Disruption of the development of cholinergic-induced translocation/activation of PKC isoforms after prenatal heroin exposure.
Prenatal exposure of mice to heroin resulted in behavioral deficits present at adulthood, and related to septohippocampal cholinergic innervation accompanied by both pre- and postsynaptic cholinergic hyperactivity; including an increase in membrane PKC activity, and a desensitization of PKC to cholinergic input, which correlated highly with the behavioral performance, and was reversed by cholinergic grafting. The effect was shown in the behaviorally relevant PKCgamma and beta whereas the less behaviorally relevant PKCalpha isoform was not affected. The present study was designed to establish the effect of heroin exposure on the expression of the PKC isoforms level and on the more functionally relevant cholinergic translocation/activation of the isoforms throughout postnatal development. The hippocampi of mice pups, exposed to heroin transplacentally, were assayed after incubation with carbachol for PKC isoforms on postnatal days (PN) 1, 7, 14, 21, 30 and 50. Prenatal heroin exposure increased basal PKCgamma, beta and alpha levels. PKCgamma and alpha levels returned to control levels on PN50. While in PKCbeta, this increase lasted until PN50. Translocation/activation of the PKC isoforms gamma and beta by cholinergic receptor stimulation was present from PN1, concurrent with the presence of the isoforms. Prenatal exposure to heroin completely abolished the translocation/activation throughout the entire postnatal development. This defect was shown from the very beginning, PN1, the day when the PKC isoforms appear. The results suggest that the PKCgamma and beta isoforms are functional concurrent with their developmental appearance. Unlike findings on some other teratogens, the prenatal heroin effect on the isoforms function is similar throughout postnatal development.
Huleihel
Rabab
R
Department of Anatomy and Cell Biology, The Hebrew University-Hadassah Medical School, Box 12272, 91120 Jerusalem, Israel.
Yanai
Joseph
J
D000109:Acetylcholine / Q000378:metabolism; D000701:Analgesics, Opioid / Q000009:adverse effects; D000818:Animals; D000831:Animals, Newborn; D018679:Cholinergic Agonists / Q000494:pharmacology; D002799:Cholinergic Fibers / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005260:Female; D003932:Heroin / Q000009:adverse effects*; D006556:Heroin Dependence / Q000201:enzymology* / Q000503:physiopathology; D006624:Hippocampus / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D051379:Mice; D009434:Neural Pathways / Q000187:drug effects / Q000201:enzymology; D009924:Organ Culture Techniques; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000201:enzymology* / Q000503:physiopathology; D020033:Protein Isoforms / Q000187:drug effects / Q000378:metabolism; D011493:Protein Kinase C / Q000187:drug effects* / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D011950:Receptors, Cholinergic / Q000187:drug effects / Q000378:metabolism; D012686:Septal Nuclei / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology
D000701:Analgesics, Opioid; D018679:Cholinergic Agonists; D020033:Protein Isoforms; D011950:Receptors, Cholinergic; D003932:Heroin; D011493:Protein Kinase C; D000109:Acetylcholine