Biphasic Effects of Selegiline on Striatal Dopamine: Lack of Effect on Methamphetamine-Induced Dopamine Depletion

We tested the hypothesis that selegiline can attenuate dopamine depletion if administered following high doses of methamphetamine that cause neurotoxicity in the striatum. Methamphetamine produced decreases of 50% or greater in both striatal concentrations of dopamine and combined concentrations of homovanillic acid and DOPAC in mice. For animals not exposed to methamphetamine, chronic treatment with selegiline over 18 days caused biphasic effects on striatal dopamine content, with decreases, no effect, or increases observed for mice receiving treatment with 0.02, 0.2, and 2.0 mg/kg, respectively. Selegiline failed to modify methamphetamine-induced reductions in striatal dopamine content or combined concentrations of homovanillic acid and DOPAC. Significant increases in mortality following the onset of selegiline treatment (24 hours after the initial dose of methamphetamine) occurred in methamphetamine-treated mice that received saline or 2.0 mg/kg of selegiline, but not for mice treated with 0.02 or 0.2 mg/kg of selegiline. These results indicate that selegiline fails to attenuate dopamine depletion when administered chronically following exposure to methamphetamine, but may attenuate methamphetamine-induced mortality. In control animals that did not receive methamphetamine, low doses of selegiline produced decreases the concentration of striatal dopamine, while high dose treatment caused increases in striatal dopamine content.