Preservation of dopamine neurotransmission during nigrostriatal neuron loss in rat Parkinson model: evidence for increased dopamine signaling in substantia nigra

Abstract

During progressive nigrostriatal neuron loss in Parkinsons disease (PD), compensatory mechanisms are thought to maintain dopamine (DA) signaling at levels sufficient to mitigate locomotor impairment prior to substantial neuron loss. Whereas increased DA turnover in striatum has been considered a keystone compensatory mechanism indicative of augmented DA signaling, recent work indicates that increased DA biosynthesis in substantia nigra (SN), not striatum, compensates for tyrosine hydroxylase (TH) protein and neuronal loss. To extend interrogation of compensatory mechanisms that augment DA signaling during nigrostriatal neuron loss, we contemporaneously evaluated extracellular DA against tissue DA levels and quantified TH protein in the striatum and SN. Our unilateral 6-hydroxydopamine (6-OHDA) lesion approach produces progressive neuronal loss between 7 and 28 days, enabling evaluation of multiple DA signaling components in striatum vs SN. Loss of TH was [~]90% in striatum and [~]70% in the SN by 7 days after lesion induction. However, whereas loss of tissue DA matched TH loss in striatum (>90%) on both days after lesion, tissue DA loss in SN occurred only at day 28 (36%), despite major TH loss by day 7. This preservation of nigral DA tissue levels during lesion progression was associated with increased extracellular DA in SN after K+-dependent depolarization in striatum, which was not evident in a sham-operation group at the same time, early after lesion induction, signifying a DA lesion-specific adaptation in SN. In contrast in the striatum, lesion abolished the robust increase in extracellular DA, as seen in the sham-operation group. Together, these results indicate compensatory mechanisms that augment nigrostriatal DA signaling are engaged in the SN, not striatum, during progressive nigrostriatal neuron loss.