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

• Published in: The Journal of pharmacology and experimental therapeutics 2004-06, Vol.309 (3), p.1043-1050
• Main Authors: Damjanoska, K J, Heidenreich, B A, Kindel, G H, D'Souza, D N, Zhang, Y, Garcia, F, Battaglia, G, Wolf, W A, Van de Kar, L D, Muma, N A
• Format: Article
• Language: English
• Subjects: Amphetamines - pharmacology; Animals; Body Weight - drug effects; Hypothalamus - drug effects; Hypothalamus - metabolism; Male; Paraventricular Hypothalamic Nucleus - drug effects; Paraventricular Hypothalamic Nucleus - metabolism; Prefrontal Cortex - drug effects; Prefrontal Cortex - metabolism; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A - metabolism; Serotonin Receptor Agonists - pharmacology; Signal Transduction - drug effects; Type C Phospholipases - metabolism
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.103.062067

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 G α11 , regulator of G protein signaling (RGS)4, or RGS7 proteins in the frontal cortex, whereas G αq 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 αq or G α11 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 α proteins or RGS proteins.