Individuals who consume cocaine illegally have long since adopted or explored the nasal route of administration. This study was designed to determine in an animal model whether nasally applied cocaine could be transported directly from the nasal cavity to the central nervous system. Male Sprague-Dawley rats were used in the study. The nasal cavity was isolated to prevent drainage of nasally applied dosing solution to nonnasal regions. Cocaine was then administered, either by intranasal (in) administration or by intravenous (iv) injection. At different times post dose, blood and tissues from different regions of the brain were collected. Cocaine concentrations in plasma and tissue samples were analyzed by HPLC. After iv administration, similar cocaine contents in different brain regions were observed. Following in administration, cocaine content in samples collected within 60 min post dose were found to differ considerably in different brain regions. The highest content was observed in the olfactory bulb, followed by the olfactory tract and then the remaining part of the brain. To allow comparison of brain cocaine content after iv and in administration, brain cocaine contents were normalized by plasma cocaine concentrations. The ratios of the area under the cocaine concentration-time curve (AUC) between the olfactory bulb and plasma at early times following in administration were significantly higher than those obtained after the iv dose (13.4 +/- 5.56 vs 6.16 +/- 0.94, p < 0.05, for AUC ratio up to 2 min post dose; 9.39 +/- 1.47 vs 7.34 +/- 0.59, p < 0.05, for AUC ratio up to 4 min post dose). At 1 min post dose, the olfactory bulb-to-plasma cocaine concentration ratios following in administration was three times those obtained after iv administration. After 1 min, the olfactory bulb-to-plasma concentration ratios following in administration were found to be similar to or smaller than those obtained after iv administration. The tissue-to-plasma concentration ratios in other brain regions following in administration were found to be smaller than those obtained following iv dosing. We conclude that nasally administered cocaine was transported directly from the nasal cavity to the brain but that only a very small fraction of the dose was transported via the direct pathway.