Desensitization of 5-HT2A receptor function by chronic administration of selective serotonin reuptake inhibitors.
We have previously shown that chronic treatment with selective serotonin reuptake inhibitors (SSRIs), fluvoxamine and paroxetine, attenuated m-chlorophenylpiperazine (mCPP)-induced hypolocomotion in rats. The effect of these SSRIs on the response to mCPP is thought to be caused by the desensitization of 5-HT2C receptor function. In the present study, we investigated whether chronic administration of SSRI could reduce another pharmacological response to mCPP in rats, i.e., the induction of the secretion of corticosterone. The mCPP-induced increase in the serum concentration of corticosterone was not blocked by the 5-HT2C antagonist SB242084, but was blocked by the 5-HT2A antagonist ketanserin. Chronic treatment with fluvoxamine and paroxetine attenuated the response to mCPP, while these SSRIs had no effects in control rats. These results suggest that the desensitization of 5-HT2A receptor function occurs in the same way as that of 5-HT2C receptor function through chronic treatment with either fluvoxamine or paroxetine as a consequence of prolonged exposure to elevated levels of serotonin. The hypersensitivity of 5-HT2A receptors is observed in depressed patients, and chronic treatment with many antidepressants such as tricyclic antidepressants have been reported to reduce 5-HT2A receptor density and/or efficacy. The desensitization of 5-HT2A receptor function might contribute to the therapeutic mechanism of action of these SSRIs, as seen with other classes of antidepressants.
Yamauchi
Miki
M
Pharmaceutical Research Department, Meiji Seika Kaisha, Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan.
Miyara
Takako
T
Matsushima
Tetsuya
T
Imanishi
Taiichiro
T
D000818:Animals; D003345:Corticosterone / Q000097:blood; D016666:Fluvoxamine / Q000494:pharmacology; D007650:Ketanserin / Q000494:pharmacology*; D017374:Paroxetine / Q000494:pharmacology; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects / Q000502:physiology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
D003345:Corticosterone; D016666:Fluvoxamine; D007650:Ketanserin; D017374:Paroxetine; D044402:Receptor, Serotonin, 5-HT2A; D017367:Selective Serotonin Reuptake Inhibitors