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Desensitization of post-synaptic serotonin(1A) (5-HT(1A)) receptors may underlie the clinical improvement of neuropsychiatric disorders. In the hypothalamic paraventricular nucleus, Galpha(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 Galpha(z) proteins. RGSZ1 regulates the duration of interaction between Galpha(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 beta 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-aminopropane 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 ED(50)). 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.

Comment: I included this study because it brings together the issues of estrogen, serotonin receptors, and gender differences in neurologic disorders, also raised in the Pringsheim and Gooren study above.—Stewart J. Tepper, MD