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Mechanisms of platelet inhibition by the selective serotonin reuptake inhibitor citalopram 10.17863/CAM.22708 Roweth, Harvey George Jarvis, Gavin Sage, Stewart Background: Selective serotonin reuptake inhibitor (SSRI) antidepressants prevent serotonin (5-HT) uptake by the serotonin transporter (SERT). Since blood platelets express SERT, SSRIs may modify platelet function and the risk of cardiovascular disease. However, the beneficial or adverse effects of SSRIs on arterial thrombosis are poorly characterised and detailed in vitro experimental data is limited. The SSRI citalopram is a racemate, the (S)-isomer being the more potent SERT inhibitor. Although citalopram has been shown to inhibit platelets in vitro, it is unclear whether this is mediated via SERT blockade. Aim: To determine if citalopram inhibits platelet function via SERT blockade, or through a novel mechanism of action. Findings: 5-HT uptake into platelets was blocked by both citalopram isomers at concentrations that had no apparent effect on platelet function. Despite the (S)-citalopram isomer being the more potent SERT inhibitor, (R)-citalopram was equally potent at inhibiting other platelet functions. These findings strongly suggest that inhibition of platelet function by citalopram in vitro is not mediated by blocking SERT. Subsequent experiments identified two putative mechanisms for citalopram-mediated platelet inhibition: 1) citalopram did not inhibit calcium store release induced by the platelet agonist U46619, despite blocking subsequent Rap1 activation. A credible target for this inhibitory mechanism is the calcium and diacylglycerol guanine nucleotide exchange factor-1 (CalDAG-GEFI): 2) citalopram suppressed early protein phosphorylation within the GPVI pathway, resulting in the inhibition of subsequent platelet responses. Further experiments show that other commonly used antidepressants also inhibit platelets. As with citalopram, inhibition was only observed at concentrations above those required to block SERT, suggesting that alternative inhibitory mechanism(s) are responsible. Conclusions: Data presented in this thesis support two novel putative mechanisms of citalopram-induced platelet inhibition. These findings demonstrate that citalopram and other antidepressants inhibit platelets independently of their ability to block SERT-dependent 5-HT transport. The identification of thesemechanisms provides a pharmacological approach to develop novel antiplatelet agents based on current antidepressants. University of Cambridge 2018-05-19 Thesis Doctoral Doctor of Philosophy (PhD) en British Heart Foundation (FS/13/63/30437) (£113,200 - total direct costs for current funding cycle beginning in 2014) https://www.repository.cam.ac.uk/handle/1810/275477 https://www.repository.cam.ac.uk/bitstreams/f1af3c12-e527-4f14-8010-2cb4959b122c/download 87eda9de84448d1f82354d60eee3eb5f https://www.repository.cam.ac.uk/bitstreams/29de5842-3474-4e81-9852-2f1dfe73af3d/download 2456af66fd5de84c5c28866d17aca461 https://www.rioxx.net/licenses/all-rights-reserved/ Platelet Citalopram Selective serotonin reuptake inhibitor CalDAG-GEFI GPVI Aggregation Rap1 Calcium Serotonin Serotonin transporter Neutrophil Thrombosis