An evaluation of I-ephedrine neurotoxicity with respect to hyperthermia and caudate/putamen microdialysate levels of ephedrine, dopamine, serotonin, and glutamate

l-Ephedrine is an active ingredient in several herbal formulations with a m echanism of action similar to amphetamine and methamphetamine. However, its potential to damage dopaminergic terminals in the caudate/putamen (CPu) ha s yet to be fully evaluated. The studies here used in vivo brain microdialy sis experiments to determine the systemic doses and extracellular brain lev els of E-ephedrine necessary to produce similar increases in CPu extracellu lar dopamine and marked hyperthermia that were previously shown necessary f or amphetamine-induced neurotoxicity in male Sprague-Dawley rats. At an env ironmental temperature of 23 degrees C, a single 40 mg/kg intraperitoneal ( ip) dose of I-ephedrine produced marked hyperthermia (greater than or equal to 40 degrees C), peak microdialysate ephedrine levels of 7.3 +/- 1.2 mu M , and a 20-fold increase in microdialysate dopamine levels. Twenty-five mg/ kg produced a lesser degree of hyperthermia, peak microdialysate ephedrine levels of 2.6 +/- 0.4 mu M, and a 10-fold increase in dopamine levels. Thre e doses: of 40 mg/kg given at 3-h intervals or 4 doses of 25 mg/kg I-ephedr ine given at 2-h intervals were compared with 4 doses of 5 mg/kg d-amphetam ine given at 2-h intervals. Multiple doses of either ephedrine or amphetami ne caused severe hyperthermia (greater than or equal to 41.3 degrees C) but striatal tissue levels of dopamine 7 days after dosing were reduced only 2 5% or less by ephedrine compared to the 75% reductions produced by amphetam ine. The increases in CPu microdialysate levels of serotonin produced by ei ther 4 x 25 mg/kg E-ephedrine or 4 x 5 mg/kg d-amphetamine did not signific antly differ, but elevation of dopamine levels by d-amphetamine were over 2 -fold times the level caused by I-ephedrine. Microdialysate glutamate level s were elevated to the same extent by either 25 mg/kg E-ephedrine or 4 x 5 mg/kg d-amphetamine. E-Ephedrine may not be as neurotoxic to dopaminergic t erminals as d-amphetamine, because non-lethal doses of I-ephedrine do not s ufficiently increase the CPu dopamine levels within nerve terminals or the extracellular space to those necessary for a more pronounced long-term dopa mine depletion.