Maternal smoking during pregnancy can cause persistent cognitive impairments. Variability in the expression of the adverse functional effects may be due to converging risk factors. Prenatal nicotine has the potential to impair neuroplasticity normally seen during development. In rats and humans, the developing frontal cortex is very plastic and substantial functional recovery can occur after neonatal frontal cortical damage. This recovery is dependent on the integrity of norepinepherine (NE) systems. NE response has been found in our studies to be substantially compromised by prenatal nicotine exposure. Prenatal nicotine administration in Sprague-Dawley rats (2 mg/kg/day GD4-birth) significantly decreases cortical NE levels, and essentially eliminates the ability of acute nicotine to elicit NE release. Subsensitivity of NE systems is also seen with regard to cognitive function. Radial-arm maze memory deficits can be induced in control rats by either the alpha-adrenergic agonist phenylpropanolamine or the beta-adrenergic antagonist propranolol. Prenatal nicotine eliminates significant response to either phenylpropanolamine or propranolol. The under-responsivity of NE systems after prenatal nicotine exposure may impair the ability of the offspring to recover from frontal cortical trauma during and after birth. In this way prenatal nicotine exposure may predispose the offspring to lasting deficits after neonatal frontal cortical damage.