RT Journal Article
SR Electronic
T1 Agonist-Induced Serotonin 2A Receptor Desensitization in the Rat Frontal Cortex and Hypothalamus
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1043
OP 1050
DO 10.1124/jpet.103.062067
VO 309
IS 3
A1 K. J. Damjanoska
A1 B. A. Heidenreich
A1 G. H. Kindel
A1 D. N. D'Souza
A1 Y. Zhang
A1 F. Garcia
A1 G. Battaglia
A1 W. A. Wolf
A1 L. D. Van de Kar
A1 N. A. Muma
YR 2004
UL http://jpet.aspetjournals.org/content/309/3/1043.abstract
AB 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-HT2A/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 Gα11, regulator of G protein signaling (RGS)4, or RGS7 proteins in the frontal cortex, whereas Gαq protein levels in the frontal cortex decreased (47%) only after 7 daily (-)-DOI injections. The functional status of 5-HT2A receptors in the hypothalamic paraventricular nucleus was examined using 5-HT2A receptor-mediated increases in plasma hormone levels. Plasma adrenocorticotrophic hormone (ACTH) and oxytocin measurements showed that 5-HT2A 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 Gαq or Gα11 lamic paraventricular proteins in the hypothanucleus. In conclusion, these results suggest that chronically administered (-)-DOI induces desensitization of 5-HT2A receptors in vivo, via a reduction in the ability of 5-HT2A receptors to activate G proteins without consistently altering levels of Gα proteins or RGS proteins. The American Society for Pharmacology and Experimental Therapeutics