Convergent effects on cell signaling mechanisms mediate the actions of different neurobehavioral teratogens: alterations in cholinergic regulation of protein kinase C in chick and avian models.

Journal Article (Journal Article)

Although the actions of heroin on central nervous system (CNS) development are mediated through opioid receptors, the net effects converge on dysfunction of cholinergic systems. We explored the mechanisms underlying neurobehavioral deficits in mouse and avian (chick, Cayuga duck) models. In mice, prenatal heroin exposure (10 mg/kg on gestation days 9-18) elicited deficits in behaviors related to hippocampal cholinergic innervation, characterized by concomitant pre- and postsynaptic hyperactivity, but ending in a reduction of basal levels of protein kinase C (PKC) isoforms betaII and gamma and their desensitization to cholinergic receptor-induced activation. PKCalpha, which is not involved in the behaviors studied, was unaffected. Because mammalian models possess inherent confounding factors from maternal effects, we conducted parallel studies using avian embryos, evaluating hyperstriatal nucleus (intermedial part of the hyperstriatum ventrale, IMHV)-related, filial imprinting behavior. Heroin injection to the eggs (20 mg/kg) on incubation days 0 and 5 diminished the post-hatch imprinting ability and reduced PKCg and bII content in the IMHV membrane fraction. Two otherwise unrelated agents that converge on cholinergic systems, chlorpyrifos and nicotine, elicited the same spectrum of effects on PKC isoforms and imprinting but had more robust actions. Pharmacological characterization also excluded direct effects of opioid receptors on the expression of imprinting; instead, it indicated participation of serotonergic innervation. The avian models can provide rapid screening of neuroteratogens, exploration of common mechanisms of behavioral disruption, and the potential design of therapies to reverse neurobehavioral deficits.

Full Text

Duke Authors

Cited Authors

  • Yanai, J; Beer, A; Huleihel, R; Izrael, M; Katz, S; Levi, Y; Rozenboim, I; Yaniv, SP; Slotkin, TA

Published Date

  • October 2004

Published In

Volume / Issue

  • 1025 /

Start / End Page

  • 595 - 601

PubMed ID

  • 15542768

International Standard Serial Number (ISSN)

  • 0077-8923

Digital Object Identifier (DOI)

  • 10.1196/annals.1316.074


  • eng

Conference Location

  • United States