Neurodevelopmental vulnerability to nicotine extends from fetal stages through adolescence. The recently proposed "sensitization-homeostasis" model postulates that, even in adulthood, nicotine treatment permanently reprograms synaptic activity. We administered nicotine to rats throughout gestation or in adulthood (postnatal days PN90-107), using regimens that reproduce plasma levels in smokers, assessing effects on serotonin (5HT) receptors, the 5HT transporter and responses mediated through adenylyl cyclase (AC). Evaluations were then made on PN105, PN110, PN120 and PN180. Prenatal nicotine exposure elicited persistent suppression of 5HT1A receptors and upregulation of 5HT2 receptors, effects that were selective for males and that first emerged in young adulthood. In addition, AC activity was reduced and there was uncoupling of receptor-mediated responses. With nicotine exposure restricted to adulthood, there were few changes in 5HT synaptic proteins during treatment or in the first 2 weeks post-treatment, distinctly different from the robust alterations seen earlier with similar nicotine regimens given in adolescence. Nevertheless, there was long-term upregulation of the proteins in males at 6 months of age; females were unaffected. Exposure to prenatal nicotine followed by adult nicotine overcame the protection of females, so that they, too showed long-term effects not seen with either treatment alone; the effects in males were exacerbated in an additive manner. 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.