Assessment of 5-hydroxytryptamine efflux in rat brain during a mild, moderate and severe serotonin-toxicity syndrome.
Serotonin (5-hydroxytryptamine; 5-HT)-toxicity syndrome, an iatrogenic brain disorder induced by excessive efflux of 5-HT, has received much attention because of increasing incidents of serotonergic antidepressants. However, the neural mechanism by which extracellular 5-HT is elevated to a toxic level for the syndrome remains to be determined. The goal of the present study was to test the hypothesis that extracellular 5-HT is composed of two component effluxes responsible for distinct aspects of the syndrome. The first set of experiments was to characterize the syndrome by measuring changes in neuromuscular signs, body-core temperature and mortality rate. Our results indicate that the syndrome severity can be categorized into mild, moderate and severe levels. The second set of experiments was to determine a threshold of extracellular 5-HT for induction of each level of the syndrome. Our results demonstrate that there were an 11-fold increase in the mild syndrome and an over 55-fold increase in the severe syndrome. In the last series of experiments, the excessive increases in 5-HT were pharmacologically separated into primary and secondary component effluxes with the 5-HT2A receptor antagonists cyproheptadine and ketanserin and NMDA receptor antagonist (+)-MK-801. Our results suggest that the primary component efflux was caused by direct drug effects on 5-HT biosynthetic and metabolic pathways and secondary efflux ascribed to indirect drug effect on a positive-feedback circuit involving 5-HT2A and NMDA receptors. In summary, the primary efflux could be an initial cause for the induction of the syndrome while the secondary efflux might involve deterioration of the syndrome.
Zhang
Gongliang
G
Charles E. Schmidt College of Biomedical Science, Florida Atlantic University, 777 Glades Road, Boca Raton, Florida 33431, USA.
Krishnamoorthy
Swapna
S
Ma
Zhiyuan
Z
Vukovich
Nick P
NP
Huang
Xupei
X
Tao
Rui
R
D006916:5-Hydroxytryptophan / Q000378:metabolism*; D000818:Animals; D000928:Antidepressive Agents / Q000633:toxicity; D001831:Body Temperature / Q000187:drug effects; D003010:Clorgyline / Q000633:toxicity; D003533:Cyproheptadine / Q000494:pharmacology; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D017551:Microdialysis; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D012701:Serotonin / Q000378:metabolism*; D058830:Serotonin 5-HT2 Receptor Antagonists; D020230:Serotonin Syndrome / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology
D000928:Antidepressive Agents; D016194:Receptors, N-Methyl-D-Aspartate; D058830:Serotonin 5-HT2 Receptor Antagonists; D003533:Cyproheptadine; D012701:Serotonin; D016291:Dizocilpine Maleate; D007650:Ketanserin; D006916:5-Hydroxytryptophan; D003010:Clorgyline