Perinatal exposure to
nicotine has been shown to cause morphological and neurobehavioral abnormalities in developing brain. In the current study, neonatal rats were given an acute injection of
nicotine (3 mg/kg) at 1, 3, 8, 10 or 15 days of age, and [3H]
thymidine incorporation into
DNA examined over the 30-min period after
drug administration. Three brain/regions were used that differ in their timetables of cell maturation and in their concentrations of
nicotinic receptors.
Nicotine inhibited
DNA synthesis in all brain regions but with a rank order of effect corresponding to the concentration of
nicotinic receptors, namely midbrain + brainstem greater than or equal to cerebral cortex greater than cerebellum. Superimposed on this hierarchy, periods of rapid cell replication were more sensitive to
nicotine, so that
drug effects in the cerebellum, which develops last, became significant past the point at which
nicotine no longer affected
DNA synthesis in the other regions. The inhibitory effect of
nicotine was also found in fetal brain on gestational day 20 after injection of
nicotine to pregnant rats. Studies with
adrenergic and
ganglionic blocking agents and with 100% O2 indicated that autonomic and respiratory actions of
nicotine, including
ischemia,
cardiac arrhythmias and
hypoxia, could not solely account for the inhibition of
DNA synthesis in neonatal brain. In contrast, injection of a small amount (2 micrograms) of
nicotine directly into the central nervous system readily caused inhibition; the same small dose given systemically had no effect. These data suggest that
nicotine damages the developing brain, in part, through direct actions on cell replication.