Combinatorial targeting of NMDARs and 5-HT4Rs exerts beneficial effects in a mouse model of Alzheimer's disease.
Briana K Chen, Holly C Hunsberger, Alicia Whye, Louise C Matthews, Alyson Yook, Moshe J Willner, Ryan W Logan, Stefanie Johns, Eric Weisblum, Christine A Denny
Alzheimer's Research & Therapy July 15, 2025 DOI: 10.1186/s13195-025-01804-9 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Male and female APP/PS1 mice (a mouse model of Alzheimer's disease) and control mice |
| Interventions | (R S)-ketamine prucalopride S)-ketamine + prucalopride |
| Topics | Ketamine Serotonin |
| Keywords | Adjunctive treatment Neuroinflammation Prucalopride Multi-pronged approach Dual strategy Multimodal therapy Neurodegenerative diseases: neurodegeneration Alzheimer's Cognitive decline Memory Complex diseases Recent investigation |
| Key points | Combined administration of (R,S)-ketamine and prucalopride improved cognitive decline by increasing memory retrieval in a contextual fear conditioning paradigm in APP/PS1 mice. |
Abstract
Alzheimer's disease (AD) is the leading cause of dementia. There are limited approved medications that delay cognitive decline or lessen neuropsychiatric symptoms. Numerous clinical trials for AD using a single drug administration have failed to meet therapeutic endpoints, which is most likely due to the complexity of AD. A multimodal therapeutic intervention is more likely to improve symptoms by targeting multiple targets implicated in AD. Here, we investigated if targeting both N-Methyl-D-aspartic acid receptors (NMDARs) and serotonin type 4 receptors (5-HT4R) may have beneficial effects in a mouse model of AD, as they have separately been shown to improve cognition and/or mood. Male and female control (Ctrl) or APP/PS1 mice were administered single, intermittent, or chronic administration of 1) saline; 2) (R,S)-ketamine, an NMDAR antagonist; 3) prucalopride, a 5-HT4R agonist; or 4) (R,S)-ketamine + prucalopride to simultaneously target co-morbid neuropsychiatric and cognitive deficits. Behavioral assays were then administered to measure cognition, perseverative behavior, hyponeophagia, and/or sleep. Brains were processed for glial fibrillary acidic protein (GFAP) immunohistochemistry. Single and chronic administration of (R,S)-ketamine + prucalopride administration improved cognitive decline by increasing memory retrieval in a contextual fear conditioning (CFC) paradigm in APP/PS1 mice. Drug efficacy was less effective in females than in males and was age dependent. Hippocampal GFAP immunoreactivity was decreased by chronic (R,S)-ketamine + prucalopride treatment in females. Our results indicate that combined administration of (R,S)-ketamine + prucalopride is a novel multimodal therapeutic strategy to treat cognitive decline in AD. Future work will further characterize these interactions with the goal of clinical development.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
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