Abnormal dopaminergic transmission is implicated in schizophrenia, attention deficit hyperactivity disorder, and drug addiction. In an attempt to model aspects of these disorders, we have generated hyperdopaminergic mutant mice by reducing expression of the dopamine transporter (DAT) to 10% of wild-type levels (DAT knockdown). Fast-scan cyclic voltammetry and in vivo microdialysis revealed that released dopamine was cleared at a slow rate in knockdown mice, which resulted in a higher extracellular dopamine concentration. Unlike the DAT knockout mice, the DAT knockdown mice do not display a growth retardation phenotype. They have normal home cage activity but display hyperactivity and impaired response habituation in novel environments. In addition, we show that both the indirect dopamine receptor agonist amphetamine and the direct agonists apomorphine and quinpirole inhibit locomotor activity in the DAT knockdown mice, leading to the hypothesis that a shift in the balance between dopamine auto and heteroreceptor function may contribute to the therapeutic effect of psychostimulants in attention deficit hyperactivity disorder.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC29368 | PMC |
http://dx.doi.org/10.1073/pnas.98.4.1982 | DOI Listing |
FEBS J
January 2025
Research Center for Pharmaceutical Development, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Circulation
October 2024
Departments of Anesthesiology & Perioperative Medicine (L.M., W.S., G.R., L.A., M.L., S.U., M. Eghbali), University of California, Los Angeles.
Background: Integrative multiomics can elucidate pulmonary arterial hypertension (PAH) pathobiology, but procuring human PAH lung samples is rare.
Methods: We leveraged transcriptomic profiling and deep phenotyping of the largest multicenter PAH lung biobank to date (96 disease and 52 control) by integration with clinicopathologic data, genome-wide association studies, Bayesian regulatory networks, single-cell transcriptomics, and pharmacotranscriptomics.
Results: We identified 2 potentially protective gene network modules associated with vascular cells, and we validated , coding for asporin, as a key hub gene that is upregulated as a compensatory response to counteract PAH.
Nat Genet
August 2024
Regeneron Genetics Center, Tarrytown, NY, USA.
Circulation
August 2024
PARCC, INSERM (Z.R.A.S., C.P., C.J., N.M., J.-S.H.), Université Paris Cité, Paris, France.
Background: Drug-induced QT prolongation (diLQT) is a feared side effect that could expose susceptible individuals to fatal arrhythmias. The occurrence of diLQT is primarily attributed to unintended drug interactions with cardiac ion channels, notably the hERG (human ether-a-go-go-related gene) channels that generate the delayed-rectifier potassium current (I) and thereby regulate the late repolarization phase. There is an important interindividual susceptibility to develop diLQT, which is of unknown origin but can be reproduced in patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs).
View Article and Find Full Text PDFParkinsons Dis
July 2023
The Second Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, China.
Objective: To investigate the role of aberrant Dyrk1a expression in phosphorylation modification at the -synuclein serine 129 (Ser129) site to analyze its molecular mechanism in mediating apoptosis of PD.
Methods: The protein level of P--synuclein (Ser129), -synuclein, Bcl-2, Bax, active caspase 3, GSK3, PI3K, AKT, and cyclinD1 were detected. The mRNA transcript levels of Dyrk1a and DAT and protein levels of IL-1, IL-6, COX-2, and TNF- were detected.
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!