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The Journal of Neuroscience, November 8, 2006, 26(45):11522-11531; doi:10.1523/JNEUROSCI.3612-06.2006

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Neurobiology of Disease
Cocaine Increases the Intracellular Calcium Concentration in Brain Independently of Its Cerebrovascular Effects

Congwu Du,^1,5 Mei Yu,¹ Nora D. Volkow,³ Alan P. Koretsky,⁴ Joanna S. Fowler,² and Helene Benveniste^1,5

¹Medical Department and ²Department of Chemistry, Brookhaven National Laboratory, Upton, New York 11973-5000, ³National Institute on Alcohol Abuse and Alcoholism and ⁴Laboratory of Functional and Molecular Imaging, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, and ⁵Department of Anesthesiology, State University of New York at Stony Brook, Stony Brook, New York 11794-8700

Correspondence should be addressed to either Dr. Helene Benveniste or Dr. Congwu Du at the above address. Email: Benveniste{at}bnl.gov or Email: congwu{at}bnl.gov

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 (S_tO₂), and intracellular calcium ([Ca²⁺]_i) to test the hypothesis that cocaine increases [Ca²⁺]_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 [Ca²⁺]_i that were independent of its hemodynamic effects and of the anesthetic used (isofluorance or -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 [Ca²⁺]_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.

Key words: cocaine; cerebrovascular; calcium; blood volume; oxygenation; neurotoxicity

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Received March 20, 2006; revised Sept. 24, 2006; accepted Sept. 25, 2006.

Correspondence should be addressed to either Dr. Helene Benveniste or Dr. Congwu Du at the above address. Email: Benveniste{at}bnl.gov or Email: congwu{at}bnl.gov

This article has been cited by other articles:

				Z. Luo, M. Yu, S. D. Smith, M. Kritzer, C. Du, Y. Ma, N. D. Volkow, P. S. Glass, and H. Benveniste The Effect of Intravenous Lidocaine on Brain Activation During Non-Noxious and Acute Noxious Stimulation of the Forepaw: A Functional Magnetic Resonance Imaging Study in the Rat Anesth. Analg., January 1, 2009; 108(1): 334 - 344. [Abstract] [Full Text] [PDF]

				S. D Treadwell and T. G Robinson Cocaine use and stroke Postgrad. Med. J., June 1, 2007; 83(980): 389 - 394. [Abstract] [Full Text] [PDF]

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