Long-lasting teratogenic effects of nicotine on cognition: gender specificity and role of AMPA receptor function

Nicotine, the main psychoactive ingredient in tobacco, readily crosses the placental barrier to cause growth and neurobehavioral abnormalities in the offspring. The current study was designed to assess whether nicotinic action causes long lasting teratogenic effects and synaptic dysfunctions. Pregnant Sprague-Dawley rats were infused with nicotine via osmotic minipumps at a dose of 6 mg/kg/day corresponding to the dose receiving during heavy smoking. A battery of behavioral tests and electrophysiological experiments were performed during specific postnatal periods. A spectrum of developmental and behavioral modifications in adolescent, young-adult and aged animals resulted after prenatal nicotine exposure. The potentially teratogenic effect of nicotine was clearly demonstrated in both genders by changes in developmental reflexes, exploratory and novelty seeking behavior, as well as a higher level of anxiety, and changes in individual and group responses in learning and memory. Most of the behavioral abnormalities were transitional with advancing age (6 months), although cognitive deficits measured by a two-way active avoidance task were long-lasting for male rats. Electrophysiological studies show decreased excitatory postsynaptic responses (mEPSCs) mediated by AMPA receptors in the hippocampus. These results suggest that teratogenic effect of nicotine on cognition is age and gender-specific, long-lasting and associated with AMPA receptor function.