Physiological effects of SSRI administration: Negative feedback control of serotonin production and release

Serotonin (5-HT) is a neuromodulator with important roles in the regulation of physiological processes, particularly those regulating affect in humans. Drugs which selectively potentiate serotonergic neurotransmission by inhibiting the reuptake of serotonin (SSRIs) are widely used for the treatment of psychiatric disorders. It is thought that the therapeutic efficacy of SSRIs is limited by homeostatic mechanisms which counteract the ability of the drug to potentiate serotonergic neurotransmission. Here, I describe my work on two such mechanisms. First, I describe a role for 5-HT 2C receptors in counteracting the physiological and behavioral effect of SSRIs. In serotonin 2C receptor null mutant mice, extracellular 5-HT was unaltered at baseline. Upon administration of the SSRI fluoxetine, extracellular 5-HT rapidly increased in both wild-type and null mutant mice; this effect was potentiated in mutant mice. Furthermore, mutant mice had a greater response to fluoxetine in a behavioral assay for antidepressant effect. Pharmacological blockade of 5-HT 2C receptors also potentiated the effects of fluoxetine and another SSRI, citalopram, in wild-type mice and rats. In a second line of investigation, we investigated the effects of chronic citalopram treatment on 5-HT synthesis, which is an important factor in the clinical effects of SSRIs. Administration of citalopram for 2 days, 14 days or 28 days suppressed 5-HT synthesis. 5-HT content was not significantly reduced by citalopram at any time point. However, chronic citalopram did cause a significant reduction in forebrain 5-HT content when monoamine synthesis was completely inhibited by acute administration of an amino acid decarboxylase inhibitor. 5-HIAA content was reduced in citalopram-treated brains at all time points. These results demonstrate a sustained suppression of serotonin synthesis by chronic citalopram administration and suggest that serotonergic neurons are particularly dependent on de novo synthesis of 5-HT when the reuptake of 5-HT is inhibited. In technical appendices I describe novel tools for the study of serotonin biology. Taken together, these studies improve our understanding of the physiological actions of SSRIs and suggest strategies for improving their efficacy.