PT - JOURNAL ARTICLE AU - Yahong Zhang AU - Deborah D'Souza AU - Danı́ K. Raap AU - Francisca Garcia AU - George Battaglia AU - Nancy A. Muma AU - Louis D. Van de Kar TI - Characterization of the Functional Heterologous Desensitization of Hypothalamic 5-HT<sub>1A</sub> Receptors after 5-HT<sub>2A</sub>Receptor Activation AID - 10.1523/JNEUROSCI.21-20-07919.2001 DP - 2001 Oct 15 TA - The Journal of Neuroscience PG - 7919--7927 VI - 21 IP - 20 4099 - http://www.jneurosci.org/content/21/20/7919.short 4100 - http://www.jneurosci.org/content/21/20/7919.full SO - J. Neurosci.2001 Oct 15; 21 AB - Desensitization of 5-HT1A receptors could be involved in the long-term therapeutic effect of anxiolytic and antidepressant drugs. Pretreatment of rats with the 5-HT2A/2C agonist DOI induces an attenuation of hypothalamic 5-HT1Areceptor–Gz-protein signaling, measured as the ACTH and oxytocin responses to an injection of the 5-HT1A agonist 8-OH-DPAT. We characterized this functional heterologous desensitization of 5-HT1A 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 (Emax). The 5-HT2A receptor antagonist MDL 100,907 prevented the DOI-induced desensitization, indicating that 5-HT2Areceptors mediate the effect of DOI. Analysis of the components of the 5-HT1A receptor–Gz-protein signaling system showed that DOI did not alter the level of membrane-associated Gz-proteins in the hypothalamus. Additionally, DOI did not alter the binding of [3H]8-OH-DPAT or the inhibition by GTPγS of [3H]8-OH-DPAT binding in the hypothalamus. In conclusion, the activation of 5-HT2Areceptors induces a transient functional desensitization of 5-HT1A receptor signaling in the hypothalamus, which may occur distal to the 5-HT1A receptor–Gz-protein interface.