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The role of serotonin (5-HT) and protein kinases in the regulation of the beta-receptor induced by typical and atypical antidepressants was investigated. Treatment with either mianserin or maprotiline for seven days produced a significant decrease in the beta-receptor density measured 6h after the last dose. The reduction in beta-receptors disappeared within 24h. However, combined treatment of mianserin or maprotiline with either fluoxetine or 5-hydroxytryptophan significantly decreased beta-receptors even 24h after the last dose. Following treatment with p-chlorophenylalanine the reduction in beta-receptors induced by desipramine was reversible within 24h. These results demonstrate that an increase in the synaptic 5-HT availability may contribute to the prolongation of the beta-receptor down-regulation by antidepressants. The intraventricular infusion of 12-0-tetradecanoyl-phorbol-13-acetate (TPA), a potent protein kinase C (PK-C) activator for seven days caused a significant decrease in beta-receptors, while forskolin or dibutyryl cyclic adenosine monophosphate had no influence on the receptor. The TPA-induced and desipramine-induced decreases in beta-receptors were not additive, suggesting that a similar mechanism is involved. The infusion of the PK-C inhibitor 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7) caused an inhibition of the desipramine-induced decrease in beta-receptors. It is suggested that the beta-receptor down-regulation by antidepressants might be also regulated by PK-C through 5-HT-Ca2+-inositol-phospholipid systems.

The role of serotonin (5-HT) in the regulation of the beta-receptor density induced by long-term treatment with typical and atypical antidepressants was examined. Treatment with either mianserin (15 mg/kg, twice daily) or maprotiline (10 mg/kg, twice daily) for 7 days caused a significant decrease in the beta-receptor density, measured 6 h after the last dose, without a change in affinity. The reduction in beta-receptors disappeared rapidly (within 24 h). However, treatment with mianserin or maprotiline combined with fluoxetine, a selective 5-HT uptake inhibitor, significantly decreased the beta-receptor density even 24 h after the last dose. The combined administration of mianserin and 5-hydroxytryptophan (5-HTP) mimicked the effect of the combination with fluoxetine. Following pretreatment with p-chlorophenylalanine (PCPA) for 6 days, desipramine treatment for 3 days significantly decreased the beta-receptors 6 h after the last dose but this desipramine-induced decrease in beta-receptors was rapidly reversible (within 24 h). These results demonstrate that while intrasynaptic 5-HT levels are not a factor in the decrease in beta-receptors, they do play an important role in the preservation of the down-regulated state of the beta-receptor caused by antidepressants from rapid reversibility.