Repeated exposure to cocaine during sensitive periods of forebrain development produces specific, long-lasting changes in the structure and function of maturing neural circuits. Similar regimens of drug exposure in adult animals with mature, homeostatically regulated nervous systems produce neuroadaptations that appear to be quite different in nature and magnitude. We studied the ability of cocaine to induce behavioral sensitization and/or tolerance following repeated administration of i.v. cocaine (3 mg/kg, twice daily) to pregnant rabbits during the period of peak differentiation within the rabbit cerebral cortex (embryonic day [E] 16-E25). Offspring and the adult mothers were behaviorally tested following acute administration of amphetamine 2 months after the litters were born. The offspring, having received cocaine during the prenatal sensitive period, showed profound behavioral tolerance to the amphetamine challenge. In contrast, the mothers of these offspring, who received cocaine at the same dose and duration, and experienced the same period of withdrawal, exhibited robust behavioral sensitization. These data indicate that specific adaptive changes in neural signaling and/or circuitry that occur in response to repeated exposure to psychostimulants are highly dependent upon the maturational state of the brain during which the exposure occurs.