title: Multiple microvascular and astroglial 5-hydroxytryptamine receptor subtypes in human brain: molecular and pharmacologic characterization.
abstract: 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-HT1B, h5-HT1D, 5-HT1F, 5-HT2A but not 5-HT7 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-HT1D and for the 5-HT7 receptors whereas microvascular smooth muscle cells, in addition to h5-HT1D and 5-HT7, also showed polymerase chain reaction products for h5-HT1B receptors. Expression of 5-HT1F and 5-HT2A 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-HT2A and 5-HT7 subtypes. In all cultures, sumatriptan inhibited (35-58%, P < .05) the forskolin-stimulated production of cyclic AMP, an effect blocked by the 5-HT1B/1D receptor antagonists GR127935 and GR55562. In contrast, 5-carboxamidotryptamine induced strong increases (> or = 400%, P < .005) in basal cyclic AMP levels that were abolished by mesulergine, a nonselective 5-HT7 receptor antagonist. Only astroglial cells showed a ketanserin-sensitive increase (177%, P < .05) in IP3 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.
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute, Montréal, Québec, Canada.
authors.forename: Z
authors.initials: Z
authors.lastname: Cohen
authors.forename: I
authors.initials: I
authors.lastname: Bouchelet
authors.forename: A
authors.initials: A
authors.lastname: Olivier
authors.forename: J G
authors.initials: JG
authors.lastname: Villemure
authors.forename: R
authors.initials: R
authors.lastname: Ball
authors.forename: D B
authors.initials: DB
authors.lastname: Stanimirovic
authors.forename: E
authors.initials: E
authors.lastname: Hamel
mesh_terms: D001253:Astrocytes / Q000378:metabolism*; D001921:Brain / Q000098:blood supply* / Q000378:metabolism*; D002540:Cerebral Cortex / Q000098:blood supply / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000502:physiology*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D006801:Humans; D008833:Microcirculation / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D020033:Protein Isoforms / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D011985:Receptors, Serotonin / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015290:Second Messenger Systems / Q000187:drug effects
chemical_list: D020033:Protein Isoforms; D011985:Receptors, Serotonin; D005576:Colforsin; D000242:Cyclic AMP