LS and SS mice develop their differential sensitivity to the motor-incoordinating and hypothermic effects of ethanol at 10-16 days after birth, when thyroid hormones (T4) show a transient peak. This rise in the thyroid hormones is an important element in the normal development of monoaminergic systems and thyroid hormones reach a significantly higher level in the less ethanol-sensitive SS mice than in the more ethanol-sensitive LS mice. Previous investigation have suggested the differential ethanol response of brain monoaminergic neuronal systems in adult LS and SS mice may be related to this development difference in thyroid status. To test the hypothesis that neonatal thyroid status can influence adult CNS ethanol sensitivity. LS and SS mice were treated neonatally with the thyrotropin-releasing hormone (TRH) and propylthiouracil (PTU) to enhance or diminish, respectively, thyroid status at this critical developmental period. The subsequent effect on adult CNS ethanol sensitivity was then determined. Contrary to expectations, both PTU and TRH administration attenuated the transient rise in plasma T4 levels at postnatal days 10-16 in LS mice and in both instances this was associated with decreased CNS ethanol sensitivity (sleep time and hypothermia) in adults. In SS mice, PTU treatment attenuated the postnatal rise in T4 levels as expected, whereas TRH treatment had no significant effect. However, neither neonatal treatment altered CNS ethanol sensitivity in adult SS mice. The decrease in ethanol-induced sleep times and hypothermia of neonatally treated LS mice was associated with an attenuation of ethanol-induced decreases in in vivo tyrosine and tryptophan hydroxylase activity that was not seen in the SS mice. These findings are consistent with the notion that the response of monoaminergic neuronal systems to ethanol is an important determinant of behavioral intoxication. However, the observation that neonatal administration of both TRH and PTU blunted the postnatal rise in thyroid levels in LS mice, yet both treatments resulted in a decrease in adult ethanol sensitivity in LS mice, indicates that the relationship between postnatal thyroid development and CNS ethanol sensitivity is more complex than originally hypothesized.