Abstract
Whether dopamine (DA) release is compensated during the presymptomatic phase of Parkinson's disease (PD) is controversial. Here we use in vivo voltammetry in the parkinsonian rat and an electrical stimulation protocol established to fatigue nigrostriatal dopaminergic (DAergic) neurons to investigate the plasticity of DA-release mechanisms. Amplitudes of evoked voltammetric signals recorded in intact rat striata decreased with repetitive, high-frequency stimulation (60 Hz, every 5 min/60 min). Strikingly, DA levels were maintained during an identical "fatiguing" protocol in 6-hydroxydopamine-lesioned (<40% denervation) striata in the absence of enhanced DA synthesis. In contrast, more severely lesioned striata (>55% denervation) also appeared to sustain DA release, however, this was demonstrated in the presence of enhanced synthesis. Sustained release was replicated in intact animals after irreversible blockade of the dopamine transporter (DAT) via RTI-76, implicating neuronal uptake as a trigger. We further demonstrate through kinetic analysis that lesions and compromised uptake target a "long-term" (time constant of minutes) presynaptic depression, which underlies the maintenance of release. Taken together, our findings identify a denervation-induced maintenance of DA release that was independent of activated synthesis and driven by altered uptake. This novel neuroadaptation may contribute to early preclinical normalization of function and help resolve discrepant findings regarding compensatory changes in DA release during progression of the parkinsonian state.