Fetal nicotine exposure alters ontogeny of M1-receptors and their link to G-proteins.
Prenatal nicotine exposure has been shown to disrupt the development of cholinergic presynaptic tone and behaviors mediated through muscarinic cholinergic receptors. The current study examines nicotine's effects on ontogeny of postsynaptic muscarinic M1-receptors in rat striatum and hippocampus after continuous maternal infusions of 2 mg/kg/day or 6 mg/kg/day from gestational days 4 through 20. Although brain region weights were unaffected by nicotine exposure, significant alterations in receptor development and receptor regulation by G-proteins were found. Postnatal development of striatal M1-receptor binding, as identified with [3H]pirenzepine, was significantly impaired with either of the fetal nicotine regimens. Treatment with 2 mg/kg/day also produced alterations in striatal receptor affinity state, characterized by enhanced ability of an agonist (oxotremorine-M) to displace [3H]pirenzepine; raising the dose to 6 mg/kg/day masked the affinity shift by affecting G-protein regulatory mechanisms, such that addition of the GTP analog, GppNHp, produced a larger decrease in agonist affinity. In the hippocampus, no such effects on receptor binding, affinity state, or G-protein regulation were seen with either regimen. These data thus indicate that fetal nicotine exposure, even at doses that do not cause overt signs of maternal/fetal/neonatal toxicity or growth impairment, influences cholinergic receptor development and regulation of cell signaling mediated by G-proteins. The selectivity of effects toward M1-receptors in the striatum, a region with a prenatal peak of neuronal mitosis, as compared to hippocampus, where mitosis peaks postnatally, suggests that vulnerability to nicotine involves a critical phase of cell development, rather than being targeted toward receptors of a given subtype.
Department of Pharmacology, Duke University Medical Center, Durham, NC 27710.
E A
EA
Zahalka
F J
FJ
Seidler
J
J
Yanai
T A
TA
Slotkin
D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development*; D003342:Corpus Striatum / Q000187:drug effects / Q000254:growth & development; D004305:Dose-Response Relationship, Drug; D005314:Embryonic and Fetal Development / Q000187:drug effects; D005260:Female; D019204:GTP-Binding Proteins / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects / Q000254:growth & development; D008297:Male; D009538:Nicotine / Q000494:pharmacology*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011869:Radioligand Assay; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000187:drug effects*
D011976:Receptors, Muscarinic; D009538:Nicotine; D019204:GTP-Binding Proteins