title: Methamphetamine causes sustained depression in cerebral blood flow.
abstract: The use prevalence of the highly addictive psychostimulant methamphetamine (MA) has been steadily increasing over the past decade. MA abuse has been associated with both transient and permanent alterations in cerebral blood flow (CBF), hemorrhage, cerebrovascular accidents and death. To understand MA-induced changes in CBF, we exposed C56BL/6 mice to an acute bolus of MA (5mg/kg MA, delivered IP). This elicited a biphasic CBF response, characterized by an initial transient increase (~ 5 minutes) followed by a prolonged decrease (~ 30 minutes) of approximately 25% relative to baseline CBF--as measured by laser Doppler flowmetry over the somatosensory cortex. To assess if this was due to catecholamine derived vasoconstriction, phentolamine, an α-adrenergic antagonist was administered prior to MA treatment. This reduced the initial increase in CBF but failed to prevent the subsequent, sustained decrease in CBF. Consistent with prior reports, MA caused a transient increase in mean arterial blood pressure, body temperature and respiratory rate. Elevated respiratory rate resulted in hypocapnia. When respiratory rate was controlled by artificially ventilating mice, blood PaCO(2) levels after MA exposure remained unchanged from physiologic levels, and the MA-induced decrease in CBF was abolished. In vivo two-photon imaging of cerebral blood vessels revealed sustained MA-induced vasoconstriction of pial arterioles, consistent with laser Doppler flowmetry data. These findings show that even a single, acute exposure to MA can result in profound changes in CBF, with potentially deleterious consequences for brain function.
authors.affiliation: Department of Microbiology and Immunology, the University of Rochester Medical Center, 575 Elmwood Avenue, Rochester, NY 14642, USA.
authors.forename: Oksana
authors.initials: O
authors.lastname: Polesskaya
authors.forename: Jharon
authors.initials: J
authors.lastname: Silva
authors.forename: Christine
authors.initials: C
authors.lastname: Sanfilippo
authors.forename: Taylor
authors.initials: T
authors.lastname: Desrosiers
authors.forename: Anita
authors.initials: A
authors.lastname: Sun
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
authors.forename: Changyong
authors.initials: C
authors.lastname: Feng
authors.forename: Aleksey
authors.initials: A
authors.lastname: Polesskiy
authors.forename: Rashid
authors.initials: R
authors.lastname: Deane
authors.forename: Berislav
authors.initials: B
authors.lastname: Zlokovic
authors.forename: Karl
authors.initials: K
authors.lastname: Kasischke
authors.forename: Stephen
authors.initials: S
authors.lastname: Dewhurst
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001776:Blood Circulation Time / Q000379:methods; D001794:Blood Pressure / Q000187:drug effects*; D000697:Central Nervous System Stimulants / Q000009:adverse effects*; D002550:Cerebral Veins / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D017078:Laser-Doppler Flowmetry / Q000379:methods; D008694:Methamphetamine / Q000009:adverse effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D010646:Phentolamine / Q000494:pharmacology; D012121:Respiration, Artificial / Q000379:methods; D013003:Somatosensory Cortex / Q000098:blood supply / Q000187:drug effects*; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D000317:Adrenergic alpha-Antagonists; D000697:Central Nervous System Stimulants; D008694:Methamphetamine; D010646:Phentolamine