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Anticholinergic drugs rescue synaptic plasticity in DYT1 dystonia: role of M1 muscarinic receptors.
Maltese M, Martella G, Madeo G, Fagiolo I, Tassone A, Ponterio G, Sciamanna G, Burbaud P, Conn PJ, Bonsi P, Pisani A
(2014) Mov Disord 29: 1655-65
MeSH Terms: Animals, Biophysics, Cholinergic Antagonists, Corpus Striatum, Electric Stimulation, Excitatory Postsynaptic Potentials, In Vitro Techniques, Long-Term Potentiation, Mice, Mice, Transgenic, Molecular Chaperones, Mutation, Neurons, Patch-Clamp Techniques, Synapses, Thalamus
Show Abstract · Added February 19, 2015
Broad-spectrum muscarinic receptor antagonists have represented the first available treatment for different movement disorders such as dystonia. However, the specificity of these drugs and their mechanism of action is not entirely clear. We performed a systematic analysis of the effects of anticholinergic drugs on short- and long-term plasticity recorded from striatal medium spiny neurons from DYT1 dystonia knock-in (Tor1a(+/Δgag) ) mice heterozygous for ΔE-torsinA and their controls (Tor1a(+/+) mice). Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, trihexyphenydil, biperiden, orphenadrine, and a novel selective M1 antagonist, VU0255035. Tor1a(+/Δgag) mice exhibited a significant impairment of corticostriatal synaptic plasticity. Anticholinergics had no significant effects on intrinsic membrane properties and on short-term plasticity of striatal neurons. However, they exhibited a differential ability to restore the corticostriatal plasticity deficits. A complete rescue of both long-term depression (LTD) and synaptic depotentiation (SD) was obtained by applying the M1 -preferring antagonists pirenzepine and trihexyphenidyl as well as VU0255035. Conversely, the nonselective antagonist orphenadrine produced only a partial rescue of synaptic plasticity, whereas biperiden and ethopropazine failed to restore plasticity. The selectivity for M1 receptors was further demonstrated by their ability to counteract the M1 -dependent potentiation of N-methyl-d-aspartate (NMDA) current recorded from striatal neurons. Our study demonstrates that selective M1 muscarinic receptor antagonism offsets synaptic plasticity deficits in the striatum of mice with the DYT1 dystonia mutation, providing a potential mechanistic rationale for the development of improved antimuscarinic therapies for this movement disorder.
© 2014 International Parkinson and Movement Disorder Society.
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16 MeSH Terms
Nocturnal enuresis in sickle cell disease.
Wolf RB, Kassim AA, Goodpaster RL, DeBaun MR
(2014) Expert Rev Hematol 7: 245-54
MeSH Terms: Anemia, Sickle Cell, Antidiuretic Agents, Brain, Cholinergic Antagonists, Deamino Arginine Vasopressin, Humans, Nocturnal Enuresis, Quality of Life, Sleep Apnea Syndromes, Urinary Bladder
Show Abstract · Added October 7, 2014
Nocturnal enuresis is a prevalent and challenging problem in children and young adults with sickle cell disease (SCD). Limited progress has been made in elucidating etiology and pathophysiology of nocturnal enuresis in individuals with SCD. Among adults with SCD ages 18-20 years, approximately 9% report nocturnal enuresis. Nocturnal enuresis contributes to decreased health related quality of life in people with SCD, resulting in low self-esteem and sometimes social isolation. Postulated non-mutually exclusive causes of nocturnal enuresis in individuals with SCD include hyposthenuria leading to nocturnal polyuria, decreased bladder capacity or nocturnal bladder overactivity, increased arousal thresholds, and sleep disordered breathing. No evidence-based therapy for nocturnal enuresis in SCD exists. This review is focused on describing the natural history, postulated causes and a rational approach to the evaluation and management of nocturnal enuresis in children and adults with SCD.
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10 MeSH Terms
Monitoring cholinergic activity during attentional performance in mice heterozygous for the choline transporter: a model of cholinergic capacity limits.
Paolone G, Mallory CS, Cherian AK, Miller TR, Blakely RD, Sarter M
(2013) Neuropharmacology 75: 274-85
MeSH Terms: Acetylcholine, Alkaloids, Animals, Atropine, Attention, Azocines, Cholinergic Antagonists, Conditioning, Operant, Female, Humans, Male, Mecamylamine, Membrane Transport Proteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Protein Binding, Quinolizines, Sodium Channel Blockers, Tetrodotoxin, Tritium
Show Abstract · Added September 28, 2015
Reductions in the capacity of the human choline transporter (SLC5A7, CHT) have been hypothesized to diminish cortical cholinergic neurotransmission, leading to risk for cognitive and mood disorders. To determine the acetylcholine (ACh) release capacity of cortical cholinergic projections in a mouse model of cholinergic hypofunction, the CHT+/- mouse, we assessed extracellular ACh levels while mice performed an operant sustained attention task (SAT). We found that whereas SAT-performance-associated increases in extracellular ACh levels of CHT+/- mice were significantly attenuated relative to wildtype littermates, performance on the SAT was normal. Tetrodotoxin-induced blockade of neuronal excitability reduced both dialysate ACh levels and SAT performance similarly in both genotypes. Likewise, lesions of cholinergic neurons abolished SAT performance in both genotypes. However, cholinergic activation remained more vulnerable to the reverse-dialyzed muscarinic antagonist atropine in CHT+/- mice. Additionally, CHT+/- mice displayed greater SAT-disrupting effects of reverse dialysis of the nAChR antagonist mecamylamine. Receptor binding assays revealed a higher density of α4β2* nAChRs in the cortex of CHT+/- mice compared to controls. These findings reveal compensatory mechanisms that, in the context of moderate cognitive challenges, can overcome the performance deficits expected from the significantly reduced ACh capacity of CHT+/- cholinergic terminals. Further analyses of molecular and functional compensations in the CHT+/- model may provide insights into both risk and resiliency factors involved in cognitive and mood disorders.
Copyright © 2013 Elsevier Ltd. All rights reserved.
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21 MeSH Terms
Tamoxifen improves cholinergically modulated cognitive performance in postmenopausal women.
Newhouse P, Albert K, Astur R, Johnson J, Naylor M, Dumas J
(2013) Neuropsychopharmacology 38: 2632-43
MeSH Terms: Aged, Attention, Cholinergic Antagonists, Cognition Disorders, Estrogen Antagonists, Female, Humans, Mecamylamine, Memory, Middle Aged, Neuropsychological Tests, Pain Measurement, Postmenopause, Psychiatric Status Rating Scales, Scopolamine, Tamoxifen, Time Factors, Verbal Learning
Show Abstract · Added May 29, 2014
Tamoxifen (TMX) is a selective estrogen receptor modulator that is used as an estrogen receptor antagonist for the treatment and prevention of breast cancer. Whether TMX has antagonist activities in the human brain is less clear and its effects on cognitive function have not been experimentally explored. This study examined how TMX affected cognitive performance in older women using a model of anticholinergic drug-induced cognitive dysfunction. Twenty-one postmenopausal women were administered 20 mg of oral TMX or placebo for 3 months. Participants then took part in five drug challenges using the anticholinergic antinicotinic agent mecamylamine (MECA) and antimuscarinic agent scopolamine (SCOP) and were tested on a comprehensive battery including tasks of attention and psychomotor function, verbal episodic memory, and spatial navigation. After a 3-month placebo washout, participants were then crossed over to the alternate treatment and repeated the drug challenges after 3 months. Compared with placebo treatment, TMX significantly attenuated the impairment from cholinergic blockade on tasks of verbal episodic memory and spatial navigation, but effects on attentional/psychomotor tasks were more variable. Analysis by APOE genotype showed that APO ɛ4+ women showed a greater beneficial effect of TMX on reversing the cholinergic impairment than APO ɛ4- women on most tasks. This study provides evidence that TMX may act as an estrogen-like agonist to enhance cholinergic system activity and hippocampally mediated learning.
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18 MeSH Terms
C. elegans dopaminergic D2-like receptors delimit recurrent cholinergic-mediated motor programs during a goal-oriented behavior.
Correa P, LeBoeuf B, García LR
(2012) PLoS Genet 8: e1003015
MeSH Terms: Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Cholinergic Antagonists, Cholinergic Neurons, Copulation, Disorders of Sex Development, Dopamine, Female, Male, Muscle Contraction, Receptors, Cholinergic, Receptors, Dopamine D2, Sexual Behavior, Animal, Signal Transduction, Vulva
Show Abstract · Added September 3, 2013
Caenorhabditis elegans male copulation requires coordinated temporal-spatial execution of different motor outputs. During mating, a cloacal circuit consisting of cholinergic sensory-motor neurons and sex muscles maintains the male's position and executes copulatory spicule thrusts at his mate's vulva. However, distinct signaling mechanisms that delimit these behaviors to their proper context are unclear. We found that dopamine (DA) signaling directs copulatory spicule insertion attempts to the hermaphrodite vulva by dampening spurious stimulus-independent sex muscle contractions. From pharmacology and genetic analyses, DA antagonizes stimulatory ACh signaling via the D2-like receptors, DOP-2 and DOP-3, and Gα(o/i) proteins, GOA-1 and GPA-7. Calcium imaging and optogenetics suggest that heightened DA-expressing ray neuron activities coincide with the cholinergic cloacal ganglia function during spicule insertion attempts. D2-like receptor signaling also attenuates the excitability of additional mating circuits to reduce the duration of mating attempts with unproductive and/or inappropriate partners. This suggests that, during wild-type mating, simultaneous DA-ACh signaling modulates the activity threshold of repetitive motor programs, thus confining the behavior to the proper situational context.
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16 MeSH Terms
Estradiol interacts with the cholinergic system to affect verbal memory in postmenopausal women: evidence for the critical period hypothesis.
Dumas J, Hancur-Bucci C, Naylor M, Sites C, Newhouse P
(2008) Horm Behav 53: 159-69
MeSH Terms: Aged, Aged, 80 and over, Aging, Analysis of Variance, Cholinergic Antagonists, Cognition, Critical Period, Psychological, Cross-Over Studies, Double-Blind Method, Estradiol, Female, Humans, Mecamylamine, Memory Disorders, Mental Recall, Middle Aged, Postmenopause, Scopolamine, Verbal Learning
Show Abstract · Added March 3, 2020
Estradiol has been shown to interact with the cholinergic system to affect cognition in postmenopausal women. This study further investigated the interaction of estradiol and cholinergic system functioning on verbal memory and attention in two groups of healthy younger (ages 50-62) and older (ages 70-81) postmenopausal women. Twenty-two postmenopausal women were randomly and blindly placed on 1 mg of 17-beta estradiol orally for 1 month then 2 mg for 2 months or matching placebo pills after which they participated in three anticholinergic challenge sessions when verbal memory and attention were assessed. Subjects were administered either the antimuscarinic drug scopolamine (SCOP), the antinicotinic drug mecamylamine (MECA), or placebo. After the first challenge phase, they were crossed over to the other hormone treatment for another 3 months and repeated the challenges. Results showed that estradiol pretreatment significantly attenuated the anticholinergic drug-induced impairments on a test of episodic memory (the Buschke Selective Reminding Task) for the younger group only, while estradiol treatment impaired performance of the older group. The results suggest that younger subjects may experience more cholinergic benefit from estradiol treatment than older subjects, supporting the concept of a critical period for postmenopausal estrogen use.
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MeSH Terms
Acceleration of HIV dementia with methamphetamine and cocaine.
Nath A, Maragos WF, Avison MJ, Schmitt FA, Berger JR
(2001) J Neurovirol 7: 66-71
MeSH Terms: AIDS Dementia Complex, Adult, Amphetamine-Related Disorders, Antiretroviral Therapy, Highly Active, Blood-Brain Barrier, Brain, Cholinergic Antagonists, Cocaine-Related Disorders, Disease Progression, Humans, Levodopa, Magnetic Resonance Imaging, Male, Methamphetamine, Movement Disorders
Show Abstract · Added December 10, 2013
We report a patient with rapidly accelerating HIV dementia accompanied by seizures and an unusual movement disorder despite highly potent antiretroviral therapy. This clinical constellation was associated with the non-parenteral use of methamphetamine and cocaine. Fractional enhancement time on post contrast magnetic resonance imaging studies revealed a progressive breakdown of the blood brain barrier particularly in the basal ganglia. The movement disorder but not the dementia responded to a combination of dopamine replacement and anticholinergic therapy. While the movement disorder may have been unmasked by concomitant anticonvulsant therapy, we suggest in this instance, that prior drug abuse synergized with HIV to cause a domino effect on cerebral function. Careful attention and analysis to histories of remote non-injecting drug abuse may help substantiate our hypothesis.
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15 MeSH Terms