Relationship between brain serotonin transporter binding, plasma concentration and behavioural effect of selective serotonin reuptake inhibitors.

1. The present study was undertaken to characterise the relationship between in vivo brain serotonin transporter (SERT) binding, plasma concentration and pharmacological effect of selective serotonin reuptake inhibitors (SSRIs) in mice. Oral administration of fluvoxamine, fluoxetine, paroxetine and sertraline at pharmacologically relevant doses exerted dose- and time-dependent binding activity of brain SERT as revealed by significant increases in KD for specific [3H]paroxetine binding, and the in vivo SERT-binding potency was in the order of paroxetine>>fluoxetine, sertraline>fluvoxamine. 2. The time courses of brain SERT binding by SSRIs in mice were mostly in parallel to those of their plasma concentrations. Also, norfluoxetine (active metabolite) has been suggested to contribute largely to the long-lasting binding activity of brain SERT after the fluoxetine administration. 3. Oral administration of each SSRI suppressed significantly the marble-burying behaviour with no change in locomotor activity in mice, and the extent and time course of suppression agreed well with those of brain SERT binding. Thus, the pharmacological potencies of SSRIs in the attenuation of marble-burying behaviour correlated significantly with their brain SERT binding activities. 4. In conclusion, the present study has provided the first in vivo evidences to support that fluvoxamine, fluoxetine, paroxetine and sertraline orally administered bind to the pharmacologically relevant brain SERT in mice and that their SERT-binding characteristics is closely associated with the pharmacokinetics and inhibition of marble-burying behaviour.