title: Cocaine Constrictor Mechanisms of the Cerebral Vasculature.
abstract: Cocaine constriction of the cerebral vasculature is thought to contribute to the ischemia associated with cocaine use. However, the mechanisms whereby cocaine elicits relevant vasoconstriction remain elusive. Indeed, proposed intra- and intercellular mechanisms based on over 3 decades of ex vivo vascular studies are, for the most part, of questionable relevancy due to the generally low contractile efficacy of cocaine combined with the use of nonresistance-type vessels. Furthermore, the significance attached to mechanisms derived from in vivo animal studies may be limited by the inability to demonstrate cocaine-induced decreased cerebral blood flow, as observed in (awake) humans. Despite these apparent limitations, we surmise that the vasoconstriction relevant to cocaine-induced ischemia is elicited by inhibition of dilator and activation of constrictor pathways because of cocaine action on the neurovascular unit (neuron, astrocyte, and vessel) and on vessels outside the unit. Furthermore, previous cocaine exposure, that is, conditions present in human subjects, downregulates and sensitizes these dilator and constrictor pathways, respectively, thereby enhancing constriction to acute cocaine. Identification of specific intra- and intercellular mechanisms requires investigations in the isolated microvasculature and the neurovascular unit from species chronically exposed to cocaine and in which cocaine decreases cerebral blood flow.
authors.affiliation: *Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH; †Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Newark, NJ; and ‡Department of Neurosurgery, Neuroscience Institute, University of Cincinnati College of Medicine, Cincinnati, OH.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Rapoport
authors.forename: SeongHun
authors.initials: S
authors.lastname: Yoon
authors.forename: Mario
authors.initials: M
authors.lastname: Zuccarello
mesh_terms: D000208:Acute Disease; D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D002908:Chronic Disease; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000503:physiopathology; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D006801:Humans; D007511:Ischemia / Q000139:chemically induced; D009569:Nitric Oxide / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D011453:Prostaglandins; D009569:Nitric Oxide; D003042:Cocaine; D004298:Dopamine; D009638:Norepinephrine