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NEUROPHARMACOLOGY

Agonist-Induced Serotonin 2A Receptor Desensitization in the Rat Frontal Cortex and Hypothalamus

Center for Serotonin Disorders Research and Department of Pharmacology and Experimental Therapeutics, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois (K.J.D., B.A.H., G.H.K., D.N.D., Y.Z., F.G., G.B., W.A.W., L.D.V.d.K., N.A.M.); and Biological Psychiatry and Research Services, Edward Hines Veterans Administration Medical Center, Hines, Illinois (W.A.W.)

This study examined the time course and possible mechanisms of agonist-induced desensitization of 5-hydroxytryptamine serotonin 2A receptors in the rat frontal cortex and hypothalamic paraventricular nucleus after 1, 4, and 7 days of treatment with (-)-1-(2,5-dimethoxy-4-iodophenyl)2-aminopropane HCl [(-)-DOI] (1 mg/kg i.p.), a selective 5-HT_2A/2C receptor agonist. In the frontal cortex, 5-HT-mediated phospholipase C (PLC) enzyme activity decreased by 24 to 30% after 4 to 7 days of (-)-DOI treatment without any significant changes in the guanosine 5'-3-O-(thio)triphosphate-mediated PLC enzyme activity. Additionally, treatment with (-)-DOI did not significantly change the levels of G₁₁, regulator of G protein signaling (RGS)4, or RGS7 proteins in the frontal cortex, whereas G_q protein levels in the frontal cortex decreased (47%) only after 7 daily (-)-DOI injections. The functional status of 5-HT_2A receptors in the hypothalamic paraventricular nucleus was examined using 5-HT_2A receptor-mediated increases in plasma hormone levels. Plasma adrenocorticotrophic hormone (ACTH) and oxytocin measurements showed that 5-HT_2A receptor desensitization began after only 1 day of (-)-DOI treatment, and the desensitization continued to increase after 4 and 7 days of treatment (ACTH response decreased 64.2–67.7%; oxytocin response decreased 82.3–90.1%). There were no significant alterations in levels of G_q or G₁₁ lamic paraventricular proteins in the hypothanucleus. In conclusion, these results suggest that chronically administered (-)-DOI induces desensitization of 5-HT_2A receptors in vivo, via a reduction in the ability of 5-HT_2A receptors to activate G proteins without consistently altering levels of G proteins or RGS proteins.

Address correspondence to: Dr. Nancy A. Muma, Department of Pharmacology, Loyola University Chicago, Stritch School of Medicine, 2160 South First Ave., Maywood, IL 60153. E-mail: nmuma{at}lumc.edu

This article has been cited by other articles:

				J. Shi, K. J. Damjanoska, R. K. Singh, G. A. Carrasco, F. Garcia, A. J. Grippo, M. Landry, N. R. Sullivan, G. Battaglia, and N. A. Muma Agonist Induced-Phosphorylation of G{alpha}11 Protein Reduces Coupling to 5-HT2A Receptors J. Pharmacol. Exp. Ther., October 1, 2007; 323(1): 248 - 256. [Abstract] [Full Text] [PDF]

				J. Shi, B. Zemaitaitis, and N. A. Muma Phosphorylation of G{alpha}11 Protein Contributes to Agonist-Induced Desensitization of 5-HT2A Receptor Signaling Mol. Pharmacol., January 1, 2007; 71(1): 303 - 313. [Abstract] [Full Text] [PDF]