Nicotine is a neurotoxin in the adolescent brain: critical periods, patterns of exposure, regional selectivity, and dose thresholds for macromolecular alterations

Abstract

In the fetus, nicotine is a neuroteratogen that elicits cell damage and loss and subsequent abnormalities of synaptic function. We explored whether these effects extend into adolescence, the period when most people begin smoking. Beginning on postnatal day 30, rats were given a 1 week regimen of nicotine infusions or twice-daily injections, at doses (0.6, 2 and 6 mg/kg/day) set to achieve plasma levels found in occasional to regular smokers. We assessed indices of cell packing density and cell number (DNA concentration and content), cell size (total protein/DNA ratio) and neuritic projections (membrane/total protein) in the midbrain, hippocampus and cerebral cortex, three regions known to be vulnerable to developmental effects of nicotine. With either route of administration, nicotine evoked shortfalls in DNA concentration and content, compensatory elevations of total protein/DNA, and reductions in the membrane/total protein ratio. Nearly all of the effects were apparent even at the lowest dose of nicotine and remained fully evident 1 month posttreatment. Although both males and females showed significant alterations, in general the effects were larger in females. Our results indicate that in adolescence, even a brief period of continuous or intermittent nicotine exposure, elicits lasting alterations in biomarkers associated with cellular and neuritic damage. As the effects are detected at exposures that produce plasma concentrations one-tenth of those in regular smokers, the exquisite sensitivity of the adolescent brain to nicotine neurotoxicity may contribute to lasting neurobehavioral damage even in occasional smokers.