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Effects of early postnatal dopamine transporter (DAT) inhibition on social and cognitive behavior in a rat model of autism.

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Title: Effects of early postnatal dopamine transporter (DAT) inhibition on social and cognitive behavior in a rat model of autism.
Authors: Gibula-Tarlowska E; Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, Lublin 20-093, Poland., Grochecki P; Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, Lublin 20-093, Poland., Lubinska J; Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, Lublin 20-093, Poland., Sliwa M; Department of Drug Addiction Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, Krakow 31-343, Poland., Smaga I; Department of Drug Addiction Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, Krakow 31-343, Poland., Marszalek-Grabska M; Department of Neurotoxicology, Institute of Rural Health, Lublin 20-090, Poland., Lubec G; Department of Neuroproteomics, Paracelsus Medical University, Salzburg 5020, Austria., Slowik T; Experimental Medicine Center, Medical University, Jaczewskiego 8, Lublin 20-090, Poland., Slotwinska W; Medical Faculty, Medical University of Lublin, Lublin 20-059, Poland., Kotlinski R; Clinical Department of Cardiac Surgery, University of Rzeszow, Rzeszow 35-301, Poland., Listos J; Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, Lublin 20-093, Poland., Kedzierska E; Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, Lublin 20-093, Poland., Filip M; Department of Drug Addiction Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, Krakow 31-343, Poland., Kotlinska JH; Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, Lublin 20-093, Poland. Electronic address: jolanta.kotlinska@umlub.edu.pl.
Source: Behavioural brain research [Behav Brain Res] 2026 Oct 02; Vol. 514, pp. 116400. Date of Electronic Publication: 2026 Jul 25.
Publication Type: Journal Article
Language: English
Journal Info: Publisher: Elsevier/North-Holland Biomedical Press Country of Publication: Netherlands NLM ID: 8004872 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1872-7549 (Electronic) Linking ISSN: 01664328 NLM ISO Abbreviation: Behav Brain Res Subsets: MEDLINE
Imprint Name(s): Original Publication: Amsterdam, Elsevier/North-Holland Biomedical Press.
MeSH Terms: Dopamine Plasma Membrane Transport Proteins*/metabolism , Dopamine Plasma Membrane Transport Proteins*/antagonists & inhibitors , Cognition*/drug effects , Cognition*/physiology , Autistic Disorder*/metabolism , Behavior, Animal*/drug effects , Behavior, Animal*/physiology , Autism Spectrum Disorder*/metabolism , Autism Spectrum Disorder*/chemically induced , Social Behavior*, Prenatal Exposure Delayed Effects/metabolism ; Valproic Acid/pharmacology ; Brain-Derived Neurotrophic Factor/metabolism ; Brain/metabolism ; Brain/drug effects ; Dopamine Uptake Inhibitors/pharmacology ; Receptors, Dopamine D2/metabolism ; Animals ; Female ; Male ; Disease Models, Animal ; Rats, Wistar ; Pregnancy ; Rats ; Anxiety
Abstract: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social behavior and cognition. Increasing evidence suggests that alterations in dopaminergic neurotransmission, including changes in dopamine transporter (DAT) function, may contribute to ASD-related behavioral abnormalities. This study investigated whether selective DAT inhibition during early postnatal development influences behavioral and molecular alterations in a rat model of ASD induced by prenatal exposure to sodium valproate (NaVP). Pregnant Wistar rats received NaVP (600 mg/kg, i.p.) on gestational day 12.5. Male offspring were treated with the selective DAT inhibitor CE-123 (10 mg/kg, i.p.) once daily from postnatal day (PND) 10-23. Behavioral assessments during adolescence (PND25-42) evaluated social interaction, recognition memory, spatial preference, anxiety-like behavior, locomotor activity, and aversive memory. DAT, dopamine D2 receptor, brain-derived neurotrophic factor (BDNF), and interleukin-1β (IL-1β) protein expression were assessed in selected brain regions. Prenatal NaVP exposure impaired social novelty discrimination, declarative, spatial, and aversive memory, reduced locomotor activity, and increased anxiety-like behavior. These behavioral alterations were accompanied by elevated DAT and dopamine D2 receptor expression. Early postnatal CE-123 treatment attenuated several ASD-like behavioral abnormalities, normalized DAT and dopamine D2 receptor expression, increased BDNF levels in the prefrontal cortex (PFC), and increased IL-1β expression, without inducing non-specific locomotor stimulation. Together, these findings demonstrate that early postnatal CE-123 treatment was associated with long-lasting behavioral improvements accompanied by alterations in dopaminergic markers and BDNF expression. Although these findings support a role for dopaminergic regulation and neuroplasticity in the observed behavioral effects, the underlying mechanisms require further investigation.
(Copyright © 2026 Elsevier B.V. All rights reserved.)
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Contributed Indexing: Keywords: Autism spectrum disorder; CE-123; Cognition; Dopamine D2 receptor; Dopamine transporter; Sodium valproate
Substance Nomenclature: 0 (Dopamine Plasma Membrane Transport Proteins)
614OI1Z5WI (Valproic Acid)
0 (Brain-Derived Neurotrophic Factor)
0 (Dopamine Uptake Inhibitors)
0 (Receptors, Dopamine D2)
Entry Date(s): Date Created: 20260725 Date Completed: 20260812 Latest Revision: 20260812
Update Code: 20260813
DOI: 10.1016/j.bbr.2026.116400
PMID: 42501761
Database: MEDLINE
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  Data: Effects of early postnatal dopamine transporter (DAT) inhibition on social and cognitive behavior in a rat model of autism.
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  Data: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social behavior and cognition. Increasing evidence suggests that alterations in dopaminergic neurotransmission, including changes in dopamine transporter (DAT) function, may contribute to ASD-related behavioral abnormalities. This study investigated whether selective DAT inhibition during early postnatal development influences behavioral and molecular alterations in a rat model of ASD induced by prenatal exposure to sodium valproate (NaVP). Pregnant Wistar rats received NaVP (600 mg/kg, i.p.) on gestational day 12.5. Male offspring were treated with the selective DAT inhibitor CE-123 (10 mg/kg, i.p.) once daily from postnatal day (PND) 10-23. Behavioral assessments during adolescence (PND25-42) evaluated social interaction, recognition memory, spatial preference, anxiety-like behavior, locomotor activity, and aversive memory. DAT, dopamine D2 receptor, brain-derived neurotrophic factor (BDNF), and interleukin-1β (IL-1β) protein expression were assessed in selected brain regions. Prenatal NaVP exposure impaired social novelty discrimination, declarative, spatial, and aversive memory, reduced locomotor activity, and increased anxiety-like behavior. These behavioral alterations were accompanied by elevated DAT and dopamine D2 receptor expression. Early postnatal CE-123 treatment attenuated several ASD-like behavioral abnormalities, normalized DAT and dopamine D2 receptor expression, increased BDNF levels in the prefrontal cortex (PFC), and increased IL-1β expression, without inducing non-specific locomotor stimulation. Together, these findings demonstrate that early postnatal CE-123 treatment was associated with long-lasting behavioral improvements accompanied by alterations in dopaminergic markers and BDNF expression. Although these findings support a role for dopaminergic regulation and neuroplasticity in the observed behavioral effects, the underlying mechanisms require further investigation.<br /> (Copyright © 2026 Elsevier B.V. All rights reserved.)
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  Data: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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  Data: <i>Keywords: </i>Autism spectrum disorder; CE-123; Cognition; Dopamine D2 receptor; Dopamine transporter; Sodium valproate
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