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Physiologic and anatomic evidence suggest that 5-hydroxytryptamine (5-HT) neurons regulate local cerebral blood flow and blood-brain barrier permeability. To evaluate the possibility that some of these effects occur directly on the blood vessels, molecular and/or pharmacologic approaches were used to assess the presence of 5-HT receptors in human brain microvascular fractions, endothelial and smooth muscle cell cultures, as well as in astroglial cells which intimately associate with intraparenchymal blood vessels. Isolated microvessels and' capillaries consistently expressed messages for the h5-HT 1B , h5-HT 1D , 5-HT 1F , 5-HT 2A  but not 5-HT 7  receptors. When their distribution within the vessel wall was studied in more detail, it was found that capillary endothelial cells exhibited mRNA for the h5-HT 1D  and for the 5-HT 7  receptors whereas microvascular smooth muscle cells, in addition to h5-HT 1D  and 5-HT 7 , also showed polymerase chain reaction products for h5-HT 1B  receptors. Expression of 5-HT 1F  and 5-HT 2A  receptor mRNAs was never detected in any of the microvascular cell cultures. In contrast, messages for all 5-HT receptors tested were detected in human brain astrocytes with a predominance of the 5-HT 2A  and 5-HT 7  subtypes. In all cultures, sumatriptan inhibited (35–58%, P &lt; .05) the forskolin-stimulated production of cyclic AMP, an effect blocked by the 5-HT 1B/1d  receptor antagonists GR127935 and GR55562. In contrast, 5-carboxamidotryptamine induced strong increases (≥ 400%, P &lt; .005) in basal cyclic AMP levels that were abolished by mesulergine, a nonselective 5-HT 7  receptor antagonist. Only astroglial cells showed a ketanserin-sensitive increase (177%, P &lt; .05) in IP 3  formation when exposed to 5-HT. These results show that specific populations of functional 5-HT receptors are differentially distributed within the various cellular compartments of the human cortical microvascular bed, and that human brain astroglial cells are endowed with multiple 5-HT receptors. These findings emphasize the complex interactions between brain serotonergic pathways and non-neuronal cells within the CNS and, further, they raise the possibility that some of these receptors may be activated by antimigraine compounds such as brain penetrant triptan derivatives.

Multiple Microvascular and Astroglial 5-Hydroxytryptamine Receptor Subtypes in Human Brain: Molecular and Pharmacologic Characterization