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-HT1A) 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-HT1A 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, 17beta-estradiol (80 microg/kg), tamoxifen (1 mg/kg) or raloxifene (1 mg/kg) subcutaneously for 2 weeks. Specific binding to 5-HT1A receptors was assessed by autoradiography of brain sections using the 5-HT1A agonist [3H]8-OH-DPAT. 5-HT1A receptor stimulation was measured using R-(+)-8-OH-DPAT-stimulated [35S]GTPgammaS-binding autoradiography.

Results: Ovariectomy decreased uterine weight, which was corrected by estradiol; tamoxifen and raloxifene partially corrected this decrease. Hormonal withdrawal and replacement left [3H]8-OH-DPAT-specific binding unchanged in the cortex. In contrast, ovariectomy induced a decrease in R-(+)-8-OH-DPAT-stimulated [35S]GTPgammaS-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 [3H]8-OH-DPAT-specific binding, whereas only 17beta-estradiol treatment decreased this binding in a subregion of the CA3. Ovariectomy increased R-(+)-8-OH-DPAT-stimulated [35S]GTPgammaS-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 [3H]8-OH-DPAT-specific binding and R-(+)-8-OH-DPAT-stimulated [35S]GTPgammaS-specific binding; estradiol corrected this increase, but this was not corrected significantly by tamoxifen or raloxifene.

Conclusions: An overall stimulation by estradiol of 5-HT1A receptor-specific binding and coupling was observed, decreasing raphe somatodendritic receptors and increasing cortical postsynaptic receptors.