Adolescent nicotine exposure causes persistent upregulation of nicotinic cholinergic receptors in rat brain regions.

Whereas numerous studies have explored the consequences of fetal or adult nicotine exposure, little or no basic research has been conducted for nicotine exposure during adolescence, the developmental period in which regular cigarette use typically begins. We administered nicotine to adolescent rats on postnatal days 30-47 via continuous infusion with implanted osmotic minipumps, using a dose rate (3-6 mg kg-1 day-1) set to achieve plasma nicotine levels found in smokers; results were compared to exposure of adult rats. During and after exposure, we assessed nicotinic cholinergic receptor binding in the midbrain, cerebral cortex, and hippocampus, using [3H]cytisine. Robust receptor upregulation was observed with both adolescent and adult nicotine exposure but there were major differences in the regional specificity and persistence of effect. In adolescents, upregulation was uniform across all regions during the infusion period, whereas in adults, there was a distinct regional hierarchy: midbrain < cerebral cortex < hippocampus; accordingly, receptors in the adolescent midbrain were upregulated far more than with adult exposure. In addition, adolescent nicotine treatment produced long-lasting effects on the receptors, with significant increases still apparent in male rats 1 month after the termination of drug exposure. We also obtained evidence for hippocampal cell damage in adolescent female rats exposed to nicotine, characterized by increases in total membrane protein concentration indicative of a decrease in overall cell size. Adolescent nicotine exposure thus elicits region- and gender-selective effects that differ substantially from those in adults, effects that may contribute to increased addictive properties and lasting deficits in behavioral performance.