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The Journal of Neuroscience, October 15, 2001, 21(20):7919-7927

Characterization of the Functional Heterologous Desensitization of Hypothalamic 5-HT_1A Receptors after 5-HT_2A Receptor Activation

Yahong Zhang, Deborah D'Souza, Daní K. Raap, Francisca Garcia, George Battaglia, Nancy A. Muma, and Louis D. Van de Kar

Center for Serotonin Disorder Research and Department of Pharmacology, Loyola University of Chicago, Stritch School of Medicine, Maywood, Illinois 60153

Desensitization of 5-HT_1A receptors could be involved in the long-term therapeutic effect of anxiolytic and antidepressant drugs. Pretreatment of rats with the 5-HT_2A/2C agonist DOI induces an attenuation of hypothalamic 5-HT_1A receptor-G_z-protein signaling, measured as the ACTH and oxytocin responses to an injection of the 5-HT_1A agonist 8-OH-DPAT. We characterized this functional heterologous desensitization of 5-HT_1A receptors in rats and examined some of the mechanisms that are involved. A time course experiment revealed that DOI produces a delayed and reversible reduction of the ACTH and oxytocin responses to an 8-OH-DPAT challenge. The maximal desensitization occurred at 2 hr, and it disappeared 24 hr after DOI injection. The desensitization was dose-dependent, and it shifted the oxytocin and ACTH dose-response curves of 8-OH-DPAT to the right (increased ED₅₀) with no change in their maximal responses (E_max). The 5-HT_2A receptor antagonist MDL 100,907 prevented the DOI-induced desensitization, indicating that 5-HT_2A receptors mediate the effect of DOI. Analysis of the components of the 5-HT_1A receptor-G_z-protein signaling system showed that DOI did not alter the level of membrane-associated G_z-proteins in the hypothalamus. Additionally, DOI did not alter the binding of [³H]8-OH-DPAT or the inhibition by GTPS of [³H]8-OH-DPAT binding in the hypothalamus. In conclusion, the activation of 5-HT_2A receptors induces a transient functional desensitization of 5-HT_1A receptor signaling in the hypothalamus, which may occur distal to the 5-HT_1A receptor-G_z-protein interface.

Key words: neuroendocrine; serotonin; oxytocin; ACTH; G_z-protein; [³H]8-OH-DPAT binding; GTPS

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21207919-09$05.00/0

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