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The Journal of Neuroscience, May 1, 2000, 20(9):3095-3103

Evidence That G_z-Proteins Couple to Hypothalamic 5-HT_1A Receptors In Vivo

F. Serres, Q. Li, F. Garcia, D. K. Raap, G. Battaglia, N. A. Muma, and L. D. Van de Kar

Department of Pharmacology, Stritch School of Medicine, Loyola University of Chicago, Maywood, Illinois 60153

Using in situ hybridization and immunoblot analysis, the present studies identified G_z mRNA and G_z-protein in the hypothalamic paraventricular nucleus. The role of G_z-proteins in hypothalamic 5-HT_1A receptor signaling was examined in vivo. Activation of 5-HT_1A receptors increases the secretion of oxytocin and ACTH, but not prolactin. Intracerebroventricular infusion (3-4 d) of G_z antisense oligodeoxynucleotides, with different sequences and different phosphorothioate modification patterns, reduced the levels of G_z-protein in the hypothalamic paraventricular nucleus, whereas missense oligodeoxynucleotides had no effect. Neither antisense nor missense oligodeoxynucleotide treatment altered basal plasma levels of ACTH, oxytocin, or prolactin, when compared with untreated controls. An antisense-induced decrease in hypothalamic G_z-protein levels was paralleled by a significant decrease in the oxytocin and ACTH responses to the 5-HT_1A agonist 8-hydroxy-dipropylamino-tetralin (8-OH-DPAT). In contrast, the prolactin response to 8-OH-DPAT (which cannot be blocked by 5-HT_1A antagonists) was not inhibited by G_z antisense oligodeoxynucleotides. G_z-proteins are the only members of the G_i/G_o-protein family that are not inactivated by pertussis toxin. In a control experiment, pertussis toxin treatment (1µg/5 µl, i.c.v.; 48 hr before the 8-OH-DPAT challenge) did not inhibit the ACTH response, potentiated the oxytocin response, and eliminated the prolactin response to 8-OH-DPAT. Thus, pertussis toxin-sensitive G_i/G_o-proteins do not mediate the 5-HT_1A receptor-mediated increase in ACTH and oxytocin secretion. Combined, these studies provide the first in vivo evidence for a key role of G_z-proteins in coupling hypothalamic 5-HT_1A receptors to effector mechanisms.

Key words: serotonin; receptor; oxytocin; ACTH; prolactin; G-protein; signaling; signal transduction; hormones; neuroendocrine; hypothalamus; paraventricular

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Copyright © 2000 Society for Neuroscience  0270-6474/00/2093095-09$05.00/0

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