The serotonergic system plays a key role in the modulation of olfactory processing. The present study examined the plastic response of this centrifugal system after unilateral naris occlusion, analysing both serotonergic afferents and receptors in the main olfactory bulb. After 60 days of sensory deprivation, the serotonergic system exhibited adaptive changes. Olfactory deprivation caused a general increase in the number of fibres immunopositive for serotonin but not of those immunopositive for the serotonin transporter. HPLC data revealed an increase in serotonin levels but not in those of its major metabolite, 5-hydroxyindole acetic acid, resulting in a decrease in the 5-hydroxyindole acetic acid/serotonin ratio. These changes were observed not only in the deprived but also in the contralateral olfactory bulb. Double serotonintyrosine hydroxylase immunolabelling revealed that the glomerular regions of the deprived olfactory bulb with a high serotonergic fibre density showed a strong reduction in tyrosine hydroxylase. Finally, the serotonin 2A receptor distribution density and the number of juxtaglomerular cells immunopositive for serotonin 2A receptor remained unaltered after olfactory deprivation. Environmental stimulation modulated the serotonergic afferents to the olfactory bulb. Our results indicate the presence of a bilateral accumulation of serotonin in the serotonergic axon network, with no changes in serotonin 2A receptor density after unilateral olfactory deprivation. Keywords: 5-hydroxyindole acetic acid, olfactory system, serotonin, serotonin receptor, serotonin transporter, unilateral deprivation. J. Neurochem. (2007) 100, 924-938. Afferent activity is needed for the development and maintenance of the normal structural and biochemical features of the olfactory system (Brunjes 1994). Dramatic alterations occur in the main olfactory bulbs (MOBs) ipsilateral to deprivation of rats and mice after occlusion of an external naris. Marked anatomical changes, including volume reduction, occur after deprivation from birth up to postnatal day (P)20. However, naris closure performed after P20 results in few anatomical changes (Brunjes 1994). One day of deprivation (from P1 to P2) causes the attenuation of electrophysiological and metabolic neural activities in the rat MOB (Korol and Brunjes 1990). Forty-five days of odour deprivation affects the maturation of newborn granule cells, causing a decrease in the complexity of their dendritic arborization and spine density (Saghatelyan et al. 2005). Some changes are dependent on a temporal window. Thus, volume reduction is not observed in the MOB after naris closure on P40, although down-regulation of activity has been clearly demonstrated using 2-deoxyglucose uptake analysis (Korol and Brunjes 1990). Finally, some changes