Mechanism-based approaches for the reversal of drug neurobehavioral teratogenicity

Joseph Yanai*, Tamar L. Ben-Shaanan, Hana Haimovitch, Sophia Katz, Meital Kazma

*Corresponding author for this work

Research output: Chapter in Book/Report/Conference proceedingConference contributionpeer-review

9 Scopus citations

Abstract

Understanding the mechanism of neurobehavioral teratogenicity is the primary prerequisite for reversal of the defect. Progress in such studies can be best achieved if the investigation focuses on behaviors related to a specific brain region and innervation. Our model focused on teratogen-induced deficits in hippocampus-related eight-arm and Morris maze behaviors. Different "cholinergic" teratogens, mainly heroin, induced both pre- and postsynaptic hyperactivity in the hippocampal cholinergic innervation that terminated in desensitization of Protein Kinase C (PKC) isoforms to cholinergic receptor stimulation. Understanding this mechanism enabled its reversal with a pharmacological therapy-nicotine infusion. Studies by others provided similar findings by targeting the deficits respective to the model investigated. Consistently, destruction of the A10-septal dopaminergic pathways that downregulate the septohippocampal cholinergic innervation ameliorated maze performance. Grafting of embryonic differentiated cholinergic cells or neural progenitors similarly reversed the biochemical/molecular alterations and the resulting deficits. Reversal therapies offer a model for the understanding of neurobehavioral teratogenicity and, clinically, offer a model for potential treatment of these deficits. Whereas neural progenitor grafting appears to be the most effective treatment, pharmacological reversal with nicotine infusion seems to possess the most feasible and immediate therapy for neurobehavioral birth defects produced by various teratogens, including drugs. This is true even though the effect of pharmacological therapies is diffuse, affecting multiple areas of the brain.

Original languageEnglish
Title of host publicationCellular and Molecular Mechanisms of Drugs of Abuse and Neurotoxicity
Subtitle of host publicationCocaine, GHB, and Substituted Amphetamines
PublisherBlackwell Publishing Inc.
Pages659-671
Number of pages13
ISBN (Print)1573316296, 9781573316293
DOIs
StatePublished - Aug 2006

Publication series

NameAnnals of the New York Academy of Sciences
Volume1074
ISSN (Print)0077-8923
ISSN (Electronic)1749-6632

Keywords

  • A10
  • Grafting of neural progenitors
  • Heroin
  • Hippocampal behavior
  • Hippocampal cholinergic innervation
  • Neurobehavioral teratogenicity
  • Nicotine therapy
  • PKC isoforms
  • Reversal therapies

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