Separate or sequential exposure to nicotine prenatally and in adulthood: persistent effects on acetylcholine systems in rat brain regions.
Nicotine is a developmental neurotoxicant but the proposed "sensitization-homeostasis" model postulates that even in adulthood nicotine permanently reprograms synaptic function. We administered nicotine to rats throughout gestation or in adulthood (postnatal days PN90-107), simulating plasma levels in smokers, with evaluations on PN105, PN110, PN120, PN130 and PN180. We assessed nicotinic acetylcholine receptor (nAChR) binding, choline acetyltransferase activity, a marker for acetylcholine (ACh) terminals, and hemicholinium-3 (HC3) binding to the choline transporter, an index of ACh presynaptic activity. Prenatal nicotine exposure elicited persistent deficits in HC3 binding in male cerebral cortex and female striatum, but little change in other parameters. Nicotine given in adulthood produced profound nAChR upregulation lasting 2 weeks after discontinuing treatment. Decrements in cerebrocortical and striatal HC3 binding emerged during withdrawal and persisted through PN180, indicative of reduced ACh synaptic activity. Prenatal nicotine did not evoke any major alterations in the response to nicotine given in adulthood. The effects seen here are substantially different from those found previously for nicotine given to adolescent rats, which showed more prolonged nAChR upregulation and profound, widespread and persistent deficits in markers of ACh synaptic function; for adolescents, prenatal nicotine exposure desensitized nAChR responses, exacerbated withdrawal-induced ACh functional deficits, and worsened the long-term outcome. Our results indicate that the effects of nicotine during prenatal or adolescent stages are indeed distinct from the effects in adults, but that even adults show persistent changes after nicotine exposure, commensurate with the sensitization-homeostasis model. These effects may contribute to lifelong vulnerability to readdiction.
Slotkin, TA; Ryde, IT; Seidler, FJ
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