Role of the serotonin transporter and the 5-HT2A and 5-HT4 receptors for platelet function in blood

The field of serotonin (5-HT) research continues to expand. A
variety of physiological and pathophysiological functions regulated
by 5-HT has been identified. Selective serotonin reuptake
inhibitors (SSRIs) and 5-HT-3-receptor antagonists are used in
medical therapy, and more 5-HT-related medicaments are expected in
the future. Circulating 5-HT is stored mainly in the dense granules
of platelets. 5-HT stimulates platelets, which has been observed,
apart from humans, in various other species. Therefore, the
stimulatory effect of exogenous 5-HT in high concentrations (>
0.5 μM) on human platelets in blood is unambiguous. However,
results of the platelet-stimulating effect of the endogenous 5-HT,
which is stored in dense granules and released upon platelet
activation, are contradictory. The aim of this thesis was to
investigate the acute effect of SSRIs on human platelet
aggregation, the role of the 5-HT2A receptor for platelet function
in human blood, and the role of the newly discovered 5-HT4 receptor
for platelet function. In some—but not all—clinical studies, SSRIs
on the one hand have been suspected to cause bleeding
complications, on the other hand they may protect against ischemic
cardiovascular diseases. In our studies, the acute addition of the
SSRI fluoxetine to blood, alone or in combination with aspirin,
indeed inhibited the potentiation of platelet aggregation by
exogenous 5-HT (probably by unspecific inhibition of 5-HT2A
receptors), the platelet aggregation induced by physiological
stimuli was, however, not affected. Therefore, we conclude that the
serotonin transporter is not involved in the physiological platelet
aggregation process. Yet, SSRIs could cause bleeding complications
by reducing the platelet 5-HT content, consequently leading to a
reduced 5-HT-mediated vasoconstriction, or contribute to stomach
ulcers by disruption of the 5-HT-mediated wound healing. Our
results indicate that 5-HT2A receptors mediate the potentiation of
aggregation of human platelets in the blood by exogenous 5-HT.
However, 5-HT2A receptor antagonists do not inhibit platelet
activation by physiological stimuli, shear stress, or flow over
atherosclerotic plaque material. Therefore, endogenous 5-HT, which
is released upon platelet activation, plays no role in human
platelet aggregation. Finally, our studies support the expression
of platelet-inhibiting 5-HT4 receptors. However, these played only
a minor role in the regulation of human platelet aggregation
induced by epinephrine. The question why platelet 5-HT plays a role
in platelet aggregation of mice, rats, cats, rabbits, and dogs, but
not of men, is intriguing, but has no explanation according to our
present knowledge. Species-specific structural differences of the
5-HT2A receptors are suggested. Based on the current knowledge and
our experiments, it can be concluded that human platelet function
is not influenced by endogenous 5-HT, but platelets are important
for transporting 5-HT in the blood to diseased organs and tissues.
The absence of a stimulating action of endogenous 5-HT on platelets
precludes the use of 5-HT2A receptor antagonists as anti-thrombotic
medications.