Changes in 5-HT1A receptor binding and G-protein activation in the rat brain after estrogen treatment: comparison with tamoxifen and raloxifene

Objective: It is thought that an imbalance in serotonergic neurotransmission may underlie many affective disorders. Thus, the serotonin-1A (5-HT 1A ) receptor is a target for antidepressant and neuroleptic drugs. It has been reported that estrogens modulate serotonergic neurotransmission. Therefore, we investigated the effect of long-term ovariectomy on 5-HT 1A receptor–specific binding and G-protein activation in the brain. Correction therapy with estradiol was compared with treatments using the selective estrogen receptor modulators tamoxifen and raloxifene. Methods: Four months after ovariectomy, Sprague–Dawley rats were treated with vehicle, 17β-estradiol (80 μg/kg), tamoxifen (1 mg/kg) or raloxifene (1 mg/kg) subcutaneously for 2 weeks. Specific binding to 5-HT 1A receptors was assessed by autoradiography of brain sections using the 5-HT 1A agonist [ 3 H]8-OH-DPAT. 5-HT 1A receptor stimulation was measured using R-(+)-8-OH-DPAT-stimulated [ 35 S]GTPγS-binding autoradiography. Results: Ovariectomy decreased uterine weight, which was corrected by estradiol; tamoxifen and raloxifene partially corrected this decrease. Hormonal withdrawal and replacement left [ 3 H]8-OH-DPAT-specific binding unchanged in the cortex. In contrast, ovariectomy induced a decrease in R-(+)-8-OH-DPAT-stimulated [ 35 S]GTPγS-specific binding in the cortex; this was corrected by estradiol but was not corrected significantly by tamoxifen or raloxifene. In the hippocampus, ovariectomy had no effect on [ 3 H]8-OH-DPAT-specific binding, whereas only 17β-estradiol treatment decreased this binding in a subregion of the CA3. Ovariectomy increased R-(+)-8-OH-DPAT-stimulated [ 35 S]GTPγS-specific binding in the dentate gyrus (but not in the CA1 or CA3); this was corrected by estradiol and raloxifene, but not by tamoxifen. In the dorsal raphe nucleus, ovariectomy increased [ 3 H]8-OH-DPAT-specific binding and R-(+)-8-OH-DPAT-stimulated [ 35 S]GTPγS-specific binding; estradiol corrected this increase, but this was not corrected significantly by tamoxifen or raloxifene. Conclusions: An overall stimulation by estradiol of 5-HT 1A receptor–specific binding and coupling was observed, decreasing raphe somatodendritic receptors and increasing cortical postsynaptic receptors.