We studied the influence of olfactory bulbectomy in rats on three different parameters of serotonin (5-HT) presynapses, 5-HT transporter density, tryptophan hydroxylase apoenzyme concentration, and the levels of 5-HT and 5-hydroxyindole acetic acid (5-HIAA) in various brain regions. Compared with sham-operated controls, the Bmax values of [3H]paroxetine binding, the apoenzyme concentration of tryptophan hydroxylase and the level of 5-HIAA, and, therefore, the 5-HIAA/5-HT ratio were significantly and selectively increased in the frontal cortex of bulbectomized rats, measured 12 weeks after surgery. The most likely explanation of the concomitant increase in levels of all three markers of 5-HT presynapses in the frontal cortex is an increased density of 5-HT innervation in this remote projection field of the raphe nuclei. It is suggested that the bulbectomy-associated axotomy of 5-HT fibers projecting to the bulb stimulates collateral sprouting and synaptogenesis, especially in the frontal cortex. The resulting 5-HT hyperinnervation must be expected to alter global neuronal activity in this region and to impair the balance of information flow between this and other brain regions, resulting in a multitude of secondary behavioral and neurochemical changes. The frontocortical abnormalities observed by brain imaging studies in the brains of depressed patients may also be explained by a selective 5-HT hyperinnervation of this brain region.