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

A. M. Smith, K. A. Wellmann, T. M. Lundblad, M. L. Carter, S. Barron, L. P. Dwoskin

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

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 "third trimester" 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.

Original languageEnglish
Pages (from-to)245-254
Number of pages10
JournalNeuroscience
Volume206
DOIs
StatePublished - Mar 29 2012

Bibliographical note

Funding Information:
The research reported was supported in part by the Kentucky Tobacco Research and Development Center and NIH grants R21 AA14032 and T32 DA16176 . We thank A. Gabriela Deaciuc and Ben Lewis for their assistance. For purposes of full disclosure, the University of Kentucky holds patents on lobeline, which have been licensed by Yaupon Therapeutics, Inc. (Lexington, KY). A potential royalty stream to L.P.D. may occur consistent with University of Kentucky policy, and L.P.D. is a founder of, and has financial interest in, Yaupon Therapeutics, Inc.

Keywords

  • Dopamine transporter
  • Ethanol
  • Hyperactivity
  • Lobeline
  • Preadolescent
  • Prefrontal cortex

ASJC Scopus subject areas

  • General Neuroscience

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