Locomotor hyperactivity following prenatal exposure to 5-bromo-2'-deoxyuridine: neurochemical and behavioral evidence of dopaminergic and serotonergic alterations.
Prenatal exposure to 5-bromo-2'-deoxyuridine (BrdU) has been reported to induce abnormal behaviors in offspring, including marked hyperactivity. In this study, the contribution of the serotonin (5-HT) and dopamine (DA) systems to BrdU-induced developmental neurotoxicity was investigated. Sprague-Dawley rats were treated with BrdU on gestational days 9 through 15 (50mg/kg, i.p.) and male offspring (BrdU-rats) were examined. The BrdU-rats exhibited a 3.5-fold increase in locomotor activity. The dopamine D2 receptor antagonist sulpiride increased locomotor activity in the BrdU-rats, but decreased it in control rats. The BrdU-rats responded to the 5-HT1A receptor antagonist NAN190 much more than the controls. The measurement of monoamines revealed significant decreases in DA, dihydroxyphenylacetic acid, and homovanilic acid, and significant increases in 5-HT and 5-hydroxy-3-indolacetic acid, with a decrease in the 5-HT turnover ratio in the striatum of BrdU-rats. Thus, prenatal exposure to BrdU induced alterations in both the DA and 5-HT systems.
Safety Testing Laboratory, Food and Drug Safety Center, Hatano Research Institute, 729-5 Ochiai, Hadano, Kanagawa 257-8523, Japan. mkuwagat@iupui.edu
Makiko
M
Kuwagata
Katsumasa T
KT
Muneoka
Tetsuo
T
Ogawa
Morikuni
M
Takigawa
Tetsuji
T
Nagao
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D001289:Attention Deficit Disorder with Hyperactivity / Q000503:physiopathology*; D001973:Bromodeoxyuridine / Q000633:toxicity*; D004195:Disease Models, Animal; D018492:Dopamine Antagonists / Q000494:pharmacology; D005260:Female; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000502:physiology*; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000502:physiology*
D000964:Antimetabolites, Antineoplastic; D018492:Dopamine Antagonists; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D001973:Bromodeoxyuridine