The vulnerable ventral tegmental area in Parkinson’s disease

Alberico, Stephanie L.; Cassell, Martin D.; Narayanan, Nandakumar S.

doi:10.1016/j.baga.2015.06.001

Cited by 154 publications

(118 citation statements)

References 50 publications

Supporting

Mentioning

113

Contrasting

Order By: Relevance

“…Most cases of PPX-associated gambling and ICDs have been reported in PD and RLS patients, raising the question as to whether the effects of this drug may be facilitated by pre-existing dopaminergic deficits. Notably, alterations in the mesolimbic system, albeit not pathognomonic for either PD or RLS, have been observed in a subset of patients affected by these conditions (Alberico et al, 2015; Oboshi et al, 2012); thus, these findings may suggest that deficits in the mesolimbic system may predispose to PPX-induced behavioral complications. Future analyses are warranted to verify whether animal models with lesions of the mesolimbic pathway may be more vulnerable to the adverse effects of PPX in probabilistic discounting paradigms.…”

Section: Discussionmentioning

confidence: 94%

Pramipexole enhances disadvantageous decision-making: Lack of relation to changes in phasic dopamine release

et al. 2017

View full text Add to dashboard Cite

Pramipexole (PPX) is a high-affinity D2-like dopamine receptor agonist, used in the treatment of Parkinson’s disease (PD) and restless leg syndrome. Recent evidence indicates that PPX increases the risk of problem gambling and impulse-control disorders in vulnerable patients. Although the molecular bases of these complications remain unclear, several authors have theorized that PPX may increase risk propensity by activating presynaptic dopamine receptors in the mesolimbic system, resulting in the reduction of dopamine release in the nucleus accumbens (NAcc). To test this possibility, we subjected rats to a probability-discounting task specifically designed to capture the response to disadvantageous options. PPX enhanced disadvantageous decision-making at doses (0.3 mg/kg/day, SC) that reduced phasic dopamine release in the NAcc. To test whether these modifications in dopamine efflux were responsible for the observed neuroeconomic deficits, PPX was administered in combination with monoamine-depleting agent reserpine (RES), at low doses (1 mg/kg/day, SC) that did not affect baseline locomotor and operant responses. Contrary to our predictions, RES surprisingly exacerbated the effects of PPX on disadvantageous decision-making, even though it failed to augment PPX-induced decreases in phasic dopamine release. These results collectively suggest that PPX impairs the discounting of probabilistic losses and that the enhancement in risk-taking behaviors secondary to this drug may be dissociated from dynamic changes in mesolimbic dopamine release.

show abstract

Section: Discussionmentioning

confidence: 94%

Pramipexole enhances disadvantageous decision-making: Lack of relation to changes in phasic dopamine release

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Patients with PD can have degeneration of dopaminergic neurons including a group of neurons in the medial midbrain that constitute the major dopaminergic projection to frontal and limbic cortices[23,24]. To explore mesocortical dopamine circuits in detail, we depleted dopamine in medial midbrain by targeting the ventral tegmental area (VTA) with injection of the neurotoxin 6-hydroxydopamine (6OHDA; Figure 1H).…”

Section: Resultsmentioning

confidence: 99%

“…We did not study substantia nigra pars compacta dopaminergic neurons, which are heavily involved in PD. Although neurons in both nuclei degenerate in PD, we focused on the VTA because this area projects heavily to the MFC, and nigrostriatal dopamine depletion can produce severe motor deficits[23,48]. Future studies will examine how the two ascending dopaminergic projections interact during interval timing.…”

Section: Discussionmentioning

confidence: 99%

Optogenetic Stimulation of Frontal D1 Neurons Compensates for Impaired Temporal Control of Action in Dopamine-Depleted Mice

et al. 2017

Self Cite

View full text Add to dashboard Cite

Summary Disrupted mesocortical dopamine contributes to cognitive symptoms of Parkinson’s disease (PD). Past work has implicated medial frontal neurons expressing D1 dopamine receptors (D1DRs) in temporal processing. Here, we investigate if these neurons can compensate for behavioral deficits resulting from midbrain dopamine dysfunction. We report three main results. First, both PD patients and mice with ventral tegmental area (VTA) dopamine depletion had attenuated delta activity (1–4 Hz) in the medial frontal cortex (MFC) during interval timing. Second, we found that optogenetically stimulating MFC D1DR neurons could increase ramping activity among MFC neurons. Finally, stimulating MFC D1DR neurons specifically at delta frequencies (2 Hz) compensated for deficits in temporal control of action caused by VTA dopamine depletion. Our results suggest that cortical networks can be targeted by frequency-specific brain stimulation to improve dopamine-dependent cognitive processing.

show abstract

“…In addition, post mortem studies revealed variable levels of dopaminergic neural loss in ventral tegmental area (VTA) (Alberico et al, 2015, Surmeier and Sulzer, 2013). This system, however, has been associated to a series of psychopathological states, which often occur in PD and may precede motor disturbances by many years (Gustafsson et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Axonal damage and loss of connectivity in nigrostriatal and mesolimbic dopamine pathways in early Parkinson's disease

Caminiti¹,

Presotto²,

Baroncini³

et al. 2017

NeuroImage: Clinical

106

View full text Add to dashboard Cite

A progressive loss of dopamine neurons in the substantia nigra (SN) is considered the main feature of idiopathic Parkinson's disease (PD). Recent neuropathological evidence however suggests that the axons of the nigrostriatal dopaminergic system are the earliest target of α-synuclein accumulation in PD, thus the principal site for vulnerability. Whether this applies to in vivo PD, and also to the mesolimbic system has not been investigated yet.We used [11C]FeCIT PET to measure presynaptic dopamine transporter (DAT) activity in both nigrostriatal and mesolimbic systems, in 36 early PD patients (mean disease duration in months ± SD 21.8 ± 10.7) and 14 healthy controls similar for age. We also performed anatomically-driven partial correlation analysis to evaluate possible changes in the connectivity within both the dopamine networks at an early clinical phase.In the nigrostriatal system, we found a severe DAT reduction in the afferents to the dorsal putamen (DPU) (η2 = 0.84), whereas the SN was the less affected region (η2 = 0.31). DAT activity in the ventral tegmental area (VTA) and the ventral striatum (VST) were also reduced in the patient group, but to a lesser degree (VST η2 = 0.71 and VTA η2 = 0.31). In the PD patients compared to the controls, there was a marked decrease in dopamine network connectivity between SN and DPU nodes, supporting the significant derangement in the nigrostriatal pathway.These results suggest that neurodegeneration in the dopamine pathways is initially more prominent in the afferent axons and more severe in the nigrostriatal system. Considering PD as a disconnection syndrome starting from the axons, it would justify neuroprotective interventions even if patients have already manifested clinical symptoms.

show abstract

The vulnerable ventral tegmental area in Parkinson’s disease

Cited by 154 publications

References 50 publications

Pramipexole enhances disadvantageous decision-making: Lack of relation to changes in phasic dopamine release

Pramipexole enhances disadvantageous decision-making: Lack of relation to changes in phasic dopamine release

Optogenetic Stimulation of Frontal D1 Neurons Compensates for Impaired Temporal Control of Action in Dopamine-Depleted Mice

Axonal damage and loss of connectivity in nigrostriatal and mesolimbic dopamine pathways in early Parkinson's disease

Contact Info

Product

Resources

About