Caffeine's neuroprotection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity shows no tolerance to chronic caffeine administration in mice.

We investigated the effect of chronic daily caffeine treatment on caffeine's neuroprotection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic toxicity. Mice received either caffeine (20 mg/kg) or saline daily for 9 days. Caffeine-induced locomotion tolerance developed within 3 days of treatment and persisted for the duration of the experiment. On day 10, mice were treated with MPTP (20 mg/kg, x4). Caffeine (20 mg/kg) or saline was administered 10 min before each MPTP dose. Acute pretreatment with caffeine attenuated MPTP-induced loss of striatal dopamine and dopamine transporter binding sites, and this attenuation was identical in mice pretreated chronically with caffeine or with saline. Thus, in contrast to the locomotor stimulant effect of caffeine, its neuroprotectant effect did not show tolerance to prior caffeine exposure. These data raise the possibility that caffeine may induce neuroprotection and locomotion by distinct mechanisms.