The distributional pattern of serotonin-immunoreactive nerve fibers in the hippocampal formation of six different mammalian species (rat, chipmunk, hamster, cat, dog and monkey) was studied in detail by means of a modified peroxidase-antiperoxidase immunohistochemical method, using a specific serotonin antiserum. Furthermore, the density of varicosities distributed in each layer of the hippocampus was semiquantitatively analyzed. In all species investigated, the routes of serotonin fibers entering the hippocampal formation were found to be almost the same. These fibers were extensively distributed throughout the hippocampal formation, and had a characteristic arrangement corresponding to the laminar structure of this region. A dense innervation by varicose serotonin fibers was found in the stratum lacunosum-moleculare, but a few serotonin fibers were also distributed in the stratum lucidum of the CA2 and CA3 fields. The stratum pyramidale and the granule cell layer of the dentate gyrus contained a small number of serotonin fibers. The concentration and the direction of serotonin fibers were different in each area of each animal. Two peculiar observations should be stressed: (1) in the rat, the strata oriens and radiatum of CA2 and CA3 as well as the stratum lacunosum-moleculare displayed abundant serotonin fibers; (2) in the dog, abundant serotonin fibers were diffusely distributed in the CA1 field except for the stratum pyramidale and the most dense concentratioi > of serotonin fibers was seen in the stratum oriens of CA3.The present study provides a morphological basis for further study of the functional significance of serotonin in the limbic system.

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The effect of the new substituted benzimidizole proton pump inhibitor, lansoprazole, on pharmacokinetics and metabolism of theophylline has been studied in healthy adults given oral lansoprazole 30 mg once daily for 11 days. On Days 4 and 11 of 300 mg aminophylline was simultaneously administered orally and blood samples for theophylline analysis were taken over 24 h. Urine samples were collected for up to 24 h and were assayed for theophylline and its major metabolites 1,3-dimethyluric acid (1,3-DMU), 1-methyluric acid (1-MU) and 3-methylxanthine (3-MX). The pharmacokinetic parameters of theophylline were determined, and the urinary recovery of unchanged theophylline and its major metabolites were calculated. After administration of lansoprazole for 4 days, no significant alteration in the terminal elimination half-life (t1/2beta) or the mean resistance time (MRT) was detected. However, there was a significant decrease of about 13% in the area under the plasma concentration-time curve (AUC) and a significant increase of about 19% in the apparent clearance (CLapp). Lansoprazole treatment for 11 days caused a significant decrease of approximately 12% in t1/2beta and about 10% in the MRT of theophylline, although neither AUC nor CLapp showed a significant alteration. The excretion of 3-MX in the urine was significantly increased by about 20% after lansoprazole treatment for 4 and 11 days, although there was no significant alteration in the excretion of unchanged theophylline, 1,3-DMU or 1-MU. The results indicate that repeated administration of lansoprazole to humans induces the hepatic microsomal P-450-dependent drug oxidation system that mediates N-1-demethylation of theophylline, consequently increasing its metabolism.

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