Differential effects of ovarian steroids and raloxifene on serotonin 1A and 2C receptor protein expression in macaques

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Abstract
To further understand the role of ovarian hormones in the function of the serotonin neural system, we investigated the effects of estradiol (E), progesterone (P), and raloxifene on 5HT 1A and 2C receptor protein expression in the dorsal raphe region using Western blot analysis. Adult rhesus macaques (Macaca mulatta) were ovariectomized (Ovx) and implanted with Silastic capsules containing E or P. In the first paradigm, animals that had been Ovx for 6–16 months were treated for 1 month with E (E1) or E + P (EP1) and compared to animals that were untreated and Ovx for 5 months (n = 4 per group). In the second paradigm, comparisons were made between animals that were Ovx and untreated for 5 months, or Ovx and immediately implanted with Silastic capsules containing E or E + P for 5 months (E5, EP5), or administered raloxifene in the diet for 5 months (Ral5) (n = 4 per group). The dorsal raphe region was harvested, homogenized and a crude membrane fraction was obtained for examination of receptor proteins. In the first paradigm, 5HT1A receptor protein expression was significantly lower in E1 and EP1 treatment groups compared to the Ovx-control group (ANOVA P = 0.01; posthoc P < 0.03), but 5HT2C receptor expression was unaffected by 1 month of E or EP treatment. In the second paradigm, there was no difference in 5HT1A receptor expression between the Ovx-control group and the E5 group, but 5HT1A receptor expression was significantly suppressed in the EP5 group (ANOVA P = 0.04; posthoc P < 0.05). In addition, 5HT2C expression increased in the E5 treatment group relative to the Ovx-control group. Addition of P to the E5 regimen prevented the E5-induced increase in 5HT2C receptor expression and significantly reduced 5HT2C receptor expression to a level below that observed in the Ovx-control group (ANOVA P = 0.001; posthoc P < 0.05). Thus, 5HT1A receptor may lose sensitivity to the suppressive effect of E after 5 months, whereas the 5HT2C receptor increases. However, addition of P in the EP5 regimen maintains the regulatory effects observed with 1 month of treatment. 5HT1A receptor protein levels were higher with raloxifene treatment than in Ovx-control animals (P < 0.01), suggesting that raloxifene may antagonize residual E in Ovx animals.