Serotonin receptor site in human platelets from control and chlorpromazine treated subjects.
Human platelets are activated by epinephrine (E), norepinephrine (NE), ADP, and serotonin (5-HT) by a process that can be measured as cellular aggregation and at the completion of which 5-HT is released from storage vesicles. Among the three neurotransmitters, only the 5-HT response at its maximum concentration is transient (reversible), and in a given platelet preparation can be produced only once. This effect is highly specific. Structural analogues of 5-HT, such as tryptolines (TLNs) or 5-methoxy-N,N dimethyltryptamine (5-MNDTA), with agonist properties in animal behavioral models, cannot induce a 5-HT-like response in the platelet system; however, they competitively inhibit the platelet aggregation response (PAR) to 5-HT if preincubated with the platelets. Inhibition constants of TLNs for 5-HT and E are of an order of magnitude higher than the KM values for aggregation. A transient '5-HT-like' PAR can be produced by compounds structurally unrelated to 5-HT, such as the following: a preparation of adenylylimidodiphosphate (AIP) can cause a transient PAR similar to the 5-HT response with a KM of 0.2-0.5 mM. Experimental evidence suggests that this ATP analogue is also an inhibitor of the second phase of aggregation (17) and release of dense vesicle content, thereby exhibiting only a monophasic and transient PAR. A '5-HT-like' PAR can also be produced by a combination of E and ATP at concentrations at which neither by itself causes aggregation. These transient PARs may serve as tools to investigate the underlying mechanism of the self-restricted yet exhaustible ability of platelets to respond to the aggregation inducer. Drug-free schizophrenic patients having their first psychotic episode have a transient 5-HT PAR indistinguishable from that of control subjects. However, after 2-3 weeks on chlorpromazine (CPZ) as the sole neuroleptic, the patients defined as schizophrenic could be divided into 2 sub-groups: a) those who developed an enhanced and irreversible PAR to 5-HT and were reported as good clinical responders; and b) those whose transient 5-HT PAR remained unchanged for 10-12 weeks and were reported as slow, poor or non-responders. The study of the mechanism of the enhanced 5-HT PAR in CPZ-treated patients may contribute to the understanding of certain aspects of the mode of action of CPZ.
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000266:Adenylyl Imidodiphosphate / Q000494:pharmacology; D000328:Adult; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002243:Carbolines / Q000494:pharmacology; D002746:Chlorpromazine / Q000494:pharmacology*; D004837:Epinephrine / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D010974:Platelet Aggregation / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects*; D012559:Schizophrenia / Q000188:drug therapy; D012701:Serotonin / Q000494:pharmacology
D002243:Carbolines; D011985:Receptors, Serotonin; D000266:Adenylyl Imidodiphosphate; D012701:Serotonin; C009804:tryptoline; D000255:Adenosine Triphosphate; D002746:Chlorpromazine; D004837:Epinephrine