Reinstatement of synaptic plasticity in the aging brain through specific dopamine transporter inhibition.

Aging Animals Brain Dopamine Plasma Membrane Transport Proteins Hippocampus Neuronal Plasticity / physiology Rats

Journal

Molecular psychiatry

ISSN: 1476-5578

Titre abrégé: Mol Psychiatry

Pays: England

ID NLM: 9607835

Informations de publication

Date de publication:
12 2021

Historique:

pubmed: 11 7 2021

medline: 15 3 2022

entrez: 10 7 2021

Statut: ppublish

Résumé

Aging-related neurological deficits negatively impact mental health, productivity, and social interactions leading to a pronounced socioeconomic burden. Since declining brain dopamine signaling during aging is associated with the onset of neurological impairments, we produced a selective dopamine transporter (DAT) inhibitor to restore endogenous dopamine levels and improve cognitive function. We describe the synthesis and pharmacological profile of (S,S)-CE-158, a highly specific DAT inhibitor, which increases dopamine levels in brain regions associated with cognition. We find both a potentiation of neurotransmission and coincident restoration of dendritic spines in the dorsal hippocampus, indicative of reinstatement of dopamine-induced synaptic plasticity in aging rodents. Treatment with (S,S)-CE-158 significantly improved behavioral flexibility in scopolamine-compromised animals and increased the number of spontaneously active prefrontal cortical neurons, both in young and aging rodents. In addition, (S,S)-CE-158 restored learning and memory recall in aging rats comparable to their young performance in a hippocampus-dependent hole board test. In sum, we present a well-tolerated, highly selective DAT inhibitor that normalizes the age-related decline in cognitive function at a synaptic level through increased dopamine signaling.

Identifiants

DOI: 10.1038/s41380-021-01214-x PMID: 34244620

pubmed: 34244620

doi: 10.1038/s41380-021-01214-x

pii: 10.1038/s41380-021-01214-x

doi:

Substances chimiques

Dopamine Plasma Membrane Transport Proteins 0

Types de publication

News Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

7076-7090

Informations de copyright

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