Extrastriatal D2-like receptors modulate basal ganglia pathways in normal and parkinsonian monkeys

Abstract

According to traditional models of the basal ganglia-thalamocortical network of connections, dopamine exerts D2-like receptor (D2LR)-mediated effects through actions on striatal neurons that give rise to the "indirect" pathway, secondarily affecting the activity in the internal and external pallidal segments (GPi and GPe, respectively) and the substantia nigra pars reticulata (SNr). However, accumulating evidence from the rodent literature suggests that D2LR activation also directly influences synaptic transmission in these nuclei. To further examine this issue in primates, we combined in vivo electrophysiological recordings and local intracerebral microinjections of drugs with electron microscopic immunocytochemistry to study D2LR-mediated modulation of neuronal activities in GPe, GPi, and SNr of normal and MPTP-treated (parkinsonian) monkeys. D2LR activation with quinpirole increased firing in most GPe neurons, likely due to a reduction of striatopallidal GABAergic inputs. In contrast, local application of quinpirole reduced firing in GPi and SNr, possibly through D2LR-mediated effects on glutamatergic inputs. Injections of the D2LR antagonist sulpiride resulted in effects opposite to those of quinpirole in GPe and GPi. D2 receptor immunoreactivity was most prevalent in putative striatal-like GABAergic terminals and unmyelinated axons in GPe, GPi, and SNr, but a significant proportion of immunoreactive boutons also displayed ultrastructural features of glutamatergic terminals. Postsynaptic labeling was minimal in all nuclei. The D2LR-mediated effects and pattern of distribution of D2 receptor immunoreactivity were maintained in the parkinsonian state. Thus, in addition to their preferential effects on indirect pathway striatal neurons, extrastriatal D2LR activation in GPi and SNr also influences direct pathway elements in the primate basal ganglia under normal and parkinsonian conditions.

Proteomic profiling in MPTP monkey model for early Parkinson disease biomarker discovery

“…Consistent with our previous findings [12, 13, 22], all MPTP-treated monkeys in the symptomatic (SYM) group displayed moderate to severe parkinsonian symptoms after 20–22 weeks of MPTP treatment, while monkeys in the saline control (CON) and asymptomatic (ASYM) groups did not show significant changes in their parkinsonism rating scores at the termination of the experiment. The different behavioral responses were correlated with the 18 F-FECNT uptake in all striatal regions of interest (see representative PET images in Supplementary Fig.…”

“…At the termination of the experiment, part of the brain was frozen for mass spectrometry (MS) analysis. The remaining parts were used for the postmortem dopaminergic cell counts and striatal densitometry measurement of dopamine transporter (DAT) and tyrosine hydroxylase (TH) immunoreactivity as previously described [12, 13, 22]. …”

Changing views of the pathophysiology of Parkinsonism

“…In the primate GPe, D2‐like receptors (D2LRs) are expressed on GABAergic striatopallidal inputs. Local activation of these receptors by injections of small amounts of D2LR agonists increases the firing of GPe neurons in monkeys, likely because of reduction of the GABAergic inhibition . In the monkey STN, D1 and D2 receptors are found on preterminal axons and glutamatergic and GABAergic terminals and on postsynaptic D5 receptors .…”

Abnormal bursting as a pathophysiological mechanism in Parkinson's disease

“…Application of SKF-82959 increased burst firing (PS method) in the GPi but had no effect in the SNpr [113]. Application of quinpirole reduced bursting (PS method) in the GPe, had no effect in the GPi, and increased bursting in the SNpr [114]. …”