Selected abbreviations and acronyms ADHD attention deficit-hyperactivity disorder OCD obsessive-compulsive disorder PANDAS pediatric autoimmune neuropsychiatrie disorder associated with streptococcal infection TS Tourette’s syndrome
Visual BIIB057 hallucinations came of age In 1936 with the publication of two clinical reviews. The first, a modest 2-page essay, appeared in the relative backwater of a parochial Swiss medical journal, authored by George de Morsier, then a

recently appointed lecturer in neurology.1 The second appeared in the Annales Médico-Psychologiques, the high-profile voice of French-speaking psychiatry, Inhibitors,research,lifescience,medical coauthored by the neurologist Jean L’Hermitte, an established expert in the field following his earlier description of peduncular hallucinations, and the psychiatrist Julian de Ajuriaguerra, then aged 25 and at the beginning of his career.2 Both reviews shared three important breaks with tradition. First, visual hallucinations were deemed worthy of study in their own right, distinct from Inhibitors,research,lifescience,medical hallucinations in other modalities and from other forms of psychopathology Second, they were to be considered a unitary symptom. An earlier generation

of psychiatrists had hoped that different types of visual hallucination might carry Inhibitors,research,lifescience,medical different diagnostic implications; however, from here on, the important clinical detail became whether a given patient experienced visual hallucinations of any kind, not whether they had hallucinated a simple lattice pattern Inhibitors,research,lifescience,medical as opposed to a procession of animals or an elaborately costumed figure, for example. The third break with tradition was to distance visual hallucinations from visual

illusions, giving them a higher clinical status. Yet, although sharing much in common, the two papers differed in their conception of the brain and its disorders. L’Hermitte and de Ajuriaguerra looked forward to emerging holistic models of psychopathology, viewing visual hallucinations as part of a general hallucinatory state. Although Inhibitors,research,lifescience,medical classifying the clinical conditions associated with visual hallucinations by the location of the underlying visual system lesion, their scheme was not intended to imply a range of distinct syndromes. In contrast, de Morsier’s approach looked back to the classical era of associationism (see ref 3), viewing visual hallucinations as a localizing neurological isothipendyl symptom that, when considered in its wider clinical context, formed distinct syndromic entities. This syndromic approach captured the clinical imagination and remains an important influence today, in part the result of later disagreement between de Morsier and de Ajuriaguerra over the role of the eye in visual hallucinations. In order to understand the origin of de Morsier’s syndromes, we must first turn to the Parisian Central Police station.

PFC-amygdalar projections may also play a role in the pathogenesis of depressive and anxiety symptoms in mood disorders.

Although the reciprocal PFC-amygdalar projections are excitatory in nature, these connections ultimately appear to activate inhibitory interneurons, which, in turn, lead to functional inhibition in the projected field of the amygdala (for PFC-amygdalar projections) or the medial PFC and ventrolateral PFC.96,108-110 The function of the PFC in modulating the amygdala appears to be impaired in mood disorders, according to functional MRI data showing that abnormally sustained amygdala activity in response to aversive words Inhibitors,research,lifescience,medical or sad faces in MDD is associated with blunted activation of PFC areas.108,111 Thus, the volumetric and/or histopathological changes evident in the

subgenual and pregenual ACC, lateral orbital cortex, dorsomedial/dorsal anterolateral PFC, hippocampal subiculum, amygdala, and ventral striatum may interfere with the modulation of emotional behavior, as discussed below. Ventral ACC The ACC ventral and anterior Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical to the genu of the corpus callosum (“subgenual” and “pregenual,” respectively; Figure 2) shows complex relationships between CBF, metabolism, and illness state, which appear to be accounted for by a left-lateralized reduction in the corresponding cortex, initially demonstrated by MRI-based morphometric measures6,12-16,112 and later by postmortem neuropathological studies of familial BD and MDD.9 Thus, computer simulations that correct the PET data acquired from this region for the partial volume effect of the reduction in gray matter volume measured in MRI scans of the same subject Inhibitors,research,lifescience,medical conclude the “actual” metabolic activity in the remaining subgenual PFC tissue is increased in depressives relative to controls, and decreases to normative levels during effective treatment.113 This hypothesis appears to be compatible

with the observations that effective antidepressant pharmacotherapy results in a decrease in metabolic activity in this region in M’DD,8,10,114 that during depressive episodes metabolism shows a positive relationship with depression severity,8,115,116 and that flow Inhibitors,research,lifescience,medical increases in this region in healthy, nondepressed humans during sadness induced via. contemplation of sad thoughts or memories.114,117,118 The reduction in volume in this region Sotrastaurin exists early in the illness in familial MDD11 to and BD.12The gray matter deficit may nevertheless worsen or initially become apparent, following illness onset based upon preliminary evidence in twins discordant for MDD that the affected twin has a smaller volume than their unaffected cotwin.119 Kimbrell et al120 reported that the subgenual ACC metabolism correlated inversely with the number of lifetime depressive episodes, compatible with the possibility that the reduction in metabolism in this region measured via PET reflects a partial volume effect of a gray matter reduction that worsens with repeated illness.

40 Chromosome 5 The cytokine gene cluster on chromosomal region 5q23-35 contains genes coding for IL-3, IL-4, IL-5,

IL-9, IL-12 p40, IL-13, GM-CSF, and others.26 This is of particular interest, as linkage studies pointed to a possible susceptibility locus for schizophrenia in this chromosomal region.41 The same region was recently identified as containing the susceptibility gene for Crohn’s disease.42 Chromosome 6 The genes coding for three members of the TNF family, TNF-α, TNF-β, and LT-β, are located in an immunologically important region: the HLA-III region, which is embedded between the HLA-II and the HLA-I region on the short Inhibitors,research,lifescience,medical arm of Inhibitors,research,lifescience,medical chromosome 6. Again, genome scans have indicated a linkage of this chromosomal region with schizophrenia.43 Boin and colleagues reported the association of a functional single nucleotide polymorphism in the TNF-α gene with schizophrenia,44 but a NVP-AUY922 replication study performed by our group could not confirm this finding.45 Chromosome 9 The type I IFNs are encoded on chromosomal region 9p22. This cluster contains about 15 closely linked functional IFN-α and IFN-ω genes in addition to a single IFN-β gene.46 All members of the IFN-α/β family (IFN-α, IFN-β, IFN-ω,

and IFN-τ) show at least 30% homology in their amino Inhibitors,research,lifescience,medical acid sequence.25 No conclusive data are available indicating a susceptibility gene for a psychiatric disorder in

this chromosomal region. Functional concepts Cytokines are most commonly grouped by their functional similarities, although this kind of categorization is highly arbitrary with Inhibitors,research,lifescience,medical regard to their pleiotropy. One of the most prominent concepts used to discriminate two distinct ways that the specific immune system can react on environmental stimuli is the classification of T helper 1 (Th1) and T helper 2 (Th2) cell diversity. This classification is based on the cytokine production patterns of T helper cells and reflects the polarization of Inhibitors,research,lifescience,medical the immune PD184352 (CI-1040) answer to either a cell-mediated (Thl) or a humoral (Th2) immune response.33 Th1 cells mainly produce IFN-γ, IL-2, IL-12, IL-18, and TNF-β, while Th2 cells principally secrete IL-4, IL-5, IL-6, IL-10, IL-13, and TGFβ. TNF-α and IL-10 are commonly characterized as Th2-like cytokines, although they are synthesized by both Th1 and Th2 cells.47,48 IL-12 and IL-4 are essential for the development of Th1 and Th2, respectively.49 The Th1 system promotes cell-mediated immune responses against intracellular pathogens, whereas the Th2 system helps B cell maturation and promotes humoral immune responses against extracellular pathogens. Th1 and Th2 cytokines antagonize each other in promoting their own type of response, while suppressing the other type of helper cell.

Positron emission tomography/computed tomography (PET/CT) was obtained prior to and after completion

of chemoradiotherapy (CRT). The majority of patients AZD8931 solubility dmso underwent evaluation with computed tomography (CT) with oral and intravenous contrast of the chest, abdomen and pelvis. For patients who underwent endoscopy at outside institutions, repeat endoscopy was performed on the discretion of the surgeon as Inhibitors,research,lifescience,medical was endoscopic ultrasound (EUS) with or without biopsy. All outside pathology and radiology was reviewed. All patients were discussed at a multidisciplinary conference with participation of all sub-specialty disciplines involved in the care of esophageal and GEJ carcinomas and treatment recommendations reviewed. All patients were screened and high risk anesthesia consults Inhibitors,research,lifescience,medical were obtained for those patients with significant co-morbidities. Preoperative cardiac stratification and pulmonary function tests were obtained when indicated. Patients were excluded if they were considered non-surgical candidates on the basis of medical co-morbidities, were previously treated with chemotherapy or radiation within the treatment area, were considered unresectable or had metastatic disease, or if they had lymphadenopathy outside the area of planned resection. Patient Inhibitors,research,lifescience,medical data reviewed included complete history/physical

examination, upper endoscopy/EUS, biopsy results, CT chest/abdomen Inhibitors,research,lifescience,medical and pelvis with oral and IV contrast, PET/CT, and laboratory results including albumin and protein. Treatment All patients received concurrent CRT followed by Ivor-Lewis esophagogastrectomy (ILE). Chemotherapy consisted of weekly administration of paclitaxel 50 mg/m2 and carboplatin AUC =2 given intravenously with total infusion time of 2 hours for an average of

6 weeks. Inhibitors,research,lifescience,medical These were administered on days 1, 8, 15, 22, 29 and 36. Patients were premedicated with dexamethasone 10 mg, diphenhydramine 50 mg, famotidine 20 mg, and palonosetron 0.25 mg as well as hydrated with intravenous fluid prior to the administration of chemotherapeutic medications. Conformal radiotherapy to a total dose of 50.4 Gy in 28 fractions was delivered. All patients were treated using volumetric modulated arc therapy (VMAT) with 6 MV photons. Volumes were designed to include gross tumor and nodal disease and as noted on endoscopy and on imaging studies, regional nodes and the celiac axis with margin. Organs at risk for treatment planning included lungs, heart, spinal cord, uninvolved esophagus and stomach, liver, and kidneys. Heterogeneity corrections were used in treatment planning using Eclipse Treatment Planning System version 8.5 (Varian Medical Systems, Palo Alto, CA). Dose was prescribed to the planning target volume (PTV) so that at least 95% of the PTV received 99% of prescription dose with dose constraint of 93%≤ PTV ≤107%. One or two arcs were used as needed to meet the above target constraints.

Cognitive control

tasks (designed to challenge executive function of goal-directed behavior in the presence of conflict) have identified abnormal engagement of the anterior cingulate cortex associated with COMT,DRD2, and MAOA; of the dorsolateral prefrontal cortex (DLPFC) associated with DTNBPl,DRD2,MAOA, COMT: and of the parietal cortex associated Inhibitors,research,lifescience,medical with DRD2, and MAOA.42 Memory encoding tasks recently identified abnormal engagement of hippocampus parahlppocampus region43 and association of the hippocampus with BDNF, COMT, DISCI, GRM3, and KCNH2. It is worthwhile to note that most association studies of brain function have used single gene variants and risk haplotypes emerging from linkage studies and more recently genome wide association studies, with differing levels of genetic evidence for each candidate Inhibitors,research,lifescience,medical gene, though there has been no systematic approach to date to selecting genes for imaging genetics studies. Imaging genetics approaches have progressed to associating gene variants with multiple regions of activation, with disease-relevant risk circuits and putative distributed functional networks, rather Inhibitors,research,lifescience,medical than isolated, single regions. After all, brain information processing does not occur as discrete activation “blobs,” but as activity across distributed neural systems and circuits. Thus, circuit-based phenotypes would be

expected to have greater fidelity in showing genetic association at the level of brain function, since in principle, the more realistic the phenotype, the stronger Inhibitors,research,lifescience,medical the genetic association. As schizophrenia is an emergent property of neural system function, not isolatable to a singular brain region or localized regional defect, but likely attributable to network-based neurointegrative deficits, neuroimaging and intermediate phenotyplng strategies have progressed to better understand distributed networks associated with Increased genetic risk. To identify a functional

network or interregional coupling, functional connectivity between spatially remote Inhibitors,research,lifescience,medical regions is inferred below based on temporal coherence, by identifying regions of coactivation.44 check details Statistical analyses used for functional connectivity include mapping based on seed voxel correlations, principal component analysis, independent component analysis, and partial least squares methods. The functional connectivity literature within schizophrenia research has largely focused on PFC connectivity, especially the DLPFC and anterior cingulate, and DLPFC interaction with the medial temporal lobe, specifically the hippocampal formation (HF), and interaction with the DLPFC-thalamus.45 For the DLPFC, abnormal connectivity has been identified in multiple studies in patients with schizophrenia and in high-risk subjects46-49 and various genetic associations have been established with this putative circuit, during working memory tasks.

Acknowledgments The authors thank Judy Benson for copyediting the manuscript. Conflict of interest None declared.
Selenium (Se) is an essential micronutrient that is incorporated into antioxidant Ponatinib mw enzymes. Se is unique among trace elements because it is covalently incorporated into proteins as a noncanonical amino acid, selenocysteine (Sec). Biosynthesis and integration of Sec in polypeptides is distinctive

because the residue is specified by a UGA codon, which is typically a stop codon. Recoding the UGA codon Inhibitors,research,lifescience,medical for Sec incorporation requires an mRNA that contains a Sec insertion sequence (SECIS), a tRNA that recognizes UGA, and several specific proteins beyond the conventional translation machinery (reviewed in Bellinger et al. 2009). The 25 primate, and 24 murine, Sec-containing selenoproteins Inhibitors,research,lifescience,medical identified to date include the functionally characterized glutathione peroxidase (GPX), thioredoxin reductase, and iodothyronine deiodinase enzyme families. Selenoprotein W (Sepw1) is the smallest mammalian selenoprotein and is one of the most widely distributed selenoproteins across species in all domains of life (Zhang and Gladyshev 2008; Lobanov et al. 2009). Sepw1

was initially identified by its absence in muscle of myopathic lambs suffering White Muscle disease, and was later purified and cloned (Vendeland et al. 1993, Inhibitors,research,lifescience,medical 1995; Whanger 2000). White muscle disease is a Se-responsive muscular dystrophy syndrome Inhibitors,research,lifescience,medical in sheep and cattle that is characterized by pale and dry muscle, with longitudinal striations or chalky whiteness due to abnormal calcium deposition. Leg muscles typically degenerate first, but all muscles, including cardiac, can be affected. In addition to muscle and proliferating myoblasts, mammalian Sepw1 is highly expressed in the developing and adult brain

(Gu et al. 2000; Loflin et al. 2006). Unlike in muscle, dietary Se deficiency does not reduce Sepw1 levels in sheep or rat brain, despite reducing brain Se concentration and GPX activity (Sun et al. 2001; Whanger 2001). Selenoprotein P (Sepp1) maintains stable selenoprotein Inhibitors,research,lifescience,medical expression in the brain under Se deficiency, Vasopressin Receptor and mice lacking Sepp1 have greatly reduced levels of Sepw1 mRNA and protein in the brain (Hoffmann et al. 2007). Feeding a Se-deficient diet to mice lacking Sec lyase (Scly) also reduces Sepw1 protein in the brain (Raman et al. 2012). These results suggest that preferential retention of Sepw1 in brain during dietary Se deficiency is maintained by Sepp1 and Scly. Regional analysis of Sepw1 mRNA expression in the brains of mice indicates presence in neurons, with high expression in >90% of brain regions (Zhang et al. 2008). However, the expression, regulation, and function of Sepw1 in the brain are largely unknown. Like most selenoproteins, Sepw1 is expected to be involved in oxidation–reduction (redox) reactions.

In 15 participants who had been sleepdeprived for two days, rTMS was applied at 5 Hz during the retention phase of the DMS task. The target sites for stimulation was based on the fMRI network associated with sleep deprivation-induced performance impairments in this task.79 Three stimulation sites were chosen and included the upper left occipital and midline parietal cortices, which were parts of this fMRI network, and the lower left occipital cortex, which was adjacent to the first Inhibitors,research,lifescience,medical occipital site, but outside the fMRI identified network. Stimulation with rTMS on the upper occipital

site resulted in decreased sleep-induced RT deficit without a corresponding decrease in accuracy. Stimulation of the other two sites did not produce Inhibitors,research,lifescience,medical such benefits. The subjects underwent fMRI scanning while they performed the task before and after sleep deprivation. The degree of performance enhancement with upper occipital rTMS correlated with the degree to which each individual failed to sustain activation of the fMRI network. A subset of participants (N=11) performed the same rTMS procedure after recovering from sleep deprivation, Inhibitors,research,lifescience,medical and no NLG919 supplier effects were found for rTMS. These results demonstrated that rTMS applied to the superior

occipital cortex, part of a WM network sensitive to SD, specifically reduced the adverse Inhibitors,research,lifescience,medical effects of SD on WM performance. We suggested that a proposed mechanism known as “post-tetanic facilitation,” which posits that TMS delivered just prior to task-related neural processing increases cortical excitability in a way that can enhance performance under some conditions, may have been responsible for the facilitation

effect with occipital stimulation. In the final step, we utilized two proposed methods of extending rTMS effects (multiple rTMS sessions and simultaneous task performance and application of targeted rTMS) to a new Inhibitors,research,lifescience,medical group of SD subjects and found that those who received active rTMS did not show the typical cognitive effects (eg, slowing, lapsing) of SD on WM.83 Five Hz rTMS was applied to the left occipital site while subjects performed the DMS task during four sessions over the course of 48 hours of sleep deprivation, through with performance assessed at the beginning and end of sleep deprivation. Twenty-seven subjects (13 received active TMS, 14 sham) completed the study protocol. Another twenty (10 received active TMS, 11 sham) nonsleep-deprived subjects were included and served as controls. At the end of the SD period, sham SD subjects exhibited degraded performance on the WM task, with slowed RT and lapsing typical of SD. In contrast, those who received active rTMS performed similarly to the non-SD controls, and exhibiting a speeding up of RT attributed to practice in the non-SD controls, and a significantly reduced lapsing rate.

The reaction mixture was incubated for 2 hours with vortexing for a few seconds every 30min, followed by letting the suspension stand at 4°C overnight. Residual SuPE in the buffer solution was removed by gel

filtration with a PD-10 column packed with Sephadex G-25 (GE Healthcare; Buckinghamshire, England). 2.8. Preparation of Different Types of Span 80 Vesicles In the present work, four types of Span 80 vesicles were prepared. Type 1: Span 80 vesicles with immobilized ESA and immobilized PEG (EPV), containing as inner aqueous solution PBS. Type 2: Span 80 vesicles (called “control vesicles”: CV) containing encapsulated FITC. Type 3: Span 80 vesicles with immobilized ESA (EV) containing encapsulated FITC. Type 4: Span 80 vesicles Inhibitors,research,lifescience,medical with immobilized ESA and immobilized PEG (EPV) containing encapsulated FITC.

The vesicles of types 2, 3, and 4 contained a 0.15M sodium carbonate buffer solution (pH = 9.0) containing Inhibitors,research,lifescience,medical 1mg/mL FITC as inner aqueous solution. The vesicles were prepared with the two-step emulsification method in pretty much the same way of as described in the previous papers [6, 19]. In this work, some minor modifications were applied for the preparation of EPV containing FITC. A volume Inhibitors,research,lifescience,medical of 0.6mL of the inner aqueous solutions (the sodium carbonate buffer solution containing FITC as mentioned above) was added to 6mL of a n-hexane solution containing Span 80 (264mg), purified lecithin (24mg) and cholesterol (12mg), followed by Inhibitors,research,lifescience,medical the first emulsification for 6min at 17,500rpm using a micro-homogenizer NS-310E 2 (Microtec Co., Ltd., Funabashi, Japan). Afterwards, the solvent was removed in a rotary evaporator at 28°C under reduced pressure, yielding a water-lipid emulsion to which 6mL of the ESA-SUPE solution (obtained as described above) containing Tween 80 (96mg) and DSPE-PEG2000 Inhibitors,research,lifescience,medical (14.2mg/mL) were added, followed by the second emulsification with the homogenizer for 2min at 3500rpm to obtain a heterogeneous Span 80 vesicle suspension.

After stirring with a magnetic stirrer for 3 hours at room temperature, the vesicle suspension was stored overnight at 4°C. The vesicles were then purified by ultracentrifugation Tryptophan synthase (50,000rpm at 4°C for 120min) in a Himac centrifuge CR15B (Hitachi Koki Co., Ltd., Tokyo, Japan). The lower phase was filtrated through 100-nm nucleopore track-etch polycarbonate membranes (selleck Avanti Polar Lipids; Alabaster, AL, USA) and purified by gel filtration on a 7cm (diameter) × 50cm (length) column containing Biogel-A5m (Bio-Rad Laboratories, Richmond, CA, USA). CV containing FITC and EV containing FITC were also prepared in the same manner as above, but without both ESA and PEG (for CV), and without DSPE-PEG2000 (for EV), respectively. The diameters of CV, EV, and EPV, which contained FITC were 104 ± 7nm, 100 ± 2nm, and 103 ± 5nm, respectively. 2.9. Analysis of the Binding of EPV to OST Cells OST cells were inoculated in 6-well culture plates at a cell density of 2.

Such a plethora of interactions explains why A type lamins play a central role in the physiologic processes of cell life, including formation and homeostasis of the nucleus (7), apoptosis (8), repair (9), replication and transcription of DNA (10), regulation of chromosomal positioning (10). They are also involved in other important processes including metabolic, biochemical and signal transduction pathways (11, 12). Mutations on the Lamin A/C gene cause Inhibitors,research,lifescience,medical several defined clinical conditions, commonly termed as laminopathies, consisting in a heterogeneous group of diseases which include:

the autosomal dominant and click here recessive forms of Emery Dreifuss muscular dystrophy (EDMD2 and EDMD3); the limb girdle muscular dystrophy 1B (LGMD1B); the congenital muscular dystrophy-L (CMDL); the dilated cardiomyopathy with conduction defects (DCM1A); the heart hand syndrome of Slovenian type (HHS); a recessive form of sensory-motor peripheral neuropathy (CMT2B); the familial Inhibitors,research,lifescience,medical partial lipodystrophy of the Dunnigan type (FPLD2); the Hutchinson-

Gilford progeria syndrome (HGPS); the atypical form of Werner syndrome (WS); the restrictive dermopathy (RD) and the Inhibitors,research,lifescience,medical mandibuloacral dysplasia (MADA) (13). Several clinical complex entities, obtained by the concomitant presence in the same subject of different diseases related to LMNA gene mutations, have also been reported Inhibitors,research,lifescience,medical (14-60). Diseases characterized by the compromise of skeletal muscles and/or the heart are associated to mutations spread throughout the gene (14), while diseases primarily affecting the peripheral nerves, the metabolism, the bones or causing alterations of the ageing mechanisms tend to be associated to particular mutations and to cluster to peculiar regions of the gene (62-65).

A full Inhibitors,research,lifescience,medical correlation between genetic alterations and clinical manifestations has not been established; however, genetic studies demonstrated the presence of a non random association between clinical manifestations and Lamin Tolmetin A/C gene alterations (66), and the presence of a clustering among neuromuscular phenotypes (46); in particular, phenotypes characterized by skeletal and cardiac compromise tend to be associated to LMNA gene alterations placed upstream of the NLS, while clinical entities affecting the metabolism, the bones or causing premature ageing syndromes tend to be caused by alterations located downstream of the NLS (66). It has also been reported that frameshift and nonsense mutations are frequently associated to late onset cardiac and skeletal phenotypes; the possible pathogenic mechanism invoked is haploinsufficiency due to non-sense mediated mRNA decay or a rapid degradation of the aberrant transcript (46).

.DMA also facilitated social communication, as measured by a significant increase

in the “extroversion” subscale of the Adjective Mood Rating Scale. This increase correlated with CBF in the temporal cortex, amygdala, and orbitofrontal cortex. These brain regions are richly interconnected and together form the basolateral circuit which, according to current theories, is involved in the mediation of social communication.106,107 Inhibitors,research,lifescience,medical Lesions or disturbances of this circuit can lead to decreased social interaction, inadequate social behavior, or even the inability to decode social cues.108-108 The marked modulation of activity in the basolateral circuit produced by M.DMA and its association with increased click here extroversion provide further support for a critical role of the basolateral circuit in the processing of socially relevant information. The present findings suggest that an amygdala-centered network including ventral-frontal and temporal cortices underlies the cooccurrence of pleasurable emotion and enhanced social communication, providing a rationale for the interrclatcdness

Inhibitors,research,lifescience,medical of emotional and social processes. Thus, further research into the neurochemical mechanisms of MDMA could advance our understanding of the neuroanatomical regulation of mood Inhibitors,research,lifescience,medical and social interaction. Neurotransmitter systems involved in the effects of MDMA On the basis of mechanistic studies in animals, it Inhibitors,research,lifescience,medical has been widely assumed that the psychological effects of MDMA in humans might be mediated through its potent ability to release serotonin, and to a lesser extent DA.111 In addition, MDMA has moderate affinity for the serotonergic 5-HT2 and adrenergic α2 receptors.76 To elucidate the contribution of neurotransmitter and receptor systems Inhibitors,research,lifescience,medical in the action of MDMA, the blocking effects of specific receptor antagonists on MDMA-induced psychological and behavioral alterations were investigated. In these studies, we found that pretreatment with the selective serotonin-reuptake inhibitor (SSRI) citalopram markedly reduced all of the psychological effects

of MDMA in healthy volunteers, indicating that the effects of MDMA in humans are largely due to 5-HT transporter-mediated enhanced 5-HT release.112 The 5-HT2 antagonist ketanserin only because moderately attenuated the MDM’A experience, but significantly abolished the perceptual effects.113 This suggests that stimulation of 5-HT2 receptors mediates the mild hallucinogen-like action of MDMA in humans, such as intensification of colors. Finally, the D2 antagonist haloperidol only partly reduced the euphoric effects of MDMA suggesting that DA contributes little to the psychological effects of MDMA at the dose tested.114,115 Surprisingly, MDMA dose-dependently reduced sensorimotor gating, as indexed by the PPI of startle in rats, but increased PPI in healthy human subjects under comparable conditions.