Inhibition of nitric oxide synthase enhances cocaine's developmental toxicity: Vascular and CNS effects

Mary Irene Mendoza-Baumgart, Marco Pravetoni, Sheldon B. Sparber

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Ischemia and/or reperfusion injury from free radicals may cause cocaine's toxicity, including its effect upon neurobehavioral development. We previously used salicylate to measure hydroxyl free radicals in chick embryos exposed to cocaine. The combination was more toxic than cocaine alone. We postulated that salicylate enhanced the vasoconstriction and toxicity via inhibition of compensatory processes (eg by inhibition of the synthesis of vasodilatory prostanoids and/or nitric oxide). A nontoxic dose of N(G)-nitro-L-arginine methyl ester (L-NAME) was used to inhibit nitric oxide synthase to test this hypothesis. In one experiment, cocaine was injected every 1.5 h (total dose =67.5 mg/kg egg) on day 15 of development, 1 h after injection of L-NAME (200 mg/kg egg) to determine viability and hatchability, which are measures of toxicity. Another experiment measured diameters of blood vessels after L-NAME injection, followed by NaCl or cocaine infusion (0.23 mg/egg/min; total dose=67.5 mg/kg egg) at 15 and 5 min afterwards. Lastly, brains of embryos pretreated with L-NAME before cocaine injections were analyzed for nitric oxide synthase activity. Cocaine decreased viability and hatchability. L-NAME enhanced cocaine's effect upon both parameters. Blood vessel diameters were decreased by cocaine after 15 min of infusion. L-NAME+cocaine caused a decrease in vessel diameter as soon as 5 min into the infusion and was greater with time, compared with other groups. Enzyme activity in brains was decreased only in the L-NAME+cocaine group. Thus, inhibition of nitric oxide synthesis interferes with the embryos' capacity to mount a compensatory vasodilatory response.

Original languageEnglish (US)
Pages (from-to)940-945
Number of pages6
JournalNeuropsychopharmacology
Volume32
Issue number4
DOIs
StatePublished - Mar 7 2007

Bibliographical note

Funding Information:
This work was supported in part by US Public Health Service Grants R37 DAO4979; T32 DAO7097 and a grant-in-aid from the Minnesota Medical Foundation (3200-922-02).

Keywords

  • Blood vessel
  • Brain
  • Chick embryo
  • Cocaine
  • L-NAME
  • Nitric oxide

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