In the context of PD, DA is, by far, the most studied of the catecholamines, with NE running a distant second. Since 1962, there have been ~29,000 publications associated with DA and PD vs. ~1700 associated with NE and PD. The evidence for deficient nigrostriatal DA signaling as the primary cause of motor symptoms of PD is strong. Yet there still remains a critical unresolved issue that hampers progress: a continuous perseverating focus to attribute deficient DA signaling in the striatum as the sole culprit for motor impairment. This focus is undoubtedly driven by the longstanding working model of basal ganglia circuit dysfunction that arises from the loss of striatal DA due to the progressive loss of nigrostriatal neurons. It is argued that this striato-centric focus has generated a plateau in our understanding of exactly how any of the five steps of neurotransmission with deficient DA-regulating function in striatum actually impair motor function. For definition purposes, the relation of nigrostriatal DA signaling to motor impairment will focus upon bradykinesia/hypokinesia, which is among four cardinal signs of PD which also include rigidity and postural instability and tremor at rest. Indeed, there are clinically based examples of where improvements in striatal DA signaling did not equate to alleviation of motor impairment in PD patients [60,64,65]. More evidence of this lack of alignment between striatal DA levels and severity of motor impairment is seen at the later stages of PD. Although the severity of motor impairment continues to worsen 4 to 5 years after PD diagnosis, loss of striatal DA-regulating proteins or signaling has already reached near 100% [20,66,67,68,69]. There is a comparable amount of evidence for this misalignment between striatal DA levels and motor function status in pre-clinical studies of rat PD models [22,57,58,59,70,71,72,73,74,75,76]. Motor impairment may also be present with far less than 80%, if any, striatal DA loss [54,65,70,72] or, conversely, motor impairment may not be present even though striatal DA loss meets or exceeds 80% [22,73,74]. Motor impairment can also be alleviated without any increase in or recovery of striatal DA or DA-regulating protein loss [54,57,59,73,74,75,76].

The weight of evidence that shows the influence of striatal DA signaling on basal ganglia circuits is too great to list here. However, the incongruities between the level of locomotor function and DA signaling in striatum can no longer be ignored if we are to solve which critical dopaminergic element(s) are to be targeted to maximize effective therapeutic strategies. The key question is where in the nigrostriatal pathway does DA have the greatest influence on locomotor function; particularly regarding the mechanisms that drive the initiation of self-generated movement. Although the evidence that nigral DA signaling can influence motor function is sparse, it has nonetheless been in existence since the 1980s [77,78,79,80,81]. The paucity of studies evaluating the SN is likely due to a prevailing presumption that neurotransmitter functions at the axon terminal are the sole influence of behavioral outcomes. Thus, interrogation of nigral DA signaling has not been considered in experimental designs to define how components of nigrostriatal DA signaling affect locomotor activity. In this light, it is reasonable to presume that the numerous ambiguities between striatal DA regulation and motor function that have accumulated in the literature over the past several decades could have been resolved if assessment of nigral DA signaling was included in the study design.

As goes with the loss of nigrostriatal neurons in PD, the loss of DA-regulating proteins and processes involved in neurotransmission follows. Interference with the functions of any of these proteins or processes can also affect locomotor function in naïve (non-PD) animal models. Tyrosine hydroxylase (TH) is the rate-limiting step of DA biosynthesis, converting tyrosine to L-dihydroxyphenylalanine (L-DOPA). Inhibition of TH with alpha-methyl-p-tyrosine (AMPT) decreases DA tissue levels and inhibits locomotor activity [7,82,83,84,85,86]. In humans, inhibition of hyperkinetic movements, such as chorea, dystonia, or dyskinesia, can also be produced by AMPT [87,88]. The storage of DA and NE is controlled by vesicular monoamine transporter 2 (VMAT2), which imports monoamines like DA into synaptic vesicles using a proton gradient. This function is inhibited by reserpine, which also inhibits locomotor activity [89,90,91], as first identified by a parkinsonian symptom side effect produced in hypertension treatment [92]. VMAT2 is expressed in both striatum and SN [93,94], which confers the capacity for storing DA for eventual release in the entire nigrostriatal pathway.

Once DA is packaged in synaptic vesicles, it can be released by neuronal activity or by modulation of transporter function through stimulant action. At the extracellular level, DA release from the nigrostriatal pathway is the step that delivers tissue content, via vesicular delivery, to the synapse [95,96,97,98], wherein DA has four fates, binding to the pre- or post-synaptic DA receptors, reuptake into the neuron, or diffusion away from the release site [99]. Drugs that target DA receptors, the post-synaptic DA D₁ receptor or pre- and post-synaptic DA D₂ receptor, also influence locomotor activity and are targets for pharmacotherapy in PD treatment [100]. An acute regimen of antipsychotics such as haloperidol or either DA D₁ or D₂ receptor antagonists reduce locomotor activity [101,102,103,104,105]. Conversely, DA D₁ or D₂ agonists increase locomotor activity in rodents and primates [43,106,107] and improve motor functions in late-stage human PD [108,109,110]. The release of DA can also be modulated by DA D₂ autoreceptor function [111] in both striatum and SN [31,112]. Finally, it should be mentioned that although the focus of this review on DA receptors is upon the D₁ receptor, with brief overview of the D₂ receptor, the three other DA receptors have been recently shown to play a role in locomotor impairments of PD, particularly the D₃ and D₅ receptors [113,114,115,116].

Functionally, the regulation of DA release by neuronal activity is critical for initiation of locomotor activity [117,118,119,120,121]. Deficits in DA release, such as occurs in aging or from over-expression of alpha-synuclein, are associated with decreased locomotor activity [122,123,124]. Conversely, under conditions that increase DA release, such as induced by amphetamine or methamphetamine [125,126,127], there is increased locomotor activity [128,129,130].

The termination of DA signaling occurs by reduction of extracellular DA levels in the synapse, largely, though not exclusively [99], through reuptake by the dopamine transporter (DAT) [131,132,133]; a process that occurs in SN as well as striatum [134,135,136]. DAT protein expression is considerably greater in the striatum [94], and, not withstanding possible influences of trafficking or contributions of other monoamine transporters, this difference may explain why DA release and uptake dynamics differ between these two regions [134,135,136]. Through constant trafficking between cytosol and plasma membrane, DAT function is dynamically regulated, including aging and in PD [137,138,139]. The DAT, like the DA D₂ receptor, also has considerable interaction with other components of DA neurotransmission, including DA D₂ receptors [34,112], and has considerable influence on maintaining DA tissue levels, TH expression, and phosphorylation selectively in the striatum, but not in SN [140,141]. There is also evidence of plasticity in DA uptake under conditions where DA and DAT levels are particularly low. In such cases, the NE transporter may also transport DA, with inherently low DA innervation or from severe loss of nigrostriatal neuron terminals [142,143].

Given the considerable influence of DAT on DA homeostasis, locomotor activity is strongly affected by DAT expression levels. DAT knockout mice or rats show a hyperkinetic phenotype [144,145,146]. This hyperkinetic phenotype is not likely explained by the low DA uptake capacity in the striatum due to DAT knockout, as DA tissue content levels are severely reduced to a level that is comparable to nigrostriatal lesion (>90% loss) [140,141]. Systemic delivery of nomifensine, a DAT inhibitor, increases locomotor activity [147], consistent with the hyperkinetic phenotype of the knockout [144,145,146]. While presumably this effect would be considered to be due to elevated extracellular DA levels in striatum from interference with DA uptake, we recently reported that infusion of nomifensine in striatum did not increase locomotor activity in aged rats, despite a striatum-specific increase in extracellular DA levels produced by nomifensine infusion therein [148].

4. Nigrostriatal DA Signaling and PD-Related Motor Impairment