Serotonergic Neurotransmitter Systems Research Articles

Diagnosis of major depressive disorder based on changes in multiple plasma neurotransmitters: a targeted metabolomics study

Major depressive disorder (MDD) is a debilitating psychiatric illness. However, there is currently no objective laboratory-based diagnostic tests for this disorder. Although, perturbations in multiple neurotransmitter systems have been implicated in MDD, the biochemical changes underlying the disorder remain unclear, and a comprehensive global evaluation of neurotransmitters in MDD has not yet been performed. Here, using a GC-MS coupled with LC-MS/MS-based targeted metabolomics approach, we simultaneously quantified the levels of 19 plasma metabolites involved in GABAergic, catecholaminergic, and serotonergic neurotransmitter systems in 50 first-episode, antidepressant drug-naïve MDD subjects and 50 healthy controls to identify potential metabolite biomarkers for MDD (training set). Moreover, an independent sample cohort comprising 49 MDD patients, 30 bipolar disorder (BD) patients and 40 healthy controls (testing set) was further used to validate diagnostic generalizability and specificity of these candidate biomarkers. Among the 19 plasma neurotransmitter metabolites examined, nine were significantly changed in MDD subjects. These metabolites were mainly involved in GABAergic, catecholaminergic and serotonergic systems. The GABAergic and catecholaminergic had better diagnostic value than serotonergic pathway. A panel of four candidate plasma metabolite biomarkers (GABA, dopamine, tyramine, kynurenine) could distinguish MDD subjects from health controls with an AUC of 0.968 and 0.953 in the training and testing set, respectively. Furthermore, this panel distinguished MDD subjects from BD subjects with high accuracy. This study is the first to globally evaluate multiple neurotransmitters in MDD plasma. The altered plasma neurotransmitter metabolite profile has potential differential diagnostic value for MDD.

Big Lessons from Tiny Flies: Drosophila melanogaster as a Model to Explore Dysfunction of Dopaminergic and Serotonergic Neurotransmitter Systems.

The brain of Drosophila melanogaster is comprised of some 100,000 neurons, 127 and 80 of which are dopaminergic and serotonergic, respectively. Their activity regulates behavioral functions equivalent to those in mammals, e.g., motor activity, reward and aversion, memory formation, feeding, sexual appetite, etc. Mammalian dopaminergic and serotonergic neurons are known to be heterogeneous. They differ in their projections and in their gene expression profile. A sophisticated genetic tool box is available, which allows for targeting virtually any gene with amazing precision in Drosophila melanogaster. Similarly, Drosophila genes can be replaced by their human orthologs including disease-associated alleles. Finally, genetic manipulation can be restricted to single fly neurons. This has allowed for addressing the role of individual neurons in circuits, which determine attraction and aversion, sleep and arousal, odor preference, etc. Flies harboring mutated human orthologs provide models which can be interrogated to understand the effect of the mutant protein on cell fate and neuronal connectivity. These models are also useful for proof-of-concept studies to examine the corrective action of therapeutic strategies. Finally, experiments in Drosophila can be readily scaled up to an extent, which allows for drug screening with reasonably high throughput.

O7.6. META-ANALYSIS OF EFFICACY OF COGNITIVE ENHANCERS FOR PATIENTS WITH SCHIZOPHRENIA-SPECTRUM DISORDERS

BackgroundCognitive impairment is a core feature of schizophrenia, which is predictive for functional outcomes and should therefore be one of the main treatment targets. Pharmacological enhancement of cognition has been a main field of research in the last decades, investigating almost all neurotransmitter systems and reporting positive as well as negative findings. The pathophysiology of cognitive dysfunctions in schizophrenia is complex and many different neurotransmitter systems are involved. This quantitative review provides an overview of studies of pharmacological agents targeting neurotransmitter systems relevant for cognitive deficits in schizophrenia.MethodsIn our systematic search we included pharmacological agents targeting glutamatergic, cholinergic, serotonergic, dopaminergic, GABAergic and noradrenergic neurotransmitter systems, and also a miscellaneous group of agents, including modafinil/armodafinil. We evaluated the effects of cognitive enhancers on overall cognitive functioning as well as on seven cognitive domains, including attention/vigilance, processing speed, reasoning, verbal learning and memory, visual learning and memory, working memory, and verbal fluency.ResultsIn total, 93 studies with 5630 patients were suitable for inclusion in the meta-analysis. The mean sample size was 28.73 (SD=27.13, range=4–203), mean age of the participants was 44.15 years (SD=6.36, as reported by 91 study samples), 68.54% of the sample were men (as reported by 87 study samples), and average illness duration was 15.57 years (SD=6.47, as reported by 63 study samples). Combining all cognitive enhancers across different neurotransmitter systems for the effect on overall cognitive functioning resulted in fifty-one study samples, with a total of 3635 patients. Cognitive enhancers showed a small but significant positive effect size of 0.10 over placebo treatment (p=.023; 95%CI=0.01 to 0.18). Overall, cognitive enhancers showed no positive effects as compared to placebo for the separate domains. When analysing each neurotransmitter system separately, agents acting predominantly on the glutamatergic system showed a small but significant effect size on overall cognitive functioning (Hedges’ g=0.19, p=.01), as well as on working memory (Hedges’ g=0.13, p=.04). A sub-analysis of acetylcholinesterase inhibitors (AChEI) within cholinergic system showed a small effect on working memory (Hedges’ g=0.26, p=.03). No other positive effects of cognitive enhancers as compared to placebo were revealed.DiscussionThe current meta-analysis showed very few favorable effects of cognitive enhancers for patients with schizophrenia spectrum disorders. The overall analysis showed small difference between cognitive enhancers and placebo. Most studies were on agents acting on the glutamatergic and the cholinergic system. There is some evidence of positive effects on cognitive functioning for agents acting on glutamatergic system and acetylcholinesterase inhibitors within cholinergic system. There is still a major lack of studies involving agents acting on other systems. Important issues such as dose, treatment duration, including a younger population and subtyping heterogeneous samples should be taken into account for future studies.

Resting-state functional connectivity of neurotransmitter producing sites in female patients with borderline personality disorder

Impulsive behavior, difficulties in controlling anger and suicidal behavior are typical patterns of affective/behavioral dysregulation in patients with borderline personality disorder (BPD). Previous functional MRI studies in the resting state condition demonstrated altered functional connectivity (FC) between the anterior cingulate cortex (ACC) and the frontoparietal executive control network (ECN), which was significantly associated with impulsivity in BPD. Impulsivity is often defined as a function of inhibitory control, strongly relying on the proper functioning of the fronto-cingulo-striatal network. Noradrenergic, dopaminergic and serotonergic neurotransmitter systems are assumed to be involved in different forms of impulsive behavior and inhibitory control. In our previous study, we investigated the FC of the main monoamine-producing nuclei within the midbrain and brainstem, which were functionally integrated in specific resting-state networks. In the present study we investigated the resting-state FC of midbrain/brainstem nuclei in 33 unmedicated female patients with BPD and 33 matched healthy controls. We further related altered functional connectivity of these nuclei to the patient's degree of impulsivity. The main finding was that BPD patients showed stronger FC from the noradrenergic locus coeruleus (LC) to the ACC. Functional connectivity between the LC and ACC was positively associated with the degree of motor impulsivity in the total group. Controlling for aggression, a stronger FC was also found between serotonergic nucleus centralis superior (NCS) and the frontopolar cortex (FPC) in patients compared to controls. Furthermore, patients showed a weaker “anti-correlation” from the substantia nigra (SNc) to the left dorsolateral prefrontal cortex (DLPFC). The observed enhanced LC-ACC FC in BPD and its association with the motor impulsivity might be indicative of a noradrenergic dysfunction in the neural inhibitory control network, whereas the significant relationship between NCS-FPC FC and aggression points toward serotonergic contribution to prefrontal control of aggressive reactions.

ШЛЯХ БІОСИНТЕЗУ СЕРОТОНІНУ В ГОЛОВНОМУ МОЗКУ ЩУРІВ ЗА УМОВ ЕКСПЕРИМЕНТАЛЬНОГО ОЖИРІННЯ, ВИКЛИКАНОГО ДОВГОТРИВАЛИМ УВЕДЕННЯМ ПРОГЕСТЕРОНУ

Obesity is one of the most common complex health problem. The pathway of serotonin synthesis takes part in neuroendocrine regulation, as well as in the regulation of a number of behavioral functions of the body and fat deposition. Serotonin is a mediator of the amine nature, which functions as a neurotransmitter and tissue hormone. The greatest amount of serotonin is synthesized in the brain and 12 duodenum. As a neurotransmitter, serotonin affects both directly and indirectly on the function of most brain cells. Female hormone progesterone influence on serotonin functions. One of the effect of progesterone is increasing of amount of fat tissue during the pregnancy. Long-term using of progesterone in hormone substitution therapy or as part of contraception also lead to fat accumulation effect. The levels of activity of serotonergic system enzymes, tryptophan hydroxylase, tryptophan decarboxylase and monoamine oxidase (MAO), and tryptophan, 5-hydroxytryptophan, serotonin and 5-hydroxyindoleacetic acid concentrations in the rat brain under obesity conditions caused by prolonged administration of progesterone were determined in this study. Studies have shown that the content of tryptophan, 5-hydroxytryptophan, serotonin and 5-hydroxyindoleacetic acid in the brain of rats under obesity caused by prolonged administration of progesterone increased in comparison with the rats of the control group. The levels of tryptophan hydroxylase and MAO activity decreased, and tryptophan decarboxylase activity levels increased in the rat brain under obesity conditions caused by prolonged administration of progesterone. Thus, as a result of our studies, we found an imbalance in the system of serotonin metabolism in the brain of rats with the development of hormonal obesity induced by prolonged administration of progesterone, which may indicate the involvement of the serotonergic neurotransmitter system in the mechanisms of the development of obesity and concomitant diseases.

CK2 regulates 5-HT4 receptor signaling and modulates depressive-like behavior.

The serotonergic neurotransmitter system has been widely implicated in the pathophysiology of mood-related disorders such as anxiety and major depressive disorder (MDD). The onset of therapeutic efficacy of traditional antidepressants is delayed by several weeks. The 5-HT4 receptor has emerged as a new therapeutic target since agonists of this receptor induce rapid antidepressant-like responses in rodents. Here we show that the 5-HT4 receptor is regulated by CK2, at transcriptional and post-transcriptional levels. We present evidence, in two different CK2α knockout mouse lines, that this regulation is region-specific, with the 5-HT4 receptor upregulated in prefrontal cortex (PFC) but not striatum or hippocampus where CK2α is also ablated. 5-HT4 receptor signaling is enhanced in vitro, as evidenced by enhanced cAMP production or receptor plasma membrane localization in the presence of CK2 inhibitor or shRNA targeting CK2α. In vivo, 5-HT4 receptor signaling is also upregulated since ERK activation is elevated and sensitive to the inverse agonist, GR113808 in the PFC of CK2α KO mice. Behaviorally, KO mice as well as mice with AAV-mediated deletion of CK2α in the PFC show a robust 'anti-depressed-like' phenotype and display an enhanced response to antidepressant treatment when tested in paradigms for mood and anxiety. Importantly, it is sufficient to overexpress the 5-HT4 receptor in the mPFC to generate mice with a similar 'anti-depressed-like' phenotype. Our findings identify the mPFC as the region that mediates the effect of enhanced 5-HT4 receptor activity and CK2 as modulator of 5-HT4 receptor levels in this brain region that regulates mood-related phenotypes.

Effect of Stimulation of Neurotransmitter Systems on Heart Rate Variability and β-Adrenergic Responsiveness of Erythrocytes in Outbred Rats.

We studied heart rate variability and β-adrenergic responsiveness of erythrocytes and changes in these parameters in response to single administration of β-adrenoblocker propranolol (2 mg/kg) in outbred male rats against the background of activation of the noradrenergic, serotonergic, and dopaminergic neurotransmitter systems achieved by 4-fold injections maprotiline (10 mg/kg), 5-hydroxytryptophan (50 mg/kg) combined with fluoxetine (3 mg/kg), and L-DOPA (20 mg/kg) with amantadine (20 mg/kg), respectively. Stimulation of the noradrenergic system moderately enhanced the heart rhythm rigidity and β-adrenergic responsiveness of erythrocytes. In addition, it markedly augmented the moderating effect of subsequently administered propranolol on LF and VLF components in the heart rate variability and reversed the effect of propranolol on β-adrenergic responsiveness of erythrocytes. Stimulation of the serotonergic system dramatically decreased all components in the heart rate variability and pronouncedly enhanced β-adrenergic responsiveness of erythrocytes. Subsequent injection of propranolol slightly restored all components in the heart rate variability and decreased β-adrenergic responsiveness of erythrocytes to the control level. Stimulation of the dopaminergic system made the heart rate more rigid due to decrease of all components in the heart rate variability; in addition, it slightly but significantly enhanced β-adrenergic responsiveness of erythrocytes. Subsequent injection of propranolol produced no significant effects on all components in the heart rate variability and on β-adrenergic responsiveness of erythrocytes. Stimulation of noradrenergic, serotonergic, and dopaminergic neurotransmitter systems produced unidirectional and consorted effects on heart rate variability and β-adrenergic responsiveness of erythrocytes, although the magnitudes of these effects were different. Probably, the changes in the heart rate variability in rats with stimulated neurotransmitter systems results from modification of the cellular sensitivity in peripheral organs to adrenergic influences. However, the differences in the reactions to β-adrenoblocker attest to specificity of the mechanisms underlying the changes in membrane reception and adrenergic pathways in every experimental model employed in this study.

Association of Catechol-O-methyltransferase single nucleotide polymorphisms, ethnicity, and sex in a large cohort of fibromyalgia patients

Background Fibromyalgia (FM) is a complex, centralized pain condition that is often difficult to diagnose and treat. FM is considered to have a genetic background due to its familial aggregation and due to findings from multiple candidate-gene studies implicating catecholaminergic and serotonergic neurotransmitter systems in chronic pain. However, a multi-factorial analysis of both genetic and environmental risk factors is lacking. A better characterization of the interplay of risk factors may assist in understanding the pathophysiology of FM, its clinical course, and assist in early diagnosis and treatment of the disorder.

Stress and the serotonergic system, observations from pet imaging

IntroductionStress response and the neuroendocrinologic factors through which it is mediated are disturbed in anxiety and in affective disorders. While acute stress is thought to result in hypothalamus-pituitary-adrenal- (HPA) axis hyperactivity (Varghese 2001), chronic stress may result in decreased HPA-response (Booji 2013). Antidepressant treatment, on the other hand, is thought to realign HPA–axis activity (Schüle 2007).On the other hand, dysregulation within the serotonergic neurotransmitter system is understood as a central moderator in the pathophysiology of affective and anxiety disorders. Serotonergic transmission both regulates- and is regulated by- glucocortocoids. Cortisol results in an increase in serotonin synthesis and release while serotonergic transmission is thought to downregulate HPA-axis activity (Lanfumey, 2008). Positron emission tomography (PET) studies have demonstrated the link between the serotonergic system and the HPA-axis in humans in vivo. For example, a negative correlation between cortisol and 5HT1A receptor levels in various brain regions has been shown (Lanzenberger, 2010). SERT expression, on the other hand, was shown using PET to be positively related to HPA-axis reactivity (Frokjaer 2013).Methodsn.a.AimsAvailable literature on interactions between the HPA-axis and the serotonergic system will be discussed with a focus on data acquired via PET studies.Resultsn.a.ConclusionsThe interaction between the serotonergic system and the HPA-axis is likely bilateral and may be understood as a neurobiological link by which stress may foster the development of depression and anxiety.Disclosure of interestM. Spies has received travel grants from AOP Orphan Pharmaceuticals AG, Janssen-Cilag Pharma Gmbh, and Eli Lilly, workshop participation from Eli Lilly, and speaker honoraria from Janssen-Cilag Pharma Gmbh. R. Lanzenberger received travel grants and conference speaker honoraria from AstraZeneca, Lundbeck A/S, Roche Austria GmbH, Dr. Willmar Schwabe GmbH & Co. KG, AOP Orphan Pharmaceuticals, and Janssen-Cilag Pharma Gmbh.

“Does Age Affect Treatment of Depressive Disorders? A systematic review of antidepressants versus placebo studies.”

“Does Age Affect Treatment of Depressive Disorders? A systematic review of antidepressants versus placebo studies.”

Insights into the genetic foundation of aggression in Papio and the evolution of two length-polymorphisms in the promoter regions of serotonin-related genes (5-HTTLPR and MAOALPR) in Papionini.

BackgroundAggressive behaviors are an integral part of competitive interactions. There is considerable variation in aggressiveness among individuals both within and among species. Aggressiveness is a quantitative trait that is highly heritable. In modern humans and macaques (Macaca spp.), variation in aggressiveness among individuals is associated with polymorphisms in the serotonergic (5-HT) neurotransmitter system. To further investigate the genetics underlying interspecific variation in aggressiveness, 123 wild individuals from five baboon species (Papio papio, P. hamadryas, P. anubis, P. cynocephalus, and P. ursinus) were screened for two polymorphisms in promoter regions of genes relevant for the 5-HT system (5-HTTLPR and MAOALPR).ResultsSurprisingly, despite considerable interspecific variation in aggressiveness, baboons are monomorphic in 5-HTTLPR, except for P. hamadryas, which carries one additional allele. Accordingly, this locus cannot be linked to behavioral variation among species. A comparison among 19 papionin species, including nine species of macaques, shows that the most common baboon allele is similar to the one described for Barbary macaques (Macaca sylvanus), probably representing the ancestral allele in this tribe. It should be noted that (almost) all baboons live in Africa, but within Macaca only M. sylvanus lives on this continent. Baboons are, however, highly polymorphic in the so-called ’warrior gene’ MAOALPR, carrying three alleles. Due to considerable variation in allele frequencies among populations of the same species, this genotype cannot be invoked to explain variation in aggressiveness at the species level.ConclusionsThis study provides another indication that 5-HTTLPR is not related to aggressiveness in primates per se, but may have been under differential selective pressures among taxa and potentially among populations in different geographic regions. The results on MAOALPR alleles in Papio indicate that variation in the metabolism of monoamine neurotransmitters and associated behaviors is more important among populations than among species. We, therefore, propose to compile behavioral data from additional populations of Papio to obtain further insight into the genetics underlying behavioral differences among primate species.Electronic supplementary materialThe online version of this article (doi:10.1186/s12862-016-0693-1) contains supplementary material, which is available to authorized users.

Abnormal Echogenicity of the Substantia Nigra, Raphe Nuclei, and Third-Ventricle Width as Markers of Cognitive Impairment in Parkinsonian Disorders: A Cross-Sectional Study.

Background. Patients with Parkinson's disease (PD) have a high risk of cognitive problems. Objective. This study assesses whether abnormal echogenicity of the substantia nigra (SN) and raphe nuclei (RN) and the diameter of third ventricle are markers of cognitive impairment in patients with PD and other forms of parkinsonism. Methods. 126 outpatients with early signs of parkinsonism underwent transcranial sonography (TCS). The scales for the outcome of Parkinson's disease cognition (SCOPA-COG) were used as cognitive measure. Definite neurological diagnosis was established after two-year follow-up. Results. One-third of the patients with PD and half of those with APS had signs of cognitive impairment. The echogenicity of the SN was not related to cognitive impairment. The diameter of the third ventricle was significantly larger in PD patients with cognitive impairment compared to those without. In patients with APS we found a significantly higher frequency of hypoechogenic RN in patients with cognitive problems. Conclusions. Cognitive impairment is already present in a substantial proportion of patients with PD and APS at first referral. In patients with APS the frequency of hypoechogenic RN points to the direction of other pathophysiology with more emphasis on deficits in the serotonergic neurotransmitter system. The larger diameter of the third ventricle in PD patients with cognitive impairment may reflect Alzheimer like brain atrophy, as has been reported in earlier studies.

Development of Tinnitus at a Low Dose of Sertraline: Clinical Course and Proposed Mechanisms

Introduction. Serotonin is involved in filtering of auditory stimuli. Cochlear input is processed through complex interactions between serotonergic, glutamatergic, and GABAergic neurotransmitter systems. Options for treatment of tinnitus include selective serotonin reuptake inhibitors (SSRIs); however in rare instances this symptom may occur as a side effect of this class of medications. Case Presentation. A 50-year-old woman developed bilateral tinnitus after several weeks of being treated with sertraline 50 mg. She had been on a long-standing daily dose of aspirin 325 mg which had been discontinued shortly before starting sertraline. Medical work-up was negative for her symptom. Shortly after discontinuation of the medication, her tinnitus subsided completely. Discussion. Tinnitus is a rare side effect of sertraline and may be related to particular distribution of serotonin receptor subtypes within the auditory system, and serotonergic agents may reinforce or desensitize the activity of different receptors. Also, there may be a priming effect of salicylate agents on the auditory system, predisposing particular patients to be more sensitive to how auditory stimuli are processed.

The effect of MDMA and pentoxifylline drug on bad/bcl-xl gene dosage expression changes on rat liver

MDMA generally known as ecstasy, have deleterious effects on the serotonergic neurotransmitter system. Recent findings suggest that the liver and brain are major target organs of MDMA-related toxicities. Although most research is being dynamically performed on brain, however, the molecular mechanisms by which MDMA elicits adverse effects in both organs are poorly undrestood.The present study was performed to obtain evidence for molecular mechanism of apoptosis involved in MDMA-induced hepatotoxicity in rat liver after MDMAadministration. Moreover, the antagonistic effect of pentoxifylline was assessed on hepatotoxicity after MDMA administration. In this experimental study, sample size and power in each group were calculated as 10 rats with 95% confidence level and 5% confidence interval. In the study, four experimental groups were selected including Control Normal, MDMA, MDMA+PTX and PTX+MDMA. MDMA was dissolved in PBS and intraperitoneally injected three doses of 7.5mg/kg with two hours gap between doses. Pentoxyfilline also was injected as 100mg/kg, simultaneously with third dose of MDMA. After treatment, total RNA was isolated from liver tissue (5mg). Absorbance at 260nm, 280nm and 230nm were measured and immediately reverse transcription was performed. Included target genes were BAD and BCL -XL as pro-apoptotic and anti-apoptotic gene, respectively. After set up and validation, Real-Time PCR were performed and obtaining data were statistically analyzed to determine significantly differences between groups. Using Real-Time quantitative PCR results, BCL- XL gene expression ratio significantly increased in MDMA+PTX group. Moreover, BAD gene expression ratio increased and up-regulated in PTX+MDMA group ( P -value <0.001).Our study focused on molecular mechanism of MDMA in programmed cell death using gene expression quantification of a pro-apoptotic and anti-apoptoic gene in MDMA-induced hepatotoxocity. The results shown MDMA prompted apoptosis in liver and pentoxifylline protects hepatotoxicity after and befor taking MDMA.

Inflammational Animal Models for Schizophrenia

Abstract. Inflammational-immunological processes within the pathophysiology of schizophrenia seem to play an important role. Early signals of neurobiological changes in the embryonal phase of brain in later patients with schizophrenia might lead to activation of the immunological system, for example, of cytokines and microglial cells. Microglia then induces – via the neurotoxic activities of these cells as an overreaction – a rarification of synaptic connections in frontal and temporal brain regions, that is, reduction of the neuropil. Promising inflammational animal models for schizophrenia with high validity can be used today to mimic behavioral as well as neurobiological findings in patients, for example, the well-known neurochemical alterations of dopaminergic, glutamatergic, serotonergic, and other neurotransmitter systems. Also the microglial activation can be modeled well within one of this models, that is, the inflammational PolyI:C animal model of schizophrenia, showing a time peak in late adolescence/early adulthood. The exact mechanism, by which activated microglia cells then triggers further neurodegeneration, must now be investigated in broader detail. Thus, these animal models can be used to understand the pathophysiology of schizophrenia better especially concerning the interaction of immune activation, inflammation, and neurodegeneration. This could also lead to the development of anti-inflammational treatment options and of preventive interventions.

The effects of discontinuous morphine intoxication on the pools of neuroactive amino acids and biogenic amines in brain regions

We developed a model of discontinuous morphine intoxication, which is based on 1, 2, and 3 cycles of intraperitoneal morphine administration to rats. During cycle 1, morphine was injected at a dose of 30 mg/kg twice a day for 4 days; a dose of 40 mg/kg was used in cycles 2 and 3. These periods were alternated with drug-free periods. We studied the effects of intermittent morphine administration on the levels of biogenic amines, including serotonin, dopamine, and norepinephrine, and their metabolites and several neuroactive amino acids in the cerebral cortex and midbrain of rats. The alterations in the indices of the serotonergic neurotransmitter system and the pool of free amino acids in brain regions varied depending on the duration of discontinuous morphine administration. Discontinuous morphine intoxication for 14 days was accompanied by the accumulation of serotonin and its metabolites in both brain regions that were studied. This effect became less expressed after more prolonged morphine administration. The metabolic effects of 21-day-long discontinuous morphine intoxication were reflected in the lower content of amino acids and pools of aromatic, neurotransmitter, and excitatory amino acids. Under these conditions, the levels of biogenic amines and their metabolites changed insignificantly.

Functional Magnetic Resonance Imaging in Abstinent MDMA Users: A Review.

Ecstasy or 3,4-methylenedioxymethamphetamine (MDMA) is a popular drug of abuse. In the animal studies MDMA has been shown to have deleterious effects on the serotonergic neurotransmitter system. Understanding the adverse effects of MDMA on human brain function is of considerable importance owing to the rising number of MDMA users. Various neuroimaging studies have investigated the structural, chemical and functional differences in the brain integrity of chronic MDMA users. Various neurocognitive domains like working memory, episodic memory, semantic memory, visual stimulation, motor function and impulsivity have been compared between chronic MDMA users and nonusers using fMRI. The fMRI studies remain much more sensitive in studying the neurological deficits associated with chronic MDMA use as compared to the cognitive studies alone and therefore they serve as a prelude in our understanding of MDMA induced neurotoxicity. However they still face certain limitations contributing to inconsistency in the results and further research is needed before we can draw definitive conclusions regarding the neurotoxic effects of MDMA.

Serotonin pathway polymorphisms and the treatment of major depressive disorder and anxiety disorders.

While antidepressants are widely used to treat major depressive disorder and anxiety disorders, only half of the patients will respond to antidepressant treatment and only a third of patients will experience a remission of symptoms. Identification of genetic biomarkers that predict antidepressant treatment response could thus greatly improve current clinical practice by providing guidance on which drug to use for which patient. Most antidepressant drugs for the treatment of depression and anxiety disorders have effects on the serotonergic neurotransmitter system; thus, genetic polymorphisms in the genes involved in this pathway represent logical candidates for investigation. This article reviews recent findings on the pharmacogenetics of antidepressant drugs with a focus on serotonergic pathway polymorphisms and discusses future clinical applications.

The neuropsychological hypothesis of antidepressant drug action revisited.

Depression is one of the most debilitating disorders of our times. Antidepressant medication, one of the most common (and often first-line) treatments to date, aim to alleviate symptoms, but finding which type of drug benefits which patient remains a daunting task. The underlying mechanism that translates neurochemical effects to symptom improvement is still far from precise. In this review we summarized the evidence on the effects of antidepressants on brain systems and cognitive functioning, and examined the possible value of these correlates as predictors of response. Studies using acute (or sub-chronic) antidepressant administrations in healthy subjects showed effects on affective cognition. In depressed patients, neuroimaging studies examining the effects of antidepressants in pre-post designs have shown changes in the activation of the anterior cingulate cortex and the limbic system after treatment. Increasing evidence shows that baseline anterior cingulate cortex activation could be a possibly critical biomarker of treatment response. The few studies performed to date also indicate potentially different pathways for antidepressants targeting the serotonergic neurotransmitter system versus those targeting the noradrenergic one, but findings are not always consistent. More studies are necessary to establish whether early cognitive effects of drugs are predictive of long-term efficacy in depressed patients. Considering the heterogeneity of depression and in order to approach a more personalized treatment, future studies should also elucidate the effects of antidepressants on different cognitive systems and subsequently on different symptom profiles.

Enhanced calcium responses to serotonin receptor stimulation in T-lymphocytes from schizophrenic patients – A pilot study

Even if more extensively investigated in affective disorders, the serotonergic system is likely to be also implicated in modulating the pathogenesis of schizophrenia, where it closely interacts with the dopaminergic and glutamatergic system. To substantiate this notion, we studied the intensity and dynamics of cellular Ca2+ responses to serotonin (5-hydoxytryptamine, 5-HT) in peripheral lymphocytes taken from currently non-psychotic schizophrenic patients. To this aim, peripheral lymphocytes were freshly obtained from healthy controls and a naturalistic collective of patients with schizophrenia in remission. Intracellular Ca2+ responses were recorded in real-time by ratiometric fluorometry after 5-HT or phythaemagglutinin (PHA) stimulation, which served as an internal reference for Ca2+ responsivity to non-specific stimulation.The intracellular Ca2+ peak early after applying the 5-HT trigger was significantly elevated in schizophrenic patients. No significant differences of Ca2+ peak levels were seen in response to stimulation with the mitogenic agent PHA, although responses to 5-HT and PHA were positively correlated in individual patients or controls. In conclusion, the serotonergic response patterns in peripheral lymphocytes from schizophrenic patients seem to be elevated, if employing sensitive tools like determination of intracellular Ca2+ responses. Our observations suggest that the participation of serotonergic neurotransmitter system in the pathogenesis of schizophrenia may deserve more interest, even if it should only act as a modulator on the main pathology in the dopaminergic and glutamatergic systems. We hope that this pilot study will prompt further studies with larger patient collectives to revisit this question.