AbstractBackgroundPrenatal alcohol exposure alters brain development, affecting cognitive, motor, and emotional domains, and potentially leading to greater alcohol intake during adolescence. The present study investigated whether early alcohol exposure modifies vulnerability to behavioral alterations associated with adolescent alcohol exposure in a rodent model.MethodsSprague–Dawley rats received ethanol or sham intubations during two developmental periods: (1) the third trimester equivalent of brain development in humans (postnatal days [PD] 4–9) and (2) adolescence (PD 28–42). Both exposures resulted in blood alcohol concentrations around 200 mg/dl. Subjects were tested in the open field (PD 45–48) and on hippocampal and prefrontal cortical (PFC) dependent tasks: the Morris water maze (PD 52–58) and trace fear conditioning (PD 63–64).ResultsNeonatal alcohol exposure reduced forebrain and cerebellar weight, increased open‐field activity, and slowed acquisition of trace fear conditioning. Adolescent alcohol exposure did not disrupt learning or significantly induce gross brain pathology, suggesting that 200 mg/dl/day of ethanol disrupts cognitive development during the 3rd trimester equivalent, but not during adolescence. Interestingly, females exposed to alcohol only during adolescence exhibited an increased conditioned fear response and more rapid habituation of locomotor activity in the open field, suggesting alterations in emotional responding. Moreover, subjects exposed to a combination of neonatal and adolescent alcohol exposure spent significantly more time in the center of the open field chamber than other groups. Similarly, males exposed to the combination exhibited less thigmotaxis in the Morris water maze.ConclusionsThese results indicate that combined exposure to alcohol during these two critical periods reduces anxiety‐related behaviors and/or increases risk taking in a sex‐dependent manner, suggesting that prenatal alcohol exposure may affect risk for emotional consequences of adolescent alcohol exposure.