Prenatal heroin exposure alters cholinergic receptor stimulated activation of the PKCβII and PKCγ isoforms

Shiri P. Yaniv, Zvi Naor, Joseph Yanai

Research output: Contribution to journalArticlepeer-review

Abstract

Prenatal exposure of mice to heroin (SC injection of 10 mg/kg to the dams on gestational days 9-18) resulted at adulthood in behavioral deficits related to septohippocampal cholinergic innervation accompanied with both presynaptic and postsynaptic cholinergic hyperactivity; including an increase membrane PKC activity, and a desensitization of PKC to cholinergic input which were highly correlated with the behavioral performance and were reversed by cholinergic grafting. Therefore, we studied the receptor induced activation of the behaviorally relevant PKCγ and PKCβII isoforms and the less behaviorally relevant PKCα isoform. Time course studies revealed peak translocation after 40 min incubation with carbachol for PKCγ (110% increase from basal, i.e. no carbachol level, P < 0.01), 30 min for phosphorylated PKCβII (130%, P < 0.05) and 5 min for non-phosphorylated PKCβII (64%, P < 0.05) with no peak for alpha. Prenatal heroin abolished the translocation of PKCγ and PKCβII while PKCα remained unaffected. A decrease occurred in basal phosphorylated membrane (-45%, P < 0.01) and cytosol-associated (-29%, P < 0.01) PKCβII, in membrane-associated non-phosphorylated PKCβII (-32%, P < 0.01) and PKCγ (-25%, P < 0.01) and in cytosolic PKCα (-27%, P < 0.01), while membrane-associated PKCα was slightly increased (11%, P < 0.05). The results suggest that prenatal heroin disrupts cholinergic receptor induced PKC translocation and activation with the underlying mechanism of neuroteratogenicity potentially lying in the PKCγ and PKCβII, while PKCα remains unaffected.

Original languageEnglish
Pages (from-to)339-349
Number of pages11
JournalBrain Research Bulletin
Volume63
Issue number4
DOIs
StatePublished - 30 May 2004

Keywords

  • ACh
  • DAG
  • DDT
  • ECL
  • G protein coupled receptors
  • GD
  • GPCRs
  • HS/Ibg
  • LTP
  • acetylcholine
  • cPKC
  • cellular protein kinase C
  • diacylglycerol
  • dithiothreitol
  • enhanced chemiluminescence
  • gestation day
  • heterogeneous stock mice
  • long-term potentiation
  • mAChR

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