Lobeline attenuates neonatal ethanol-mediated changes in hyperactivity and dopamine transporter function in the prefrontal cortex in rats

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• 作者：A.M. Smith^a ; K.A. Wellmann^b ; T.M. Lundblad^a ; M.L. Carter^b ; S. Barron^b ; L.P. Dwoskin^a ; ^{ldwoskin@email.uky.edu}
• 关键词：ethanol ; dopamine transporter ; prefrontal cortex ; lobeline ; hyperactivity ; preadolescent
• 刊名：Neuroscience
• 出版年：2012
• 期刊代码：50_03064522
• 类别：neu
• 出版时间：29 March, 2012
• 卷：206
• 期：Complete
• 页码：245-254
• 文件大小：904 K

摘要

Current therapies for attention deficit hyperactivity disorder (ADHD) have varying efficacy in individuals with fetal alcohol spectrum disorders (FASD), suggesting that alternative therapeutics are needed. Developmental exposure to ethanol produces changes in dopamine (DA) systems, and DA has also been implicated in ADHD pathology. In the current study, lobeline, which interacts with proteins in dopaminergic presynaptic terminals, was evaluated for its ability to attenuate neonatal ethanol-induced locomotor hyperactivity and alterations in dopamine transporter (DAT) function in striatum and prefrontal cortex (PFC). From postnatal days (PND) 1-7, male and female rat pups were intubated twice daily with either 3 g/kg ethanol or milk, or were not intubated (non-intubated control) as a model for 鈥渢hird trimester鈥?ethanol exposure. On PND 21 and 22, pups received acute lobeline (0, 0.3, 1, or 3 mg/kg), and locomotor activity was assessed. On PND 23-25, pups again received an acute injection of lobeline (1 or 3 mg/kg), and DAT kinetic parameters (Km and V_max) were determined. Results demonstrated that neonatal ethanol produced locomotor hyperactivity on PND 21 that was reversed by lobeline (1 and 3 mg/kg). Although striatal DAT function was not altered by neonatal ethanol or acute lobeline, neonatal ethanol exposure increased the V_max for DAT in the PFC, suggesting an increase in DAT function in PFC. Lobeline ameliorated this effect on PFC V_max at the same doses that decreased hyperactivity. Methylphenidate, the gold standard therapeutic for ADHD, was also evaluated for comparison with lobeline. Methylphenidate decreased DAT V_max and Km in PFC from ethanol-treated pups. Thus, lobeline and methylphenidate differentially altered DAT function following neonatal ethanol exposure. Collectively, these findings provide support that lobeline may be a useful pharmacotherapy for some of the deficits associated with neonatal ethanol exposure.