Estradiol–sertraline synergy in ovariectomized rats

Sell, Stacy L.; Craft, Rebecca M.; Seitz, Patricia K.; Stutz, Sonja J.; Cunningham, Kathryn A.; Thomas, Mary L.

doi:10.1016/j.psyneuen.2008.05.006

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Volume 33, Issue 8 , Pages 1051-1060, September 2008

Estradiol–sertraline synergy in ovariectomized rats

Stacy L. Sell
- Center for Addiction Research, Department of Pharmacology & Toxicology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1031, United States
- Corresponding author. Present address: Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX 77555-0830, United States. Tel.: +1 409 747 0717; fax: +1 409 772 6348.
Rebecca M. Craft
- Department of Psychology, Washington State University, Pullman, WA 99164-4820, United States
Patricia K. Seitz
- Center for Addiction Research, Department of Pharmacology & Toxicology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1031, United States
Sonja J. Stutz
- Center for Addiction Research, Department of Pharmacology & Toxicology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1031, United States
Kathryn A. Cunningham
- Center for Addiction Research, Department of Pharmacology & Toxicology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1031, United States
- These authors contributed equally to this work.
Mary L. Thomas
- Center for Addiction Research, Department of Pharmacology & Toxicology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1031, United States
- These authors contributed equally to this work.
- Address: Department of Pharmacology, RUSM – Dominica, 499 Thornall St. 10th Floor, Edison, NJ 08837-2235, United States.

Received 30 January 2008; received in revised form 11 April 2008; accepted 9 May 2008.

Summary

This 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rats were ovariectomized (OVX) and two-thirds of the rats received E₂ implants (OVE). 4 weeks later, implants were withdrawn in half of the OVE rats (OVW) to capture a time point when E₂ levels were rapidly declining.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 (10mg/kg) or imipramine (10mg/kg), 24, 5 and 1h 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-HT_2A receptor mRNA, and E₂-withdrawal increased 5-HT_1A, 5-HT_2A and 5-HT_2C 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.