Cocaine increases the intracellular calcium concentration in brain independently of its cerebrovascular effects

Congwu Du, Mei Yu, Nora D. Volkow, Alan P. Koretsky, Joanna S. Fowler, Helene Benveniste

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56 Scopus citations

Abstract

Cocaine abuse increases the risk of life-threatening neurological complications such as strokes and seizures. Although the vasoconstricting properties of cocaine underlie its cerebrovascular effects, the mechanisms underlying its neurotoxicity remain incompletely understood. Here, we use optical techniques to measure cerebral blood volume, hemoglobin oxygenation (StO2), and intracellular calcium ([Ca2+] i) to test the hypothesis that cocaine increases [Ca 2+]i in the brain. The effects of cocaine were compared with those of methylphenidate, which has similar catecholaminergic effects as cocaine (except for serotonin increases) but no local anesthetic properties, and of lidocaine, which has similar local anesthetic effects as cocaine but is devoid of catecholaminergic actions. To control for the hemodynamic effects of cocaine, we assessed the effects of cocaine in animals in which normal blood pressure was maintained by infusion of phenylephrine, and we also measured the effects of transient hypotension (mimicking that induced by cocaine). We show that cocaine induced significant increases (∼10-15%) in [Ca 2+]i that were independent of its hemodynamic effects and of the anesthetic used (isofluorance or α-chloralose). Lidocaine but not methylphenidate also induced significant [Ca2+]i increases (∼10-13%). This indicates that cocaine at a dose within the range used by drug users significantly increases the [Ca2+]i in the brain and its local anesthetic, but neither its catecholaminergic nor its hemodynamic actions, underlies this effect. Cocaine-induced [Ca 2+]i increases are likely to accentuate the neurotoxic effects from cocaine-induced vasoconstriction and to facilitate the occurrence of seizures from the catecholaminergic effects of cocaine. These findings support the use of calcium channel blockers as a strategy to minimize the neurotoxic effects of cocaine.

Original languageEnglish
Pages (from-to)11522-11531
Number of pages10
JournalJournal of Neuroscience
Volume26
Issue number45
DOIs
StatePublished - 8 Nov 2006
Externally publishedYes

Keywords

  • Blood volume
  • Calcium
  • Cerebrovascular
  • Cocaine
  • Neurotoxicity
  • Oxygenation

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