Estrogen treatment increases the levels of regulator of G protein signaling-Z1 in the hypothalamic paraventricular nucleus: Possible role in desensitization of 5-hydroxytryptamine_1A receptors

Desensitization of post-synaptic serotonin_1A (5-HT_1A) receptors may underlie the clinical improvement of neuropsychiatric disorders. In the hypothalamic paraventricular nucleus, Gα_z proteins mediate the 5-HT_1A receptor-stimulated increases in hormone release. Regulator of G protein signaling-Z1 (RGSZ1) is a GTPase-activating protein selective for Gα_z proteins. RGSZ1 regulates the duration of interaction between Gα_z proteins and effector systems. The present investigation determined the levels of RGSZ1 in the hypothalamic paraventricular nucleus of rats subjected to four different treatment protocols that produce desensitization of 5-HT_1A receptors. These protocols include: daily administration of β estradiol 3-benzoate (estradiol) for 2 days; daily administration of fluoxetine for 3 and 14 days; daily administration of cocaine for 7 or 14 days; and acute administration of (±)-1-(2,5 dimethoxy-4-iodophenyl)-2-amino-propane HCl (DOI; a 5-HT_2A/2C receptor agonist). Estradiol treatment was the only protocol that increased the levels of RGSZ1 protein in the hypothalamic paraventricular nucleus in a dose-dependent manner (46%-132% over control). Interestingly, previous experiments indicate that only estradiol produces a decreased Emax of 5-HT _1A receptor-stimulation of hormone release, whereas fluoxetine, cocaine and DOI produce a shift to the right (increased ED₅₀). Thus, the desensitization of 5-HT_1A receptors by estradiol might be attributable to increased levels of RGSZ1 protein. These findings may provide insight into the adaptation of 5-HT_1A receptor signaling during pharmacotherapies of mood disorders in women and the well-established gender differences in the vulnerability to depression.