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

Abstract

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 (Ϫ)-1-(2,5-dimethoxy-4-iodophenyl)2-aminopropane HCl [(Ϫ)-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 (Ϫ)-DOI treatment without any significant changes in the guanosine 5Ј-3-O-(thio)triphosphate-mediated PLC enzyme activity. Additionally, treatment with (Ϫ)-DOI did not significantly change the levels of G ␣11 , 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 (Ϫ)-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 (Ϫ)-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 G ␣11 proteins in the hypothalamic paraventricular nucleus. In conclusion, these results suggest that chronically administered (Ϫ)-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.

Sustained treatment with a 5-HT2A receptor agonist causes functional desensitization and reductions in agonist-labeled 5-HT2A receptors despite increases in receptor protein levels in rats

“…This observation is consistent with previously published studies (Damjanoska et al, 2004). Sustained agonist treatment decreased DOI-mediated responses, but with the limited number of concentrations of DOI examined and since the dose-response curve did no plateau at the maximal dose of DOI used, we are not able to calculate the Emax and the ED 50 (potency).…”

“…Because down-regulation is one reported mechanism underlying receptor desensitization and in our previous study, we did not observe a decrease G αq and G α11 protein in the PVN (Damjanoska et al, 2004), we hypothesized that the levels of 5-HT 2A receptors in the membrane are reduced in response to sustained treatment with a 5-HT 2A receptor agonist. Surprisingly, we found that 4 or 7 days DOI treatment increased 5-HT 2A receptor protein levels.…”

“…Previous data from our laboratory demonstrated that sustained treatment with DOI produces a desensitization of 5-HT 2A receptor signaling in the PVN, as indicated by reduced levels of plasma oxytocin and adrenocorticotrophic hormone (ACTH) following a challenge injection of 1 mg/kg DOI (Damjanoska, et al, 2004). Interestingly, sustained agonist treatment in previous studies had shown reductions in agonist and antagonist binding to 5-HT 2A receptors (with greater reductions in agonist binding than antagonist binding) in the cortex (McKenna, et al, 1989).…”

Cocaine-mediated supersensitivity of 5-HT2A receptors in hypothalamic paraventricular nucleus is a withdrawal-induced phenomenon

“…It is well known that chronic treatment with agonists or antagonists of 5-HT 2A receptors typically produces desensitization of 5-HT 2A receptors (Roth et al, 1998;Gray and Roth, 2001;Hanley and Hensler, 2002;Damjanoska et al, 2004). In contrast, withdrawal from cocaine produces supersensitivity of 5-HT 2A receptors (Carrasco et al, 2003;Carrasco et al, 2004b).…”

“…These include: (1) increases in 5-HT 2A receptor-mediated neuroendocrine responses, suggesting supersensitivity of postsynaptic 5-HT 2A receptors in PVN (Levy et al, 1992;Baumann et al, 1993;Baumann and Rothman, 1998); and (2) increases in GÎ q and GÎ 11 G-proteins in the membrane fraction of PVN (Carrasco et al, 2003;Carrasco et al, 2004b). Since agonists and antagonists of 5-HT 2A receptors produces desensitization of 5-HT 2A receptors (Gray and Roth, 2001;Hanley and Hensler, 2002;Damjanoska et al, 2004), the increases in 5-HT 2A receptor signaling during withdrawal from cocaine represents a unique adaptive response of this system.…”