Article ; Online: The dopamine D1 receptor positive allosteric modulator, DETQ, improves cognition and social interaction in aged mice and enhances cortical and hippocampal acetylcholine efflux.
2023 Volume 459, Page(s) 114766
Abstract: Dopamine (DA) D1 and D2 receptors (Rs) are critical for cognitive functioning. D1 positive allosteric modulators (D1PAMs) activate D1Rs without desensitization or an inverted U-shaped dose response curve. DETQ, [2-(2,6-dichlorophenyl)-1-((1S,3R)-3-( ... ...
Abstract | Dopamine (DA) D1 and D2 receptors (Rs) are critical for cognitive functioning. D1 positive allosteric modulators (D1PAMs) activate D1Rs without desensitization or an inverted U-shaped dose response curve. DETQ, [2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one] is highly selective for the human D1Rs as shown in humanized D1R knock-in (hD1Ki) mice. Here, we have ascertained the efficacy of DETQ in aged [13-23-month-old (mo)] hD1Ki mice and their corresponding age-matched wild-type (WT; C57BL/6NTac) controls. We found that in aged mice, DETQ, given acutely, subchronically, and chronically, rescued both novel object recognition memory and social behaviors, using novel object recognition (NOR) and social interaction (SI) tasks, respectively without any adverse effect on body weight or mortality. We have also shown, using in vivo microdialysis, a significant decrease in basal DA and norepinephrine, increase in glutamate (Glu) and gamma-amino butyric acid (GABA) efflux with no significant changes in acetylcholine (ACh) levels in aged vs young mice. In young and aged hD1Ki mice, DETQ, acutely and subchronically increased ACh in the medial prefrontal cortex and hippocampal regions in aged hD1Ki mice without affecting Glu. These results suggest that the D1PAM mechanism is of interest as potential treatment for cognitive and social behavioral deficits in neuropsychiatric disorders including but not restricted to neurodegenerative disorders, such as Parkinson's disease. |
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MeSH term(s) | Mice ; Humans ; Animals ; Aged ; Infant ; Acetylcholine ; Social Interaction ; Mice, Inbred C57BL ; Dopamine ; Glutamic Acid ; Hippocampus/metabolism ; Receptors, Dopamine D1/metabolism ; Cognition |
Chemical Substances | Acetylcholine (N9YNS0M02X) ; Dopamine (VTD58H1Z2X) ; Glutamic Acid (3KX376GY7L) ; Receptors, Dopamine D1 |
Language | English |
Publishing date | 2023-12-03 |
Publishing country | Netherlands |
Document type | Journal Article ; Research Support, Non-U.S. Gov't |
ZDB-ID | 449927-x |
ISSN | 1872-7549 ; 0166-4328 |
ISSN (online) | 1872-7549 |
ISSN | 0166-4328 |
DOI | 10.1016/j.bbr.2023.114766 |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
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