Nicotine therapy in adulthood reverses the synaptic and behavioral deficits elicited by prenatal exposure to phenobarbital.

Published

Journal Article

A major objective in identifying the mechanisms underlying neurobehavioral teratogenicity is the possibility of designing therapies that reverse or offset drug- or toxicant-induced neural damage. In our previous studies, we identified deficits in hippocampal muscarinic cholinergic receptor-induced membrane translocation of protein kinase C (PKC)gamma as the likely mechanism responsible for adverse behavioral effects of prenatal phenobarbital exposure. We therefore explored whether behavioral and synaptic defects could be reversed in adulthood by nicotine administration. Pregnant mice were given milled food containing phenobarbital to achieve a daily dose of 0.5-0.6 g/kg from gestational days 9-18. In adulthood, offspring showed deficits in the Morris maze, a behavior dependent on the integrity of septohippocampal cholinergic synaptic function, along with the loss of the PKCgamma response. Phenobarbital-exposed and control mice then received nicotine (10 mg/kg/day) for 14 days via osmotic minipumps. Nicotine reversed the behavioral deficits and restored the normal response of hippocampal PKCgamma to cholinergic receptor stimulation. The effects were regionally specific, as PKCgamma in the cerebellum was unaffected by either phenobarbital or nicotine; furthermore, in the hippocampus, PKC isoforms unrelated to the behavioral deficits showed no changes. Nicotine administration thus offers a potential therapy for reversing neurobehavioral deficits originating in septohippocampal cholinergic defects elicited by prenatal drug or toxicant exposures.

Full Text

Duke Authors

Cited Authors

  • Beer, A; Slotkin, TA; Seidler, FJ; Aldridge, JE; Yanai, J

Published Date

  • January 2005

Published In

Volume / Issue

  • 30 / 1

Start / End Page

  • 156 - 165

PubMed ID

  • 15496940

Pubmed Central ID

  • 15496940

Electronic International Standard Serial Number (EISSN)

  • 1740-634X

International Standard Serial Number (ISSN)

  • 0893-133X

Digital Object Identifier (DOI)

  • 10.1038/sj.npp.1300582

Language

  • eng