Prenatal heroin exposure alters cholinergic receptor stimulated activation of the PKCbetaII and PKCgamma isoforms.
Prenatal exposure of mice to heroin (SC injection of 10mg/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 PKCgamma and PKCbetaII isoforms and the less behaviorally relevant PKCalpha isoform. Time course studies revealed peak translocation after 40 min incubation with carbachol for PKCgamma (110% increase from basal, i.e. no carbachol level, P < 0.01), 30 min for phosphorylated PKCbetaII (130%, P < 0.05) and 5 min for non-phosphorylated PKCbetaII (64%, P < 0.05) with no peak for alpha. Prenatal heroin abolished the translocation of PKCgamma and PKCbetaII while PKCalpha remained unaffected. A decrease occurred in basal phosphorylated membrane (-45%, P < 0.01) and cytosol-associated (-29%, P < 0.01) PKCbetaII, in membrane-associated non-phosphorylated PKCbetaII (-32%, P < 0.01) and PKCgamma (-25%, P < 0.01) and in cytosolic PKCalpha (-27%, P < 0.01), while membrane-associated PKCalpha 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 PKCgamma and PKCbetaII, while PKCalpha remains unaffected.
Yaniv
Shiri P
SP
The Ross Laboratory for Studies in Neural Birth Defects, Department of Anatomy and Cell Biology, The Hebrew University-Hadassah Medical School, Box 12272, Jerusalem 91120, Israel.
Naor
Zvi
Z
Yanai
Joseph
J
D000818:Animals; D015153:Blotting, Western; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005260:Female; D003932:Heroin / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007527:Isoenzymes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009294:Narcotics / Q000494:pharmacology*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism*; D064546:Protein Kinase C beta; D021381:Protein Transport / Q000187:drug effects; D011950:Receptors, Cholinergic / Q000187:drug effects* / Q000378:metabolism
D007527:Isoenzymes; D009294:Narcotics; D011950:Receptors, Cholinergic; D003932:Heroin; C087857:protein kinase C gamma; D011493:Protein Kinase C; D064546:Protein Kinase C beta