scholarly journals A ROLE FOR CORTICAL DOPAMINE IN THE PARADOXICAL CALMING EFFECTS OF PSYCHOSTIMULANTS

2021 ◽  
Author(s):  
Sharonda S Harris ◽  
Sara M Green ◽  
Mayank Kumar ◽  
Nikhil M Urs
Keyword(s):  
Knockout Mice ◽  
Ex Vivo ◽  
Integrated Approach ◽  
Primary Treatment ◽  
Monoamine Transporters ◽  
Tissue Slices ◽  
Hyperactivity Disorder ◽  
Norepinephrine Depletion ◽  
Calming Effect ◽  
And Behavior

Attention deficit hyperactivity disorder (ADHD) affects young children and manifests symptoms such as hyperactivity, impulsivity and cognitive disabilities. Psychostimulants, which are the primary treatment for ADHD, target monoamine transporters and have a paradoxical calming effect, but their mechanism of action, is unclear. Studies using the dopamine (DA) transporter (DAT) knockout mice, which have elevated striatal DA levels and are considered an animal model of ADHD, have suggested that the paradoxical calming effect of psychostimulants might be through the actions on serotonin neurotransmission. On the other hand, newer non-stimulant class of drugs such as atomoxetine and Intuniv suggest that targeting the norepinephrine (NE) system in the PFC might explain this paradoxical calming effect. We sought to decipher the mechanism of this paradoxical effect of psychostimulants through an integrated approach using ex vivo monoamine efflux experiments, monoamine transporter knockout mice, drug infusions and behavior. Our ex vivo efflux experiments reveal that NE transporter (NET) blocker desipramine elevates both norepinephrine and dopamine but not serotonin levels, in PFC tissue slices from wild-type and DAT-KO but not NET KO mice. However, serotonin (5-HT) transporter (SERT) inhibitor fluoxetine elevates only serotonin in all three genotypes. Systemic administration of both desipramine and fluoxetine but local PFC infusion of only desipramine and not fluoxetine inhibits hyperactivity in the DAT-KO mice. In contrast, pharmacological norepinephrine depletion but dopamine elevation using Nepicastat also inhibits hyperactivity in DATKO mice. Together, these data suggest that elevation of PFC dopamine and not norepinephrine or serotonin as a convergent mechanism for the paradoxical psychostimulant effects observe in ADHD therapy.  

scholarly journals Neuroanatomy and behavior in mice with a haploinsufficiency of AT-rich interactive domain 1B (ARID1B) throughout development

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
J. Ellegood ◽  
S. P. Petkova ◽  
A. Kinman ◽  
L. R. Qiu ◽  
A. Adhikari ◽  
...  
Keyword(s):  
Corpus Callosum ◽  
Ex Vivo ◽  
Chromatin Modification ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Social Deficits ◽  
Altered Expression ◽  
Developmental Growth ◽  
And Behavior

Abstract Background One of the causal mechanisms underlying neurodevelopmental disorders (NDDs) is chromatin modification and the genes that regulate chromatin. AT-rich interactive domain 1B (ARID1B), a chromatin modifier, has been linked to autism spectrum disorder and to affect rare and inherited genetic variation in a broad set of NDDs. Methods A novel preclinical mouse model of Arid1b deficiency was created and validated to characterize and define neuroanatomical, behavioral and transcriptional phenotypes. Neuroanatomy was assessed ex vivo in adult animals and in vivo longitudinally from birth to adulthood. Behavioral testing was also performed throughout development and tested all aspects of motor, learning, sociability, repetitive behaviors, seizure susceptibility, and general milestones delays. Results We validated decreased Arid1b mRNA and protein in Arid1b+/− mice, with signatures of increased axonal and synaptic gene expression, decreased transcriptional regulator and RNA processing expression in adult Arid1b+/− cerebellum. During neonatal development, Arid1b+/− mice exhibited robust impairments in ultrasonic vocalizations (USVs) and metrics of developmental growth. In addition, a striking sex effect was observed neuroanatomically throughout development. Behaviorally, as adults, Arid1b+/− mice showed low motor skills in open field exploration and normal three-chambered approach. Arid1b+/− mice had learning and memory deficits in novel object recognition but not in visual discrimination and reversal touchscreen tasks. Social interactions in the male–female social dyad with USVs revealed social deficits on some but not all parameters. No repetitive behaviors were observed. Brains of adult Arid1b+/− mice had a smaller cerebellum and a larger hippocampus and corpus callosum. The corpus callosum increase seen here contrasts previous reports which highlight losses in corpus callosum volume in mice and humans. Limitations The behavior and neuroimaging analyses were done on separate cohorts of mice, which did not allow a direct correlation between the imaging and behavioral findings, and the transcriptomic analysis was exploratory, with no validation of altered expression beyond Arid1b. Conclusions This study represents a full validation and investigation of a novel model of Arid1b+/− haploinsufficiency throughout development and highlights the importance of examining both sexes throughout development in NDDs.

scholarly journals Spatially resolved microfluidic stimulation of lymphoid tissue ex vivo

The Analyst ◽  
2017 ◽  
Vol 142 (4) ◽  
pp. 649-659 ◽  
Author(s):  
Ashley E. Ross ◽  
Maura C. Belanger ◽  
Jacob F. Woodroof ◽  
Rebecca R. Pompano
Keyword(s):  
Lymph Node ◽  
Targeted Delivery ◽  
Lymphoid Tissue ◽  
Ex Vivo ◽  
Tissue Slices ◽  
Microfluidic Platform ◽  
Spatially Resolved ◽  
Local Stimulation ◽  
Stimulation Of

We present the first microfluidic platform for local stimulation of lymph node tissue slices and demonstrate targeted delivery of a model therapeutic.

scholarly journals Insight into Glutamatergic Involvement in Rewarding Effects of Mephedrone in Rats: In Vivo and Ex Vivo Study

2021 ◽  
Author(s):  
Olga Wronikowska ◽  
Maria Zykubek ◽  
Agnieszka Michalak ◽  
Anna Pankowska ◽  
Paulina Kozioł ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Interdisciplinary Approach ◽  
Nmda Antagonist ◽  
Exchange Chromatography ◽  
Resonance Spectroscopy ◽  
Monoamine Transporters ◽  
Ex Vivo Study ◽  
Insight Into

AbstractMephedrone is a widely used drug of abuse, exerting its effects by interacting with monoamine transporters. Although this mechanism has been widely studied heretofore, little is known about the involvement of glutamatergic transmission in mephedrone effects. In this study, we comprehensively evaluated glutamatergic involvement in rewarding effects of mephedrone using an interdisciplinary approach including (1) behavioural study on effects of memantine (non-selective NMDA antagonist) on expression of mephedrone-induced conditioned place preference (CPP) in rats; (2) evaluation of glutamate concentrations in the hippocampus of rats following 6 days of mephedrone administration, using in vivo magnetic resonance spectroscopy (MRS); and (3) determination of glutamate levels in the hippocampus of rats treated with mephedrone and subjected to MRS, using ion-exchange chromatography. In the presented research, we confirmed priorly reported mephedrone-induced rewarding effects in the CPP paradigm and showed that memantine (5 mg/kg) was able to reverse the expression of this effect. MRS study showed that subchronic mephedrone administration increased glutamate level in the hippocampus when measured in vivo 24 h (5 mg/kg, 10 mg/kg and 20 mg/kg) and 2 weeks (5 mg/kg and 20 mg/kg) after last injection. Ex vivo chromatographic analysis did not show significant changes in hippocampal glutamate concentrations; however, it showed similar results as obtained in the MRS study proving its validity. Taken together, the presented study provides new insight into glutamatergic involvement in rewarding properties of mephedrone.

scholarly journals Psychotherapy for child and adolescent with psychiatric disorder attending in National Institute of Mental Health, Dhaka

2017 ◽  
Vol 28 (2) ◽  
pp. 53-57
Author(s):  
Md Zahir Uddin ◽  
Muhammad Zillur Rahman Khan ◽  
Mumita Jerin Nilav ◽  
Md Faruq Alam ◽  
Md Abdul Mohit
Keyword(s):  
Mental Health ◽  
Psychiatric Disorder ◽  
Behavior Therapy ◽  
Conversion Disorder ◽  
Dropout Rate ◽  
Child And Adolescent ◽  
Cross Sectional Study ◽  
Cross Sectional ◽  
Hyperactivity Disorder ◽  
And Behavior

Psychotherapy for child and adolescent with psychiatric disorder is relatively a newer concept in Bangladesh. This cross sectional study was done to determine the pattern of psychotherapy provided by the psychotherapy department for children and adolescents with psychiatric disorder in National Institute of Mental Health (NIMH) from June 2010 to November 2014. Total 121 samples were taken purposefully from the records of psychotherapy department where data were collected retrospectively using check list. Results showed that among respondents more were boys than girls (64.5% vs. 35.5%) whereas their mean (±SD) age was 12.1 (±3.2) years. Majority (47.9%) of them were within class six to class ten. Most of the respondents (89%) were referred from the outpatient department and 11% were referred by inpatient department. Conduct disorder (27.3%), conversion disorder (13.2%), attention deficit hyperactivity disorder (12.4%) and intellectual developmental disorder (9.1%) were common diagnoses of the respondents. It was found that 74.4% respondents attended up to one to five psychotherapy sessions and cognitive behavior therapy (38%) and behavior therapy (25.6%) were most commonly used psychotherapy. Though 60.3% of the respondents improved to certain extent in psychotherapy sessions, patient’s dropout rate was found as 55.4%.Bang J Psychiatry Dec 2014; 28(2): 53-57

Abstract 292: The Role of the ATF6 Branch of the ER Stress Response in the Endocrine Heart

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Erik A Blackwood ◽  
Christopher C Glembotski
Keyword(s):  
Stress Response ◽  
Er Stress ◽  
Knockout Mice ◽  
Ex Vivo ◽  
Proteolytic Cleavage ◽  
Isolated Perfused Heart ◽  
Wild Type ◽  
Atrial Myocytes ◽  
Perfused Heart ◽  
Er Stress Response

Rationale: Atrial natriuretic peptide (ANP) is stored in the heart in large dense core granules of atrial myocytes as a biologically inactive precursor, pro-ANP. Hemodynamic stress and atrial stretch stimulate coordinate secretion and proteolytic cleavage of pro-ANP to its bioactive form, ANP, which promotes renal salt excretion and vasodilation, which, together contribute to decreasing blood pressure. While the ATF6 branch of the ER stress response has been studied in ventricular tissue mouse models of myocardial ischemia and pathological hypertrophy, roles for ATF6 and ER stress on the endocrine function of atrial myocytes have not been studied. Objective/Methods: To address this gap in our knowledge, we knocked down ATF6 in primary cultured neonatal rat atrial myocytes (NRAMs) using a chemical inhibitor of the proteolytic cleavage site enabling ATF6 activation and siRNA and measured ANP expression and secretion basally and in response to alpha- adrenergic agonist stimulation using phenylephrine. We also compared the ANP secretion from wild- type mice and ATF6 knockout mice in an ex vivo Langendorff model of the isolated perfused heart. Results: ATF6 knockdown in NRAMs significantly impaired basal and phenylephrine-stimulated ANP secretion. ATF6 knockout mice displayed lower levels of ANP in atrial tissue at baseline as well as after phenylephrine treatment. Similarly, in the ex vivo isolated perfused heart model, less ANP was detected in effluent of ATF6 knockout hearts compared to wild-type hearts. Conclusions: The ATF6 branch of the ER stress response is necessary for efficient co-secretional processing of pro-ANP to ANP and for agonist-stimulated ANP secretion from atrial myocytes. As ANP is secreted in a regulated manner in response to a stimulus and pro-ANP is synthesized and packaged through the classical secretory pathway, we posit that ATF6 is required for adequate expression, folding, trafficking, processing and secretion of biologically active ANP from the endocrine heart.

scholarly journals Elimination of FVIII-Specific B Cells By Immunotoxins Comprised of a Single FVIII Domain Fused to Pseudomonas Exotoxin a

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 561-561
Author(s):  
Kerstin Brettschneider ◽  
Anja Schmidt ◽  
Joerg Kahle ◽  
Aleksander Orlowski ◽  
Diana Stichel ◽  
...  
Keyword(s):  
B Cells ◽  
Knockout Mice ◽  
Hemophilia A ◽  
Conflicts Of Interest ◽  
Ex Vivo ◽  
Coagulation Factor ◽  
High Dose ◽  
Dependent Manner ◽  
C2 Domain ◽  
Exotoxin A

Abstract The development of inhibitory antibodies (inhibitors) against coagulation factor VIII (FVIII) is the most serious complication for patients with hemophilia A that undergo FVIII replacement therapy. In addition, healthy individuals can spontaneously develop inhibitory anti-FVIII auto-antibodies, which results in acquired hemophilia A. The current standard therapy for patients with hemophilia A and inhibitors, named immune tolerance induction (ITI), is based on frequent and mostly high dose administrations of FVIII. Unfortunately, the eradication of inhibitors can only be achieved in about 70% of patients. Alternative treatment of inhibitor patients with the monoclonal anti-CD20 antibody rituximab results in complete eradication of inhibitors; however, depletion of the entire CD20-positive B cell population is potentially accompanied by severe side effects. Recent studies in hemophilic FVIII knockout mice showed that the application of a FVIII-toxin conjugate resulted in (i) prevention of inhibitor development in naïve mice and (ii) long-term eradication of inhibitors in FVIII-immunized mice. As the use of FVIII for cell targeting of immunotoxins is presumably limited by its high molecular weight (250 kDa) and adhesiveness (off-target reactivity) we explored the potential use of alternative immunotoxins in the current study. The introduced immunotoxins are comprised of a single FVIII domain fused to the Exotoxin A (ETA) from Pseudomonas aeruginosa.The rationale for the use of a single domain instead of full length FVIII as cell-binding component is that immunodominant domains like A2 and C2 might still allow targeting of sufficient amounts of FVIII-specific B-cells by immunotoxins. For proof of concept studies, we generated a histidine-tagged C2 domain-ETA fusion protein (C2-ETA) that was bacterially expressed and purified by affinity chromatography. Purified C2-ETA was recognized by a panel of commercially available monoclonal anti-C2 antibodies in ELISA suggesting proper folding of the C2 domain in the bacterially expressed protein. To test the capacity of C2-ETA to eliminate FVIII-specific B-cells, splenocytes of FVIII-immunized FVIII knockout mice were re-stimulated with FVIII ex vivo in presence and absence of different concentrations of C2-ETA and ETA alone (as control). Re-stimulation of FVIII-specific memory B cells to FVIII- and C2-specific antibody secreting cells (ASC) was analyzed in anEnzyme linked immunospot (ELISPOT) assay using FVIII and C2 as antigens. While differentiation to FVIII-specific ASC was only partially inhibited by C2-ETA, differentiation to C2-specific ASC was completely blocked in a dose-dependent manner. In contrast, the use of ETA alone had no effect. Further analysis of the FVIII domain specificity of antibodies in plasma of FVIII-immunized FVIII knockout mice used for depletion studies revealed a strong contribution of C2-specific antibodies to the overall FVIII-specific immune response. In summary, our results show that the developed C2-ETA immunotoxin is able to specifically eliminate FVIII C2 domain-specific B cells ex vivo. Currently, C2-ETA is tested for its capacity to eliminate FVIII-specific B cells in FVIII knockout mice and additional FVIII domain-ETA immunotoxins are developed. Disclosures No relevant conflicts of interest to declare.

Yoga as a Complementary Therapy for ADHD

2021 ◽  
pp. 305-317
Author(s):  
Nikita Naresh Ahuja
Keyword(s):  
Neurodevelopmental Disorder ◽  
Complementary Therapy ◽  
Peace Of Mind ◽  
Hyperactivity Disorder ◽  
Breathing Exercises ◽  
Mind And Body ◽  
Negative Side Effects ◽  
And Behavior ◽  
Relaxation Exercises ◽  
Regular Practice

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that commonly occurs among children between the age ranges of 3-10 years. Though pharmacotherapy in combination of play therapy and behavior therapy has been proved to be effective for the treatment of ADHD, but the results derived from them does not seem to sustain for a longer period of time. There are other alternative therapies too, which can help in management of the symptoms of ADHD. This chapter talks about the different aspects of yoga and effect of different asanas, pranayama, and meditation on ADHD. As medication has its own negative side effects, practitioners have started to research other techniques to be helpful for managing ADHD, and Yoga is proved to be one of the effective ways to reduce the symptoms of ADHD. Yoga is not only limited to the physical exercise; it also includes breathing exercises, meditation, and relaxation exercises, which help to have a balance between mind and body. Through regular practice of yoga, one can attain peace of mind and can lead a happy and healthy life.

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