ABSTRACT L-DOPA is the primary drug used to treat Parkinson’s disease (PD) symptoms, but motor side effects limit its long term use. Previous experimental studies show that L-DOPA acts on supersensitive D1 receptors in the basal ganglia to induce extracellular signal-regulated kinases 1 and 2 (ERK1/2), a pair of MAP-kinase proteins that may be involved in induction of motor side effects. Since GABA is known to be intimately involved in basal ganglia function, we investigated whether elevating GABA levels via a GABA-transaminase (GABA-T) inhibitor affects the L-DOPA-induced ERK1/2 phosphorylation in the striatum and substantia nigra (SN) using a rat model of PD. Unilateral dopaminergic lesions of median forebrain bundle neurons were done using the neurotoxin 6-hydroxydopamine. Rats were prescreened for the extent of the lesion by apomorphine-induced rotation test. Lesioned rats were treated with aminooxyacetic acid (AOAA, a GABA-T inhibitor), L-DOPA, or in combination. Immunohistochemistry of tyrosine hydroxylase (TH, a direct indicator of dopaminergic lesion), substance P (SP, an indirect marker that decreases after lesion), and phospho-ERK1/2 was done using slices at the level of striatum and SN. Unilateral dopaminergic lesioned rats, as expected, exhibited >90% TH loss and a modest SP loss in the striatum and SN. L-DOPA alone induced a 343% and 330% increase in phospho-ERK1/2 in the striatum and SN, respectively. We report here a novel finding that pretreatment with AOAA attenuated the L-DOPA induced increase in phospho-ERK1/2 by 62% and 68% in the striatum and SN, respectively, suggesting a DA-GABA-ERK1/2 link in the therapeutic and/or side effects of L-DOPA.
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