In vivo effect of antidepressants on [3H]paroxetine binding to serotonin transporters in rat brain.

Amine transporters are major target for development of various pharmacological agents to treat behavioral disorders. Serotonin transporters (SERT) have been implicated in the etiology of depression and drugs acting on SERT can be effective in treating depression. The aim of the present study was to study the in vivo effect of various antidepressants on [(3)H]paroxetine binding to SERT in regions of rat brain. Rats were treated with tricyclic antidepressant (TCAs) such as amitriptyline (AMI), serotonin/norepinephrine reuptake inhibitor (SNRIs) such as clomipramine (CMI), and selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (FLX) and citalopram (CIT) (10 mg/kg body wt.) for 30 days. Density of SERT was measured in cortex and hippocampus using [(3)H]paroxetine (0.03-1.0 nM) in presence and absence of 10 muM fluoxetine as displacer. It was observed that the density of cortical SERT was significantly decreased with CMI (68%, P < 0.0001), FLX (67%, P < 0.0001), CIT (54%, P < 0.0001), and AMI (52%, P < 0.0001) treatment, when compared to the density of 120.7 +/- 4.0 fmol/mg protein in control rats, without altering the affinity (Kd) of [(3)H]paroxetine to the transporters. The density of SERT in hippocampus was also significantly decreased with FLX (65%, P < 0.0001), CMI (54%, P < 0.0001), CIT (52%, P < 0.0001) and AMI (46%, P < 0.0001) treatment, when compared to the density of 74.0 +/- 2.6 fmol/mg protein in control rats, without altering the affinity of [(3)H]paroxetine to the transporters. Displacement study showed high affinity for CMI > CIT > FLX. The results suggest that chronic antidepressant treatment significantly down-regulates both cortical and hippocampal SERT in rat brain and SSRIs have high affinity for SERT than TCAs.