Nigrostriatal denervation does not affect glutamate transporter mRNA expression but subsequent levodopa treatment selectively increases GLT1 mRNA andprotein expression in the rat striatum

There is growing evidence that the loss of the nigrostriatal dopaminergic n eurones induces an overactivity of the corticostriatal glutamatergic pathwa y which seems to be central to the physiopathology of parkinsonism. Moreove r, glutamatergic mechanisms involving NMDA receptors have been shown to int erfere with the therapeutical action of levodopa. Given the key role played by uptake processes in glutamate neurotransmission, this study examined th e effects of nigrostriatal deafferentation and of levodopa treatment on the striatal expression of the glutamate transporters GLT1, GLAST and EAAC1 in the rat. No significant changes in striatal mRNA levels of these transport ers were detected after either levodopa treatment (100 mg/kg; i.p., twice a day for 21 days) or unilateral lesion of the nigrostriatal pathway by intr anigral 6-hydroxydopamine injection. In contrast, animals with the lesion s ubsequently treated with levodopa showed a selective increase (36%) in GLT1 mRNA levels in the denervated striatum versus controls. These animals also showed increased GLT1 protein expression, as assessed by immunostaining an d western blotting. These data provide the first evidence that levodopa the rapy may interfere with striatal glutamate transmission through change in e xpression of the primarily glial glutamate transporter GLT1. We further sug gest that levodopa-induced GLT1 overexpression may represent a compensatory mechanism preventing neurotoxic accumulation of endogenous glutamate.