Effects of serotonin and serotonergic agonists and antagonists on the production of interferon-gamma and interleukin-10

Serotonin (5-HT) is a neurotransmitter and an immune modulator. In vitro, a ntidepressants with a serotonergic mode of action have, at concentrations w ithin the therapeutical range, negative immunoregulatory effects, i.e., the y increase the production rate of interleukin-10 (IL-10), a negative immuno regulatory cytokine. We have hypothesized that part of these effects may by explained by the serotonergic activities of antidepressants on immunocytes . This study was carried out to examine the effects of 5-HT, p-chlorophenyl alanine (PCPA), a 5-HT depleting agent, flesinoxan (a 5-HT1A agonist), m-ch lorophenylpiperazine (mCPP; a 5-HT2A/2C agonist), and ritanserin (a 5-HT2A/ 2C antagonist) on the production rate of interferon-gamma (IFN gamma), a pr oinflammatory cytokine, and IL-10 by whole blood stimulated with polyclonal activators. The IFN gamma/IL-10 production ratio was computed since this r atio reflects the pro- versus anti-inflammatory capacity of cultured whole blood. We found that: 1) 5-HT, 150 ng/mL, 1.5 mu g/mL, and 15 mu g/mL signi ficantly decreased the IFN gamma/IL-10 ratio; 2) PCPA (5 mu M) significantl y suppressed the production of IFN gamma and IL-10; 3) flesinoxan (15 ng/mL ; 1.5 mu g/mL) had no significant effects on the production of the above cy tokines; and 4) mCPP (2.7 mu g/mL) and ritanserin (5.0 mu g/mL) suppressed the IFN gamma/IL-10 ratio. It is concluded that intracellular 5-HT may be n ecessary for an optimal synthesis of IFN gamma and IL-10, and that extracel lular 5-HT concentrations at or above serum values may suppress the product ion of the proinflammatory cytokine IFN gamma. The negative immunoregulator y effects of antidepressive drugs are probably not related to their seroton ergic activities. [Neuropsychopharmacology 23:89-98, 2000] (C) 2000 America n College of Neuropsychopharmacology. Published by Elsevier Science Inc. Al l rights reserved.