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The Structural Basis of the Activity Cliff in Modafinil-Based Dopamine Transporter Inhibitors.
Biomolecules
June 2024
Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
Modafinil analogs with either a sulfoxide or sulfide moiety have improved binding affinities at the human dopamine transporter (hDAT) compared to modafinil, with lead sulfoxide-substituted analogs showing characteristics of atypical inhibition (e.g., JJC8-091).
View Article and Find Full Text PDFPotential therapeutics for effort-related motivational dysfunction: assessing novel atypical dopamine transport inhibitors.
Neuropsychopharmacology
July 2024
Psychological Sciences, University of Connecticut, Storrs, CT, 06269-1020, USA.
People with depression and other neuropsychiatric disorders can experience motivational dysfunctions such as fatigue and anergia, which involve reduced exertion of effort in goal-directed activity. To model effort-related motivational dysfunction, effort-based choice tasks can be used, in which rats can select between obtaining a preferred reinforcer by high exertion of effort vs. a low effort/less preferred option.
View Article and Find Full Text PDFSertraline treatment influences [F]FE-PE2I PET imaging for Parkinsonism.
EJNMMI Res
May 2023
Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital Bispebjerg, Bispebjerg Bakke 23, Copenhagen, Denmark.
Background: The dopamine transporter (DaT) PET ligand [F]FE-PE2I is used to aid the diagnosis of Parkinson's disease. After encountering four patients with a history of daily sertraline use, who all showed atypical findings on [F]FE-PE2I PET, we suspected that the selective serotonin reuptake inhibitor (SSRI), sertraline, might interfere with the results and lead to globally reduced striatal [F]FE-PE2I binding due to sertraline's high affinity for DaT.
Methods: We rescanned the four patients with [F]FE-PE2I PET after a 5-day sertraline pause.
The Effects of the Dopamine Transporter Ligands JJC8-088 and JJC8-091 on Cocaine versus Food Choice in Rhesus Monkeys.
J Pharmacol Exp Ther
March 2023
Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina (O.R., S.R.C., L.J.P., M.A.N.); Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, Maryland (J.C., J.L., A.H.N.); Department of Neurology, Johns Hopkins Drug Discovery, The Johns Hopkins University School of Medicine, Baltimore, Maryland (J.L., R.R.); and EncepHeal Therapeutics, Inc., Winston-Salem, North Carolina (O.R., S.R.C.)
Although there are no Food and Drug Administration-approved treatments for cocaine use disorder, several modafinil analogs have demonstrated promise in reducing cocaine self-administration and reinstatement in rats. Furthermore, the range of dopamine transporter (DAT) compounds provides an opportunity to develop pharmacotherapeutics without abuse liability. This study extended the comparison of JJC8-088 and JJC8-091, the former compound having higher DAT affinity and predicted abuse liability, to rhesus monkeys using a concurrent cocaine versus food schedule of reinforcement.
View Article and Find Full Text PDFA multi-pronged investigation of option generation using depression, PET and modafinil.
Brain
June 2022
Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA 02478, USA.
Article Synopsis
- Option generation is essential for decision-making, yet previous research has mainly explored pre-defined choices rather than how individuals create their own options, particularly in the context of major depressive disorder (MDD).
- A study found that individuals with MDD generated significantly fewer options compared to healthy adults; however, the options they did generate tended to be more unique, indicating a different qualitative approach to option generation among depressed individuals.
- A separate experiment demonstrated the role of dopamine in option generation, revealing that healthier individuals showed variability in generating options based on modafinil dosage, while depressed patients exhibited a correlation between dopamine receptor availability and the uniqueness of their generated options.
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