1. ¹Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA
2. ²Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA

Correspondence: Dr SB Sparber, Department of Pharmacology, University of Minnesota, 6-120 Jackson Hall, 321 Church St., SE, Minneapolis, MN 55455-0217, USA, Tel: +1 612 625 5657; Fax: +1 612 625 8408, E-mail: sparb001@umn.edu

Received 13 December 2005; Revised 6 June 2006; Accepted 8 June 2006; Published online 26 July 2006.

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.