18 nucleophilic substitution reaction. The stability and radiochemical yield was analyzed with HPLC. All five fluorine-18 labeled compounds were tested in human whole hemisphere autoradiography experiments. Five compounds (GEH200439, GEH200448, GEH200449, GEH200431A, and GEH200431B) were successfully radiolabeled with fluorine-18, and the incorporation yield of the fluorination reactions varied from 10 to 45% depending on the compound. The radiochemical purity was higher than 99% for all at the end of synthesis. Radioligands were found to be stable, with a radiochemical purity of >99% in a sterile phosphate buffered saline (pH = 7.4) over the duration of the study. The ARG binding density of only 18F-GEH200449 was consistent with known MAO-B expression in the human brain. Radiolabeling of five new fluorine-18 MAO-B reversible inhibitors was successfully accomplished. Compound 18F-GEH200449 binds specifically to MAO-B in vitro postmortem brain and could be a potential candidate for in vivo PET investigation.

The present study was designed to investigate the effect of Urtica dioica plant parts "leaves and roots" separately, known as stinging nettle, on propionic acid (PPA) induced autistic like rat model on the behavior, monoamines and bioenergetics changes in rats compared with the synthetic drug risperidone. Sixty male albino rats were divided into 5 equal groups (n=12) and treated for 17 days as follows: 1- control {received (0.1M, PBS as 1ml/kg b.wt ip) and (0.5/100 w/v as 5ml/kg b.wt p.o) of carboxy methyl cellulose (CMC), 2- PPA received (250 mg/kg as 1 ml/kg b.wt; i.p) + CMC p.o. as control, group, 3- PPA+ RISP (1mg/kg b. wt, p.o), 4- PPA+ nettle leaves (NL, 50mg/kg b. wt, p.o) and 5- PPA+ nettle roots (NR, 50mg/kg b. wt, p.o). The three-box chamber and Y maze tests were performed from 15th to the 17th day. In the 18th day, rats were sacrificed and homogenates of cortical, hippocampal and midbrain tissues were used for the estimation of dopamine (DA), norepinephrine (NE) and serotonin (5-HT) contents along with the bioenergetics (ATP, ADP and AMP). The results showed that NR extract could attenuate behavior deficits together with the improvement of the monoaminergic system and bioenenrgetics. In contrast, NL extracts had a poor effect on behavioral improvement, monoamines levels and the bioenergetics. Therefore, it may be concluded that NR extract had a protective effect due to its impact on the behavioral, monoaminergic and bioenergetics systems.

Since the 1950s, the therapeutic arsenal against depression has grown considerably. From the discovery of mono-amine oxidase inhibitors (MAOIs) to the antidepressant effect of ketamine, several pharmacological breakthroughs made the history of psychiatry. These discoveries oriented the research about the pathophysiology of depression, which is one of the most disabling diseases worldwide affecting 10 to 20% of general population. In this article, we offer a short historical review of the various therapeutic options developed over the past century and the consequences of these innovations. We then review the discovery of the antidepressant effects of ketamine (and its S-enantiomer, esketamine), the lastest development in depression treatment. Ketamine's effects are spectacular both in terms of their very short onset time, and because they are observed even in treatment-resistant depression. Just as MAOIs and tricyclic antidepressants allowed the “monoaminergic hypothesis of depression” to emerge, unravelling the mechanisms of ketamine's antidepressant effects should highlight the role of glutamatergic system and neuro-inflammation in the neurobiology of depression. Ketamine might also help to refine our understanding of the cognitive pathophysiology of depression and to deeply transform the clinical representations of depressive disorder.

Methylglyoxal (MGO) is an endogenous toxin, mainly produced as a by-product of glycolysis that has been associated to aging, Alzheimer’s disease, and inflammation. Cell culture studies reported that MGO could impair the glyoxalase, thioredoxin, and glutathione systems. Thus, we investigated the effect of in vivo MGO administration on these systems, but no major changes were observed in the glyoxalase, thioredoxin, and glutathione systems, as evaluated in the prefrontal cortex and the hippocampus of mice. A previous study from our group indicated that MGO administration produced learning/memory deficits and depression-like behavior. Confirming these findings, the tail suspension test indicated that MGO treatment for 7 days leads to depression-like behavior in three different mice strains. MGO treatment for 12 days induced working memory impairment, as evaluated in the Y maze spontaneous alternation test, which was paralleled by low dopamine and serotonin levels in the cerebral cortex. Increased DARPP32 Thr75/Thr34 phosphorylation ratio was observed, suggesting a suppression of phosphatase 1 inhibition, which may be involved in behavioral responses to MGO. Co-treatment with a dopamine/noradrenaline reuptake inhibitor (bupropion, 10 mg/kg, p.o.) reversed the depression-like behavior and working memory impairment and restored the serotonin and dopamine levels in the cerebral cortex. Overall, the cerebral cortex monoaminergic system appears to be a preferential target of MGO toxicity, a new potential therapeutic target that remains to be addressed.