Ovarian steroid regulation of 5-HT1A 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(alpha) subunit protein expression. Quantitative autoradiography for 5-HT(1A) receptors and G proteins using [3H]8-OH-DPAT and [35S]GTP-gamma-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(alpha) 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-gamma-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(alphai3), but not G(alphai1), G(alphao), and G(alphaz) 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.