Alterations in PKCgamma in the mouse hippocampus after prenatal exposure to heroin: a link from cell signaling to behavioral outcome.
Administration of heroin to pregnant mice evokes neurochemical and behavioral deficits consequent to disruption of septohippocampal cholinergic innervation, notably involving desensitization of the ability of cholinergic receptors to activate PKC activity. The present study further evaluates whether desensitization occurs specifically for the PKCgamma isoform, the behaviorally relevant subtype, as compared to PKCalpha. Mice were exposed transplacentally to heroin on gestational days (GD) 9-18 via s.c. maternal injections (10 mg/kg per day). In young adulthood (50 days old), control offspring showed an increase in hippocampal cell membrane PKCgamma after incubation with the muscarinic cholinergic receptor agonist, carbachol, indicative of translocation from the cytosol. Prenatal exposure to heroin eliminated this response, whereas basal PKCgamma levels were unchanged. In contrast, PKCalpha, which is not related to heroin-induced behavioral deficits, did not show a loss of response. The present findings strongly point to abnormalities in the responsiveness of PKCgamma as a mechanism underlying the neurobehavioral teratogenicity of heroin.
Shahak
Halit
H
The Ross Laboratory for Studies in Neural Birth Defects, Department of Anatomy and Cell Biology, The Hebrew University-Hadassah Medical School, P.O. Box 12272, 91120 Jerusalem, Israel.
Slotkin
Theodore A
TA
Yanai
Joseph
J
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D001835:Body Weight / Q000187:drug effects; D002217:Carbachol / Q000494:pharmacology; D002462:Cell Membrane / Q000201:enzymology; D004789:Enzyme Activation; D005247:Feeding Behavior / Q000187:drug effects; D005260:Female; D003932:Heroin / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology*; D008425:Maternal Behavior; D051379:Mice; D023421:Models, Animal; D011187:Posture; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011493:Protein Kinase C / Q000378:metabolism*; D012018:Reflex / Q000187:drug effects / Q000502:physiology; D013216:Reflex, Startle / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D003932:Heroin; D002217:Carbachol; C087857:protein kinase C gamma; D011493:Protein Kinase C