Fetal methylphenidate exposure induced ADHD-like phenotypes and decreased Drd2 and Slc6a3 expression levels in mouse offspring

Satoru Aoki; Asuka Kaizaki-Mitsumoto; Natsumi Hattori; Satoshi Numazawa

doi:10.1016/j.toxlet.2021.02.016

Fetal methylphenidate exposure induced ADHD-like phenotypes and decreased Drd2 and Slc6a3 expression levels in mouse offspring

Toxicol Lett. 2021 Jun 15:344:1-10. doi: 10.1016/j.toxlet.2021.02.016. Epub 2021 Feb 26.

Authors

Satoru Aoki¹, Asuka Kaizaki-Mitsumoto², Natsumi Hattori³, Satoshi Numazawa⁴

Affiliations

¹ Division of Toxicology, Department of Pharmacology, Toxicology and Therapeutics, Showa University School of Pharmacy 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan. Electronic address: s.aoki@cmed.showa-u.ac.jp.
² Division of Toxicology, Department of Pharmacology, Toxicology and Therapeutics, Showa University School of Pharmacy 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan. Electronic address: asuka.0110@pharm.showa-u.ac.jp.
³ Division of Toxicology, Department of Pharmacology, Toxicology and Therapeutics, Showa University School of Pharmacy 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan. Electronic address: n_hattori@pharm.showa-u.ac.jp.
⁴ Division of Toxicology, Department of Pharmacology, Toxicology and Therapeutics, Showa University School of Pharmacy 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan. Electronic address: numazawa@pharm.showa-u.ac.jp.

PMID: 33647392
DOI: 10.1016/j.toxlet.2021.02.016

Abstract

Methylphenidate (MPD) is used as a first-line treatment for attention-deficit/hyperactivity disorder (ADHD). The number of prescriptions for ADHD patients is increasing, suggesting that the number of fertile women using such medication might be also increasing. The purpose of this study was to clarify the effects of MPD exposure during the fetal period on infant development, behavior, learning, and memory in mice. Expression levels of candidate genes associated with ADHD were also determined in the brain of pups born to MDP-treated dams who were administered MPD orally at a dose of 2.5, 7.5, or 15 mg/kg daily from gestational day 1 to the day before delivery. Offspring aged 6-8 weeks were subjected to the spontaneous locomotor activity, elevated plus-maze, and passive avoidance tests and therapeutic treatments with MPD or atomoxetine. Fetal MPD exposure induced ADHD-like phenotypes, such as hyperactivity and impulsivity, in mouse offspring, which were suppressed by treatment with MPD and atomoxetine. These mice showed decreased Drd2 and Slc6a3 expression levels in the brain, which are often observed in ADHD model animals. Our results suggest that continuous use of MPD during pregnancy induces ADHD phenotypes in the offspring.

Keywords: ADHD; Fetal exposure; Hyperactivity; Impulsivity; Methylphenidate; Offspring.

MeSH terms

Animals
Animals, Newborn
Attention Deficit Disorder with Hyperactivity / chemically induced*
Dopamine Plasma Membrane Transport Proteins / genetics
Dopamine Plasma Membrane Transport Proteins / metabolism*
Female
Fetal Development / drug effects
Gene Expression Regulation, Developmental / drug effects
Learning
Male
Methylphenidate / administration & dosage
Methylphenidate / toxicity*
Mice
Mice, Inbred ICR
Pregnancy
Prenatal Exposure Delayed Effects*
Receptors, Dopamine D2 / genetics
Receptors, Dopamine D2 / metabolism*

Substances

DRD2 protein, mouse
Dopamine Plasma Membrane Transport Proteins
Receptors, Dopamine D2
Slc6a3 protein, mouse
Methylphenidate