141 research outputs found

    Electrophysiological evidence for rapid 5-HT1A autoreceptor inhibition by vilazodone, a 5-HT1A receptor partial agonist and 5-HT reuptake inhibitor

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    Abstract This study examined the effect of vilazodone, a combined serotonin (5-HT) reuptake inhibitor and 5-HT 1A receptor partial agonist, paroxetine and fluoxetine on the sensitivity of 5-HT 1A autoreceptors of serotonergic dorsal raphe nucleus neurons in rats. These effects were assessed by determining the intravenous dose of (±)-8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) required to suppress the basal firing rate of these neurons by 50% (ID 50 ) in anesthetized rats using in vivo electrophysiology. 5-HT uptake inhibition was determined by the ability of the compounds to reverse (±)- p -chloroamphetamine (PCA)-induced rat hypothalamic 5-HT depletion ex vivo . Acute vilazodone administration (0.63 and 2.1 µmol/kg, s.c.), compared with vehicle, significantly increased (2–3-fold) the ID 50 of 8-OH-DPAT at 4 h, but not 24 h after administration. Subchronic administration (3 days) significantly increased the ID 50 value at 4 h (3–4-fold) and at 24 h (~2-fold). In contrast, paroxetine and fluoxetine at doses that were supramaximal for 5-HT uptake inhibition did not significantly alter the ID 50 value of 8-OH-DPAT after acute or subchronic administration. Vilazodone antagonized the action of PCA 3.5 h and 5 h after a single dose (ID 50 1.49 and 0.46 µmol/kg, s.c., respectively), but was inactive 18 h post-administration, corroborating the electrophysiological results at 24 h following acute administration. The results are consistent with the concept of rapid and, following repeated treatment, prolonged inhibition of 5-HT 1A autoreceptors by vilazodone. This effect could occur by either direct interaction with, or desensitization of, these receptors, an effect which cannot be ascribed to vilazodone's 5-HT reuptake inhibiting properties

    Real-time transverse-emittance and phase-space monitor

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    A real-time multislit [1] transverse-emittance monitor has been developed for diagnosing the space-charge-dominated beam in the 10MeV injection line of the FEL at Thomas Jefferson National Accelerator Facility (formerly CEBAF). It gives emittance, Twiss parameters, and phase-space contours (without any symmetry assumptions) at the update rate of 1Hz. It reduces measurement noise in real-time, and incorporates a special algorithm for constructing the phase-space matrix, which yields more accurate results by sweeping the beam across the slits. In this paper we will discuss issues relevant to the software design and implementation. Experimental results obtained from a 250keV photocathode gun will also be presented and compared with other methods and with PARMELA simulations

    A High-Average-Power Free Electron Laser for Microfabrication and Surface Applications

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    CEBAF has developed a comprehensive conceptual design of an industrial user facility based on a kilowatt ultraviolet (UV) (160-1000 mm) and infrared (IR) (2-25 micron) free electron laser (FEL) driven by a recirculating, energy recovering 200 MeV superconducting radio frequency (SRF) accelerator. FEL users, CEBAF's partners in the Lase Processing Consortium, including AT&T, DuPont, IBM, Northrop Grumman, 3M, and Xerox, are developing applications such as metal, ceramic, and electronic material micro-fabrication and polymer and metal surface processing, with the overall effort leading to later scale-up to industrial systems at 50-100 kW. Representative applications are described. The proposed high-average-power FEL overcomes limitations of conventional laser sources in available power, cost-effectiveness, tunability, and pulse structure

    Transient Gastric Irritation in the Neonatal Rats Leads to Changes in Hypothalamic CRF Expression, Depression- and Anxiety-Like Behavior as Adults

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    A disturbance of the brain-gut axis is a prominent feature in functional bowel disorders (such as irritable bowel syndrome and functional dyspepsia) and psychological abnormalities are often implicated in their pathogenesis. We hypothesized that psychological morbidity in these conditions may result from gastrointestinal problems, rather than causing them.Functional dyspepsia was induced by neonatal gastric irritation in male rats. 10-day old male Sprague-Dawley rats received 0.1% iodoacetamide (IA) or vehicle by oral gavage for 6 days. At 8-10 weeks of age, rats were tested with sucrose preference and forced-swimming tests to examine depression-like behavior. Elevated plus maze, open field and light-dark box tests were used to test anxiety-like behaviors. ACTH and corticosterone responses to a minor stressor, saline injection, and hypothalamic CRF expression were also measured.Behavioral tests revealed changes of anxiety- and depression-like behaviors in IA-treated, but not control rats. As compared with controls, hypothalamic and amygdaloid CRF immunoreactivity, basal levels of plasma corticosterone and stress-induced ACTH were significantly higher in IA-treated rats. Gastric sensory ablation with resiniferatoxin had no effect on behaviors but treatment with CRF type 1 receptor antagonist, antalarmin, reversed the depression-like behavior in IA-treated ratsThe present results suggest that transient gastric irritation in the neonatal period can induce a long lasting increase in depression- and anxiety-like behaviors, increased expression of CRF in the hypothalamus, and an increased sensitivity of HPA axis to stress. The depression-like behavior may be mediated by the CRF1 receptor. These findings have significant implications for the pathogenesis of psychological co-morbidity in patients with functional bowel disorders

    Improving Access to Primary and Pain Care for Patients Taking Opioids for Chronic Pain in Michigan: Recommendations from an Expert Panel

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    This multidisciplinary expert panel was convened to generate recommendations to address the limited access to care that patients experience when taking opioids for chronic pain. Recent policies and guidelines instituted to reduce inappropriate opioid prescribing have had unintended consequences for the 5-8 million patients taking long-term opioid therapy for chronic pain in the U.S. As providers discontinue prescribing and turn away patients dependent on opioids, this population faces limited access to both primary and pain-related care. The root causes of this access issue can be attributed to several overarching barriers, including new opioid-related policies, payment models, a lack of care coordination, stigma, and racial biases. Over multiple rounds of deliberation, the panel brainstormed possible solutions, considering feasibility, impact, and importance, and ultimately ranked their final recommendations in order of implementation priority. The final list included 11 recommendations, from which three overarching themes emerged: 1. Improving care models to better support patients with chronic pain Three recommendations involved improving care models, including the top two: increasing reimbursement for the time needed to treat complex chronic pain and establishing coordinated care models that bundle payments for multimodal pain treatment. 2. Enhancing provider education and training Four recommendations involving provider education efforts received slightly lower rankings and included training on biopsychosocial factors of pain care and clarifying the continuum between physical dependency and opioid use disorder. 3. Implementing practices to reduce racial biases and inequities The remaining four recommendations address racial biases and inequities, ranging from standardizing pain management protocols to reduce bias to increasing recruitment and retention of providers from underrepresented racial minorities. Throughout the process, panelists emphasized the interconnectedness of their proposed solutions, and indicated that multiple approaches are likely needed to meaningfully improve access to care for this patient population. Importantly, though this panel was convened in Michigan, and its expertise grounded in Michigan’s healthcare ecosystem, there are millions of patients taking opioids for chronic pain across the country, and reports of limited access to care are not unique to Michigan. Consequently, there may also be opportunity to apply these recommendations more broadly, in other states and at multiple levels of the United States healthcare system.This research was funded by the Michigan Health Endowment Fund (grant # R-1808-143371).http://deepblue.lib.umich.edu/bitstream/2027.42/168420/1/Lagisetty - Improving Access to Care for Patients Taking Opioids - 2021.pdfDescription of Lagisetty - Improving Access to Care for Patients Taking Opioids - 2021.pdf : White PaperSEL

    Interactive effects of mGlu5 and 5-HT2A receptors on locomotor activity in mice

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    RationaleMetabotropic glutamate (mGlu) receptors have been suggested to play a role in neuropsychiatric disorders including schizophrenia, drug abuse, and depression. Because serotonergic hallucinogens increase glutamate release and mGlu receptors modulate the response to serotonin (5-HT)(2A) activation, the interactions between serotonin 5-HT(2A) receptors and mGlu receptors may prove to be important for our understanding of these diseases.ObjectiveWe tested the effects of the serotonergic hallucinogen and 5-HT(2A) agonist, 2,5-dimethoxy-4-methylamphetamine (DOM), and the selective 5-HT(2A) antagonist, M100907, on locomotor activity in the mouse behavioral pattern monitor (BPM) in mGlu5 wild-type (WT) and knockout (KO) mice on a C57 background.ResultsBoth male and female mGlu5 KO mice showed locomotor hyperactivity and diminished locomotor habituation compared with their WT counterparts. Similarly, the mGlu5-negative allosteric modulator 2-methyl-6-(phenylethynyl)pyridine (MPEP) also increased locomotor hyperactivity, which was absent in mGlu5 KO mice. The locomotor hyperactivity in mGlu5 receptor KO mice was potentiated by DOM (0.5 mg/kg, subcutaneously (SC)) and attenuated by M100907 (1.0 mg/kg, SC). M100907 (0.1 mg/kg, SC) also blocked the hyperactivity induced by MPEP.ConclusionsThese studies demonstrated that loss of mGlu5 receptor activity either pharmacologically or through gene deletion leads to locomotor hyperactivity in mice. Additionally, the gene deletion of mGlu5 receptors increased the behavioral response to the 5-HT(2A) agonist DOM, suggesting that mGlu5 receptors either mitigate the behavioral effects of 5-HT(2A) hallucinogens or that mGlu5 KO mice show an increased sensitivity to 5-HT(2A) agonists. Taken together, these studies indicate a functional interaction between mGlu5 and 5-HT(2A) receptors
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