Estradiol–sertraline synergy in ovariectomized rats

SummaryThis study investigated estradiol (E2) modulation of the antidepressant effects of a selective serotonin (5-HT) reuptake inhibitor (SSRI; sertraline) and a tricyclic antidepressant (imipramine) as measured by the forced swim test (FST) followed by assessment of gene and protein expression for the 5-HT transporter (SERT) and multiple 5-HT receptors. Female Sprague–Dawley rats were ovariectomized (OVX) and two-thirds of the rats received E2 implants (OVE). 4 weeks later, implants were withdrawn in half of the OVE rats (OVW) to capture a time point when E2 levels were rapidly declining. Rats in each hormone group were treated with vehicle, sertraline (10 mg/kg) or imipramine (10 mg/kg), 24, 5 and 1 h before the FST. Immediately after the FST, midbrain, hippocampus and prefrontal cortex tissue was removed and frozen for analysis of gene expression via quantitative real-time PCR (midbrain tissue) and protein expression via Western blot (prefrontal cortex and hippocampal tissue). In the FST, sertraline decreased immobility and increased swimming in OVE rats, as well as increased swimming in OVW rats. In contrast, no sertraline effect was observed in OVX rats. Rats treated with imipramine showed increased climbing but no changes in immobility or swimming. No changes in protein expression were detected in any treatment group. However, in vehicle-treated rats, E2 increased midbrain SERT mRNA expression, with no effect on midbrain mRNA for the 5-HT receptors. In sertraline-treated rats, E2 decreased 5-HT2A receptor mRNA, and E2-withdrawal increased 5-HT1A, 5-HT2A and 5-HT2C receptor mRNA. In imipramine-treated rats, E2 (and E2-withdrawal) did not affect mRNA expression for any of the target genes. Thus, E2 synergized behaviorally and neurochemically with an SSRI but not a tricyclic antidepressant.