Abstract
BackgroundSerotonin (5-HT) is a neurotransmitter with important roles in the regulation of neurobehavioral processes, particularly those regulating affect in humans. Drugs that potentiate serotonergic neurotransmission by selectively inhibiting the reuptake of serotonin (SSRIs) are widely used for the treatment of psychiatric disorders. Although the regulation of serotonin synthesis may be an factor in SSRI efficacy, the effect of chronic SSRI administration on 5-HT synthesis is not well understood. Here, we describe effects of chronic administration of the SSRI citalopram (CIT) on 5-HT synthesis and content in the mouse forebrain.Methodology/Principal FindingsCitalopram was administered continuously to adult male C57BL/6J mice via osmotic minipump for 2 days, 14 days or 28 days. Plasma citalopram levels were found to be within the clinical range. 5-HT synthesis was assessed using the decarboxylase inhibition method. Citalopram administration caused a suppression of 5-HT synthesis at all time points. CIT treatment also caused a reduction in forebrain 5-HIAA content. Following chronic CIT treatment, forebrain 5-HT stores were more sensitive to the depleting effects of acute decarboxylase inhibition.Conclusions/SignificanceTaken together, these results demonstrate that chronic citalopram administration causes a sustained suppression of serotonin synthesis in the mouse forebrain. Furthermore, our results indicate that chronic 5-HT reuptake inhibition renders 5-HT brain stores more sensitive to alterations in serotonin synthesis. These results suggest that the regulation of 5-HT synthesis warrants consideration in efforts to develop novel antidepressant strategies.
Highlights
Depression is a devastating illness and one of the major causes of disability in the world, affecting over 120 million people [1,2]
We demonstrate that chronic treatment with citalopram, a widely prescribed and highly selective serotonin transporter (SERT) inhibitor [3,26], causes a suppression of 5-HT synthesis in the mouse brain
We cannot infer, based on our results, what effect CIT may have on 5-HT synthesis in specific forebrain nuclei or in brain regions not analyzed, such as the raphe nuclei
Summary
Depression is a devastating illness and one of the major causes of disability in the world, affecting over 120 million people [1,2]. The primary pharmacological activity of SSRIs is inhibition of the serotonin transporter (SERT) (P31645.1, UniProtKB/Swiss-Prot), which is responsible for the reuptake of serotonin (5-HT) from the extracellular space back into the nerve terminals that release it [6,7]. Inhibition of this transport alters the spatiotemporal dynamics of serotonin signaling such that activity in the serotonergic neuron causes greater and more prolonged increases in extracellular serotonin than would normally occur [8,9,10,11,12]. We describe effects of chronic administration of the SSRI citalopram (CIT) on 5-HT synthesis and content in the mouse forebrain
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