Ovarian steroid regulation of 5-HT_1A receptor binding and G protein activation in female monkeys

Serotonin 5-HT_1A receptors play an important role in serotonin neurotransmission and mental health. We previously demonstrated that estradiol (E) and progesterone (P) decrease 5-HT_1A autoreceptor mRNA levels in macaques. In this study, we questioned whether E and P regulate 5-HT_1A binding and function and G_α subunit protein expression. Quantitative autoradiography for 5-HT_1A receptors and G proteins using [³H]8-OH-DPAT and [³⁵S]GTP-γ-S, respectively, was performed on brain sections of rhesus macaques from four treatment groups: ovariectomized controls (OVX), E (28 d), P (28 d), and E (28 d) plus P (the last 14 d) treated. Western blot analysis for G_α subunits was performed on raphe extracts from cynomolgus macaques that were OVX or OVX treated with equine estrogens (EE, 30 months). In the hypothalamus, E or E + P but not P alone decreased postsynaptic 5-HT_1A binding sites. In the dorsal raphe nucleus (DRN), E, P, and E + P treatments decreased 5-HT_1A autoreceptor binding. The Kd values for 8-OH-DPAT were the same for each treatment group. Both the basal and the R-(+)-8-OH-DPAT stimulated [³⁵S]GTP-γ-S binding were decreased during hormone replacement whereas the coupling efficiency between the receptor and G proteins was maintained. Finally, EE treatment reduced the level of G_αi3, but not G_αi1, G_αo, and G_αz in the DRN. In conclusion, these observations suggest that ovarian hormones may increase serotonin neurotransmission, in part, by decreasing 5-HT_1A autoreceptors, 5-HT_1A postsynaptic receptors, and the inhibitory G proteins for intracellular signal transduction.