Dopamine transporter blockade during adolescence increases adult dopamine function, impulsivity, and aggression.
Journal
Molecular psychiatry
ISSN: 1476-5578
Titre abrégé: Mol Psychiatry
Pays: England
ID NLM: 9607835
Informations de publication
Date de publication:
Aug 2023
Aug 2023
Historique:
received:
16
01
2022
accepted:
17
07
2023
revised:
11
07
2023
medline:
2
11
2023
pubmed:
3
8
2023
entrez:
2
8
2023
Statut:
ppublish
Résumé
Sensitive developmental periods shape neural circuits and enable adaptation. However, they also engender vulnerability to factors that can perturb developmental trajectories. An understanding of sensitive period phenomena and mechanisms separate from sensory system development is still lacking, yet critical to understanding disease etiology and risk. The dopamine system is pivotal in controlling and shaping adolescent behaviors, and it undergoes heightened plasticity during that time, such that interference with dopamine signaling can have long-lasting behavioral consequences. Here we sought to gain mechanistic insight into this dopamine-sensitive period and its impact on behavior. In mice, dopamine transporter (DAT) blockade from postnatal (P) day 22 to 41 increases aggression and sensitivity to amphetamine (AMPH) behavioral stimulation in adulthood. Here, we refined this sensitive window to P32-41 and identified increased firing of dopaminergic neurons in vitro and in vivo as a neural correlate to altered adult behavior. Aggression can result from enhanced impulsivity and cognitive dysfunction, and dopamine regulates working memory and motivated behavior. Hence, we assessed these behavioral domains and found that P32-41 DAT blockade increases impulsivity but has no effect on cognition, working memory, or motivation in adulthood. Lastly, using optogenetics to drive dopamine neurons, we find that increased VTA but not SNc dopaminergic activity mimics the increase in impulsive behavior in the Go/NoGo task observed after adolescent DAT blockade. Together our data provide insight into the developmental origins of aggression and impulsivity that may ultimately improve diagnosis, prevention, and treatment strategies for related neuropsychiatric disorders.
Identifiants
pubmed: 37532798
doi: 10.1038/s41380-023-02194-w
pii: 10.1038/s41380-023-02194-w
pmc: PMC10618097
doi:
Substances chimiques
Dopamine
VTD58H1Z2X
Dopamine Plasma Membrane Transport Proteins
0
Amphetamine
CK833KGX7E
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
3512-3523Subventions
Organisme : NIMH NIH HHS
ID : R01 MH117128
Pays : United States
Organisme : NIDA NIH HHS
ID : R01 DA038966
Pays : United States
Informations de copyright
© 2023. The Author(s).
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