Monoaminergic Neurotransmission Research Articles

Chronic Glucocorticoid Exposure Induces Depression-Like Phenotype in Rhesus Macaque (Macaca Mulatta).

It has long been observed in humans that the occurrence of depressive symptoms is often accompanied by the dysfunction of hypothalamic-pituitary-adrenal (HPA) axis. The rodent experiments also showed that chronic corticosterone exposure could induce depression-like phenotype. However, rodents are phylogenetically distant from humans. In contrast, non-human primates bear stronger similarities with humans, suggesting research on primates would provide an important complement. For the first time, we investigated the effects of chronic glucocorticoid exposure on rhesus macaques. Seven male macaques were selected and randomized to glucocorticoid or vehicle groups, which were subjected to either prednisolone acetate or saline injections, respectively. The depression-like behaviors were assessed weekly, and the body weights, HPA axis reactivity, sucrose solution consumption and monoaminergic neurotransmitters were further compared between these two groups. The glucocorticoid group was not found to display more depression-like behaviors than the vehicle group until 7 weeks after treatment. Chronic glucocorticoid exposure significantly decreased the levels of cortisol determined from blood (a biomarker for acute HPA axis reactivity) but increased the hair cortisol concentrations (a reliable indicator of chronic HPA axis reactivity) compared with controls. The glucocorticoid group was also found to consume less sucrose solution than controls, a good manifestation of anhedonia. This could be possibly explained by lower dopamine (DA) levels in cerebrospinal fluid induced by chronic glucocorticoid treatment. The results presented here indicate that chronic glucocorticoid exposure could disturb both the acute and chronic HPA axis reactivity, which eventually disturbed the neurotransmitter system and led monkeys to display depression-like phenotype.

Repeated gestational exposure to diesel engine exhaust affects the fetal olfactory system and alters olfactory-based behavior in rabbit offspring

BackgroundAirborne pollution, especially from diesel exhaust (DE), is known to have a negative effect on the central nervous system in exposed human populations. However, the consequences of gestational exposure to DE on the fetal brain remain poorly explored, with various effects depending on the conditions of exposure, as well as little information on early developmental stages. We investigated the short-term effects of indirect DE exposure throughout gestation on the developing brain using a rabbit model. We analyzed fetal olfactory tissues at the end of gestation and tested behaviors relevant to pups’ survival at birth.Pregnant dams were exposed by nose-only inhalation to either clean air or DE with a content of particles (DEP) adjusted to 1 mg/m3 by diluting engine exhaust, for 2 h/day, 5 days/week, from gestational day 3 (GD3) to day 27 (GD27). At GD28, fetal olfactory mucosa, olfactory bulbs and whole brains were collected for anatomical and neurochemical measurements. At postnatal day 2 (PND2), pups born from another group of exposed or control female were examined for their odor-guided behavior in response to the presentation of the rabbit mammary pheromone 2-methyl-3-butyn-2-ol (2MB2).ResultsAt GD28, nano-sized particles were observed in cilia and cytoplasm of the olfactory sensory neurons in the olfactory mucosa and in the cytoplasm of periglomerular cells in the olfactory bulbs of exposed fetuses. Moreover, cellular and axonal hypertrophies were observed throughout olfactory tissues. Concomitantly, fetal serotoninergic and dopaminergic systems were affected in the olfactory bulbs. Moreover, the neuromodulatory homeostasis was disturbed in a sex-dependent manner in olfactory tissues. At birth, the olfactory sensitivity to 2MB2 was reduced in exposed PND2 pups.ConclusionGestational exposure to DE alters olfactory tissues and affects monoaminergic neurotransmission in fetuses’ olfactory bulbs, resulting in an alteration of olfactory-based behaviors at birth. Considering the anatomical and functional continuum between the olfactory system and other brain structures, and due to the importance of monoamine neurotransmission in the plasticity of neural circuits, such alterations could participate to disturbances in higher integrative structures, with possible long-term neurobehavioral consequences.

Differential Genetic Effect of the Norepinephrine Transporter Promoter Polymorphisms on Attention Problems in Clinical and Non-clinical Samples.

Among the monoaminergic modulatory neurotransmitters, norepinephrine is involved in task orienting, hence noradrenergic genetic variants have been studied in connection to attentional processes. The role of this catecholamine system is also highlighted by the selective norepinephrine transporter blocking atomoxetine, which has proved to be effective in the pharmacological treatment of Attention Deficit Hyperactivity Disorder (ADHD). In the present genetic association study three single nucleotide polymorphisms (rs28386840, rs2242446, rs3785143 SNPs) were analyzed from the 5′ region of the norepinephrine transporter (NET, SLC6A2) gene, which have been linked to ADHD previously. Attention problems scores of the mother-rated Child Behavior Checklist (CBCL) were used in separate analyses of 88 preschoolers (59.1% male, 6 years of age) recruited from the general population and 120 child psychiatry patients with ADHD diagnosis (85.8% male, age: 9.8 ± 2.9). The NET SNPs showed associations with attention problems, but the direction was different in the two groups. Regarding the promoter variant rs28386840, which showed the most consistent association, the T-allele-carrier patients with ADHD had lower CBCL attention problems scores compared to patients with AA genotype (p = 0.023), whereas T-allele-carriers in the community sample had more attention problems (p = 0.042). Based on previous reports of lower NE levels in ADHD children and the inverted-U shape effect of NE on cognitive functions, we propose that rs28386840 (-3081) T-allele, which is associated with lower NET expression (and potentially higher synaptic NE level) would support attention processes among ADHD patients (similarly as atomoxetine increases NE levels), whereas it would hinder cortical functions in healthy children.

Moving from the old monoaminergic theory toward the emerging hypothesis in the rational design of rapid-onset novel antidepressants

Antidepressants can be classified into 13 different classes based on their pharmacological mechanisms of action. As of this present moment, 11 out of these 13 classes of antidepressants accomplish their pharmacoactivities by blocking one or more of the reuptake transporter pumps and/or receptors for the three monoaminergic neurotransmitters, namely serotonin, norepinephrine, and dopamine. The 12th class inhibits the enzyme monoamine oxidase, while the 13th class works by blocking the N-methyl-D-aspartate (NMDA)-glutamatergic ionoceptor. Previous experimental results suggest that depression is associated with hyperfunction of NMDA-glutamatergic receptors (NMDARs) in the subcortical regions (i.e., hippocampus, locus coeruleus, and amygdala); whereas at the same time, there is hypofunction of NMDARs in the cortical regions (i.e., prefrontal, perirhinal, and temporal cortices). Moreover, this finding has led to a conclusion that postulates the new “Glutamatergic hypothesis of depression” which is now moving our understanding of the pathophysiology of major depression disorder (MDD), a step further from the several decades' old “Monoaminergic theory of depression.” Collectively, clinical data suggest the involvement of the glutamatergic neurotransmission system in the pathophysiology of MDD or bipolar depression or schizoaffective depression, which includes disruptions in glutamatergic substrate concentrations and NMDAR alterations. Although the role of glutamatergic systems is yet to be fully elucidated, a “proof of concept” clinical study reported that the noncompetitive NMDAR antagonist ketamine produced rapid-onset and prolonged antidepressant effects in patients suffering from MDD or bipolar depression or schizoaffective depression. Still, this has generated tremendous interest in developing new drugs that will target the glutamatergic neurotransmission mechanisms for the treatment of MDD or bipolar depression or schizoaffective depression. These potential drug targets are the NMDAR as antagonist or inverse agonist or partial agonist, metabotropic glutamatergic receptors as positive or negative modulator, excitatory amino acid transporter-2 (EAAT-2) as a reuptake enhancer, and as a terminal presynaptic glutamate release inhibitor.

Garlic essential oil mediates acute and chronic mild stress-induced depression in rats via modulation of monoaminergic neurotransmission and brain-derived neurotrophic factor levels

Garlic essential oil (GEO) and its major organosulfur component (diallyl disulfide, DADS) possess diverse biological properties; however, limited information on their antidepressant-like effects is available. This study is the first to investigate these effects of GEO using the forced swimming test (FST) and unpredictable chronic mild stress (UCMS) induced depression in rats. After oral administration for 28 consecutive days, GEO (25 and 50 mg per kg bw) significantly reduced the immobility time in the FST. Additionally, GEO and DADS significantly reversed the sucrose preference index decrease induced by 5 weeks of UCMS. GEO (25 mg per kg bw) effectively decreased the frontal cortex turnover ratio of serotonin (5-HT) and dopamine (DA), thus increasing the 5-HT and DA levels, with no hippocampal effects. Chronic GEO treatment increased hippocampal brain-derived neurotrophic factor (BDNF), c-AMP response element binding protein (CREB), and protein kinase B (AKT) expression, exhibiting its effects via monoamine neurotransmitter modulation and the BDNF-related signaling pathway.

Gepirone hydrochloride: a novel antidepressant with 5-HT1A agonistic properties.

Depression is a neuropsychiatric disorder that affects more than 350 million people all over the world. There are psychological and pharmacological treatments for depression which mainly focus on monoaminergic neurotransmission theory. The main concern regarding available antidepressants is the lag period and other side effects, such as sexual dysfunction. Gepirone is a drug of the azapirone group which is a 5-HT1A receptor agonist belonging to the buspirone family. Gepirone is under clinical development and has been shown to be more effective than selective serotonin reuptake inhibitors (SSRIs), as this drug treats the psychiatric disorders without causing sexual dysfunction, which limits the use of SSRIs. It possesses greater selectivity for the 5-HT1A receptor than SSRIs. Clinical studies have shown that gepirone has differential action at pre- and postsynaptic 5-HT1A receptors. Gepirone extended-release tablets (gepirone ER, Travivo) showed promising effects in adult outpatients for the treatment of major depressive disorder (MDD) in a double-blind, randomized, placebo-controlled clinical study. Gepirone also showed an antianxiety effect in a placebo-controlled trial in generalized anxiety disorder. Absorption of gepirone is increased when administered with food as there is no substantial change in Cmax and half-life but it significantly increases AUC and mean residence time. Gepirone undergoes first-pass metabolism and its major metabolites are 1- (2-pyrimidinyl)-piperazine (1-PP) and 3-OH-gepirone, both of which are pharmacologically active. In addition to its better efficacy, gepirone is well tolerated and the major adverse effects observed have been nausea, dizziness and lightheadedness. Evidence from preclinical and clinical studies revealed that gepirone could be a breakthrough therapeutic agent in the treatment of anxiety and MDD.

Emotional Roles of Mono-Aminergic Neurotransmitters in Major Depressive Disorder and Anxiety Disorders.

A growing body of researches support a role for dysfunction of serotoninergic, noradrenergic, and dopaminergic systems in the neurobiological processes involved in major depression disorder (MDD) and anxiety disorders (ADs). The physiological changes underlying abnormal signaling of 5-HT, NE, and DA may be due to either reduced presynaptic release of these neurotransmitters or aberrant signal transductions, and thus contributing to the alterations in regulation or function of receptors and/or impaired intracellular signal processing. Animal models demonstrate crucial responsiveness to disturbance of 5-HT, NE, and DA neurotransmissions. Postmortem and biochemical studies have shown altered concentrations of 5-HT, NE, and DA metabolites in brain regions that contribute importantly to regulation of mood and motivation in patients with MDD or ADs. Neuroimaging studies have found abnormal 5-HT, NE, and DA receptors binding and regulation in regard to receptor numbers. Medications that act on 5-HT, NE, and DA neurons or receptors, such as SSRIs and SNRIs, show efficacy in both MDD and ADs. The overlapping treatment response presumably suggests a common mechanism underlying the interaction of these disorders. In this paper, we reviewed studies from multiple disciplines to interpret the role of altered 5-HT, NE and DA mono-amine neurotransmitter functions in both MDD and ADs.

Early life stress and voluntary alcohol consumption in relation to Maoa methylation in male rats.

Early life stress (ELS) or alcohol consumption can influence DNA methylation and affect gene expression. Monoamine oxidase A (Maoa) encodes the enzyme that metabolizes monoaminergic neurotransmitters crucial for the stress response, alcohol reward, and reinforcement. Previously, we reported lower Maoa expression in the nucleus accumbens and dorsal striatum of male rats exposed to ELS during the first three postnatal weeks, and to voluntary alcohol consumption in adulthood, compared with controls. The present study continued to investigate the effect of ELS and alcohol consumption on Maoa methylation, and its relation to Maoa expression in these animals. We selected candidate CpGs after performing next-generation bisulfite sequencing of the Maoa promoter, intron 1-5, and exons 5 and 6, together composed of 107 CpGs (5'-cytosine-phosphate-guanosine-3'), in a subgroup of rats. Pyrosequencing was used to analyze the methylation of 10 candidate CpGs in the promoter and intron 1 in the entire sample. ELS and alcohol displayed an interactive effect on CpG-specific methylation in the dorsal striatum. CpG-specific methylation correlated with Maoa expression, corticosterone levels, and alcohol consumption in a brain region-specific manner. CpG-specific methylation in the Maoa promoter was a potential moderator of the interaction of ELS with alcohol consumption on Maoa expression in the NAc. However, the findings were sparse, did not survive correction for multiple testing, and the magnitude of differences in methylation levels was small. In conclusion, CpG-specific Maoa methylation in the promoter and intron 1 may associate with ELS, alcohol consumption, and Maoa expression in reward-related brain regions.

Morphological changes of the brain in mood disorders.

Brain morphological changes in affective disorders occur mainly in the fronto-limbic cortex, hippocampus and amygdala - the structures regulating emotional and cognitive functioning, as well as development of somatic symptoms in the course of disorders. The largest number of reports of structural changes in the cerebral cortex include the dorsolateral prefrontal cortex, the orbitofrontal cortex and the anterior cingulate cortex. The results of neuroimaging and sectional studies reveal changes in the volume of structures involved in the creation of neuronal circuits that affect development of mood disorders. Microscopic studies show changes in cell count, density, and morphology in these areas. Some of those changes are observed only in certain layers of the cerebral cortex. A valuable addition to this data are histochemical studies of neuronal survival markers, proinflammatory cytokines, trophic factors, and markers specific for particular cellular structures. The role of monoaminergic, GABA-ergic and glutamatergic neurotransmission is confirmed by the studies on concentration of neurotransmitters, their receptors and transporters. Some of the results correlate quantitatively with the type and severity of symptoms, duration of the disorder, as well as pharmacotherapy and nonpharmacological treatment.

DARK Classics in Chemical Neuroscience: Aminorex Analogues.

Aminorex (5-phenyl-4,5-dihydro-1,3-oxazol-2-amine) and 4-methylaminorex (4-methyl-5-phenyl-4,5-dihydro-1,3-oxazol-2-amine) are psychostimulants that have long been listed in Schedules IV and I of the UN Convention on Psychotropic Substances of 1971. However, a range of psychoactive analogues exist that are not internationally controlled and therefore often classified as new psychoactive substances (NPS). Aminorex analogues encompass failed pharmaceuticals that reemerged as drugs of abuse, and newly synthesized substances that were solely designed for recreational use by clandestine chemists. NPS, sometimes also referred to as "designer drugs" in alignment with a phenomenon arising in the early 1980s, serve as alternatives to controlled drugs. Aminorex and its derivatives interact with monoaminergic neurotransmission by interfering with the function of monoamine transporters. Hence, these compounds share pharmacological and neurochemical similarities with amphetamines and cocaine. The consumption of aminorex, 4-methylaminorex and 4,4'-dimethylaminorex (4-methyl-5-(4-methylphenyl)-4,5-dihydro-1,3-oxazol-2-amine) has been associated with adverse events including death, bestowing an inglorious fame on aminorex-derived drugs. In this Review, a historical background is presented, as well as an account of the pharmacodynamic and pharmacokinetic properties of aminorex and various analogues. Light is shed on their misuse as drug adulterants of well-established drugs on the market. This Review not only provides a detailed overview of an abused substance-class, but also emphasizes the darkest aspect of the NPS market, i.e., deleterious side effects that arise from the ingestion of certain NPS, as knowledge of the pharmacology, the potency, or the identity of the active ingredients remains obscure to NPS users.

Executive (dys)function after traumatic brain injury: special considerations for behavioral pharmacology.

Executive function is an umbrella term that includes cognitive processes such as decision-making, impulse control, attention, behavioral flexibility, and working memory. Each of these processes depends largely upon monoaminergic (dopaminergic, serotonergic, and noradrenergic) neurotransmission in the frontal cortex, striatum, and hippocampus, among other brain areas. Traumatic brain injury (TBI) induces disruptions in monoaminergic signaling along several steps in the neurotransmission process – synthesis, distribution, and breakdown – and in turn, produces long-lasting deficits in several executive function domains. Understanding how TBI alters monoamingeric neurotransmission and executive function will advance basic knowledge of the underlying principles that govern executive function and potentially further treatment of cognitive deficits following such injury. In this review, we examine the influence of TBI on the following measures of executive function – impulsivity, behavioral flexibility, and working memory. We also describe monoaminergic-systems changes following TBI. Given that TBI patients experience alterations in monoaminergic signaling following injury, they may represent a unique population with regard to pharmacotherapy. We conclude this review by discussing some considerations for pharmacotherapy in the field of TBI.

Regulator of G protein signaling 2 differentially regulates nicotine-induced anxiolytic- and antidepressant-like effects in mice.

This study assessed the role of regulator of G protein signaling 2 (RGS2) in nicotine-induced anxiolytic- and antidepressant-like effects using RGS2 wildtype (WT) and RGS2 knockout (KO) mice. RGS2 negatively regulates monoaminergic neurotransmission, which is implicated in the pathology of anxiety and depression. We hypothesized that deletion of RGS2 would enhance nicotine-induced anxiolytic- and antidepressant-like effects, which were assessed using the elevated plus maze and tail suspension tests, respectively. Anxiolytic-like effects were observed in both RGS2 WT and KO mice after administration of low dose of nicotine (0.05mg/kg, base) compared to respective saline controls. Additionally, administration of nicotine (0.1mg/kg, base) compared to saline resulted in anxiolytic-like effects in RGS2 KO mice, but not RGS2 WT mice, suggesting genetic deletion of RGS2 facilitated anxiolytic-like effects of nicotine. Administration of nicotine (0.5 and 1mg/kg, base) compared to saline resulted in antidepressant-like effects in RGS2 WT mice. Antidepressant-like effects were observed in RGS2 KO mice only at the highest tested dose of nicotine (1mg/kg, base) compared to saline controls, suggesting that genetic deletion of RGS2 decreased sensitivity to antidepressant-like effects of nicotine. Together, the data suggest that RGS2 differentially regulated nicotine-induced affective behavioral responses. These data suggest that individuals with RGS2 polymorphisms may experience differential affective responses to tobacco smoking, which may make them vulnerable to developing nicotine addiction.

Butanol Fraction of Olax Subscorpioidea Produces Antidepressant Effect: Evidence for the Involvement of Monoaminergic Neurotransmission.

This study sought to investigate involvement of monoaminergic mechanism in the antidepressant action of butanol fraction (BF) of Olax subscorpioidea in rodents and the bioactive principles present. Butanol fraction was evaluated for antidepressant-like effect in the tail suspension, forced swimming and open field tests. All animals were treated with BF (5, 10 & 20 mg/kg) thirty minutes prior to the tests. On the other hand, monoaminergic neurotransmission involvement was probed by pre-treating animals with yohimbine hydrochloride (1 mg/kg, α2 antagonist), prazosin (62.5 µg/kg, α1 antagonist), propranolol (2 mg/kg, non-selective β antagonist), sulpiride (50 mg/kg, D2 receptor blocker), haloperidol (0.2 mg/kg, non-selective D receptor blocker), metergoline (4 mg/kg, i.p., a 5HT-receptor blocker) and PCPA (100 mg/kg, i.p., inhibitor of tryptophan hydroxylase), fifteen minute before treatment with BF (10 mg/kg). Identification of the major bioactive constituents was done by HPLC. The findings show that BF (5 & 10 mg/kg) significantly decreased immobility in despair tests of depression without effect on locomotor activity. The data also shows that anti-immobility effect of BF (10 mg/kg) in the TST was reversed by prazosin, yohimbine, haloperidol, sulpiride, metagoline and PCPA but not with propranolol. Bioactive principles present are caffeic acid, rutin, morin and quercetin. In conclusion, our findings show that BF produces antidepressant-like effect, which may be dependent on its interaction with the monoaminergic system.

Roles for the uptake2 transporter OCT3 in regulation of dopaminergic neurotransmission and behavior

Transporter-mediated uptake determines the peak concentration, duration, and physical spread of released monoamines. Most studies of monoamine clearance focus on the presynaptic uptake1 transporters SERT, NET and DAT. However, recent studies have demonstrated the expression of the uptake2 transporter OCT3 (organic cation transporter 3), throughout the rodent brain. In contrast to NET, DAT and SERT, OCT3 has higher capacity and lower affinity for substrates, is sodium-independent, and is multi-specific, with the capacity to transport norepinephrine, dopamine, serotonin and histamine. OCT3 is insensitive to inhibition by cocaine and antidepressant drugs but is inhibited directly by the glucocorticoid hormone corticosterone. Thus, OCT3 represents a novel, stress hormone-sensitive, monoamine transport mechanism. Incorporating this transporter into current models of monoaminergic neurotransmission requires information on: A) the cellular and subcellular localization of the transporter; B) the effects of OCT3 inhibitors on monoamine clearance; and C) the consequences of decreased OCT3-mediated transport on physiology and/or behavior. This review summarizes studies describing the anatomical distribution of OCT3, its cellular and subcellular localization, its contribution to the regulation of dopaminergic signaling, and its roles in the regulation of behavior. Together, these and other studies suggest that both Uptake1 and Uptake2 transporters play key roles in regulating monoaminergic neurotransmission and the effects of monoamines on behavior.

Regulators of G-protein signaling 2 and 4 differentially regulate cocaine-induced rewarding effects

There is a need to identify new therapeutic targets for the treatment of cocaine addiction due to the rise in cocaine abuse and deaths due to cocaine overdose. Regulator of G protein signaling (RGS) proteins such as RGS2 and RGS4 are widely distributed in brain regions that play a role in drug reward. Importantly, RGS2 and RGS4 negatively regulate G-protein coupled receptor signaling pathways of monoaminergic neurotransmitters that play a role in the rewarding effects of cocaine by enhancing the rate of hydrolysis of Gα-bound guanine nucleotide triphosphate. Thus, the objective of this study was to investigate the effects of cocaine on conditioned place preference (CPP) and locomotor activity in mice that lacked either RGS2 or RGS4 (i.e. knockout (KO) mice) and their wildtype (WT) littermates. Moreover recent studies have reported influence of sex on RGS functioning and hence studies were conducted in both male and female mice. Cocaine-induced CPP was attenuated in male, but not female RGS4 KO mice compared to respective RGS4 WT mice. Cocaine-induced CPP was not influenced by deletion of RGS2 in either male or female mice. Similarly, cocaine-induced locomotor activity was not influenced by deletion of either RGS2 or RGS4 irrespective of sex. Together, the data indicate that the rewarding effects of cocaine were attenuated in the absence of RGS4 expression, but not in the absence of RGS2 expression in a sex-dependent manner. Importantly, these data suggest that RGS4 can serve as a potential target for medications that can be used to treat cocaine addiction.

3D similarities between the binding sites of monoaminergic target proteins.

The study of binding site similarities can be relevant to understand the interaction of different drugs at several molecular targets. The increasing availability of protein crystal structures and the development of novel algorithms designed to evaluate three-dimensional similarities, represent a great opportunity to explore the existence of electronic and shape features shared by clinically relevant proteins, which could assist drug design and discovery. Proteins involved in the recognition of monoaminergic neurotransmitters, such as monoamine transporters or monoamine oxidases (MAO) have been related to several psychiatric and neurological disorders such as depression or Parkinson’s disease. In this work, we evaluated the possible existence of similarities among the binding sites of the serotonin transporter (SERT), the dopamine transporter (DAT), MAO-A and MAO-B. This study was carried out using molecular simulation methodologies linked to the statistical algorithm PocketMatch, which was modified in order to obtain similarities profiles. Our results show that DAT and SERT exhibit a high degree of 3-D similarities all along the pathway that is presumably involved in the substrate transport process. Distinct differences, on the other hand, were found both at the extracellular and the intracellular ends of the transporters, which might be involved in the selective initial recognition of the corresponding substrate. Similarities were also found between the active (catalytic) site of MAO-A and the extracellular vestibule of SERT (the S2 binding site). These results suggest some degree of structural convergence for these proteins, which have different functions, tissue distribution and genetic origin, but which share the same endogenous ligand (serotonin). Beyond the functional implications, these findings are valuable for the design of both selective and non-selective ligands.

Spatial Memory Dysfunction Induced by Vitamin C Deficiency Is Associated with Changes in Monoaminergic Neurotransmitters and Aberrant Synapse Formation.

Vitamin C (vitC) is important in the developing brain, acting both as an essential antioxidant and as co-factor in the synthesis and metabolism of monoaminergic neurotransmitters. In guinea pigs, vitC deficiency results in increased oxidative stress, reduced hippocampal volume and neuronal numbers, and deficits in spatial memory. This study investigated the effects of 8 weeks of either sufficient (923 mg vitC/kg feed) or deficient (100 mg vitC/kg feed) levels of dietary vitC on hippocampal monoaminergic neurotransmitters and markers of synapse formation in young guinea pigs with spatial memory deficits. Western blotting and high performance liquid chromatography (HPLC) were used to quantify the selected markers. VitC deficiency resulted in significantly reduced protein levels of synaptophysin (p = 0.016) and a decrease in 5-hydroxyindoleacetic acid/5-hydroxytryptamine ratio (p = 0.0093). Protein expression of the N-methyl-d-aspartate receptor subunit 1 and monoamine oxidase A were reduced, albeit not reaching statistical significance (p = 0.0898 and p = 0.067, respectively). Our findings suggest that vitC deficiency induced spatial memory deficits might be mediated by impairments in neurotransmission and synaptic development.

Regulation of monoamine transporters and receptors by lipid microdomains: implications for depression.

Lipid microdomains ("rafts") are dynamic, nanoscale regions of the plasma membrane enriched in cholesterol and glycosphingolipids, that possess distinctive physicochemical properties including higher order than the surrounding membrane. Lipid microdomain integrity is thought to affect neurotransmitter signaling by regulating membrane-bound protein signaling. Among the proteins potentially affected are monoaminergic receptors and transporters. As dysfunction of monoaminergic neurotransmission is implicated in major depressive disorder and other neuropsychiatric conditions, interactions with lipid microdomains may be of clinical importance. This systematic review evaluates what is known about the molecular relationships of monoamine transporter and receptor regulation to lipid microdomains. The PubMed/MeSH database was searched for original studies published in English through August 2017 concerning relationships between lipid microdomains and serotonin, dopamine and norepinephrine transporters and receptors. Fifty-seven publications were identified and assessed. Strong evidence implicates lipid microdomains in the regulation of serotonin and norepinephrine transporters; serotonin 1A, 2A, 3A, and 7A receptors; and dopamine D1 and β2 adrenergic receptors. Results were conflicting or more complex regarding lipid microdomain associations with the dopamine transporter, D2, D3, and D5 receptors; and negative with respect to β1 adrenergic receptors. Indirect evidence suggests that antidepressants, lipid-lowering drugs, and polyunsaturated fatty acids may exert effects on depression and suicide by altering the lipid milieu, thereby affecting monoaminergic transporter and receptor signaling. The lipid composition of membrane subdomains is involved in localization and trafficking of specific monoaminergic receptors and transporters. Elucidating precise mechanisms whereby lipid microdomains modulate monoamine neurotransmission in clinical contexts can have critical implications for pharmacotherapeutic targeting.

Neuromodulatory Inputs to Motoneurons Contribute to the Loss of Independent Joint Control in Chronic Moderate to Severe Hemiparetic Stroke.

In chronic hemiparetic stroke, increased shoulder abductor activity causes involuntary increases in elbow, wrist, and finger flexor activation, an abnormal muscle coactivation pattern known as the flexion synergy. Recent evidence suggests that flexion synergy expression may reflect recruitment of contralesional cortico-reticulospinal motor pathways following damage to the ipsilesional corticospinal tract. However, because reticulospinal motor pathways produce relatively weak post-synaptic potentials in motoneurons, it is unknown how preferential use of these pathways could lead to robust muscle activation. Here, we hypothesize that the descending neuromodulatory component of the ponto-medullary reticular formation, which uses the monoaminergic neurotransmitters norepinephrine and serotonin, serves as a gain control mechanism to facilitate motoneuron responses to reticulospinal motor commands. Thus, inhibition of the neuromodulatory component would reduce flexion synergy expression by disfacilitating spinal motoneurons. To test this hypothesis, we conducted a pre-clinical study utilizing two targeted neuropharmacological probes and inert placebo in a cohort of 16 individuals with chronic hemiparetic stroke. Test compounds included Tizanidine (TIZ), a noradrenergic α2 agonist and imidazoline ligand selected for its ability to reduce descending noradrenergic drive, and Isradipine, a dihyropyridine calcium-channel antagonist selected for its ability to post-synaptically mitigate a portion of the excitatory effects of monoamines on motoneurons. We used a previously validated robotic measure to quantify flexion synergy expression. We found that Tizanidine significantly reduced expression of the flexion synergy. A predominantly spinal action for this effect is unlikely because Tizanidine is an agonist acting on a baseline of spinal noradrenergic drive that is likely to be pathologically enhanced post-stroke due to increased reliance on cortico-reticulospinal motor pathways. Although spinal actions of TIZ cannot be excluded, particularly from Group II pathways, our finding is consistent with a supraspinal action of Tizanidine to reduce descending noradrenergic drive and disfacilitate motoneurons. The effects of Isradipine were not different from placebo, likely related to poor central bioavailability. These results support the hypothesis that the descending monoaminergic component of the ponto-medullary reticular formation plays a key role in flexion synergy expression in chronic hemiparetic stroke. These results may provide the basis for new therapeutic strategies to complement physical rehabilitation.

Conséquences de l’inter-relation des systèmes monoaminergiques dans l’activité antidépressive

Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed antidepressant treatment for treat major depressive disorders. Despite their effectiveness, only 30% of SSRI-treated patients reach remission of depressive symptoms. SSRIs by inhibiting the serotonin transporter present some limits with residual symptoms. Increasing not only serotonin but also norepinephrine and dopamine levels in limbic areas seems to improve remission. Anatomical relationships across serotoninergic, dopaminergic and noradrenergic systems suggest tight reciprocal regulations among them. This review attempts to present, from acute to chronic administration the consequences of SSRI administration on monoaminergic neurotransmission. The serotonin neurons located in the raphe nucleus (RN) are connected to the locus coeruleus (locus coeruleus), the key structure of norepinephrine synthesis, through GABAergic-inhibiting interneurons. Activation of the 5-HT2A receptors expressed on GABAergic interneurons following SERT-inhibition induces an increase in serotonin leading to inhibitory effect on NE release. Similarly, the serotonin neurons exert negative regulation on dopaminergic neurons from the ventral tegmental area (VTA) through a GABAergic interneuron. These interneurons express the 5-HT2C and 5-HT3 receptors inducing an inhibitory effect of 5-HT on DA release. Positive reciprocal connections are also observed through direct projections from the locus coeruleus to the RN and from the VTA to the RN through α1 and D2 receptors respectively, both stimulating the serotoninergic activity. Acute SSRI treatment induces only a slight increase in 5-HT levels in limbic areas due to the activation of presynaptic 5-HT1A and 5-HT1B autoreceptors counteracting the effects of the transporter blockade. No change in NE levels and a small decrease in the dopaminergic neurotransmission is also observed. These weak changes in monoamine in the limbic areas after acute SSRI treatment seems to be one of key point involved in the onset of action. Following desensitization of the 5-HT1A and 5-HT1B autoreceptors, chronic SSRI treatment induces a large increase in the 5-HT neurotransmission. Changes in 5-HT levels at the limbic areas results in a decrease in NE transmission and an increase in DA transmission through an increase in the post-synaptic D2 receptors sensitivity and not from a change in DA levels, which is mainly due to a desensitization of the 5-HT2A receptor. The observed decrease of NE neurotransmission could explain some limits of the SSRI therapy and the interest to activate NE system for producing more robust effects. On the other hand, the D2 sensitization, especially in the nucleus accumbens, stimulates the motivation behavior as well as remission of anhedonia considering the major role of DA release in this structure. Finally, we need to take into account the key role of each monoaminergic neurotransmission to reach remission. Targeting only one system will limit the therapeutic effectiveness. Clinical evidences, including the STAR*D studies, confirmed this by an increase of the remission rate following the mobilization of several monoaminergic transmissions. However, these combinations cannot constitute first line of treatment considering the observed increase of side effects. Such an approach should be adapted to each patient in regard to its particular symptoms as well as clinical history. The next generation of antidepressant therapy will need to take into consideration the interconnections and the interrelation between the monoaminergic systems.