Dopamine pathway loss in nucleus accumbens and ventral tegmental area predicts apathetic behavior in MPTP-lesioned monkeys

Abstract

Apathy, primarily defined as a lack of motivation, commonly occurs in people with Parkinson disease (PD). Although dysfunction of basal ganglia pathways may contribute to apathy, the role of dopamine remains largely unknown. We investigated the role of dopaminergic pathways in the manifestation of apathetic behaviors by measuring the effects of the selective dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on monkeys' willingness to attempt goal directed behaviors, distinct from their ability to perform tasks. Fifteen macaques received variable doses of MPTP, had PET scans with [(11)C]-dihydrotetrabenazine (DTBZ), [(11)C]-2β-3β-4-fluorophenyltropane (CFT), and [(18)F]-fluorodopa (FD) and performed tasks to assess apathetic behaviors and motor impairment. At 8 weeks post-MPTP, primates were euthanized and stereological cell counts and dopamine measurements were done. Apathy scores were compared to motor scores, in vitro and in vivo dopaminergic measures. Apathy scores increased following MPTP and correlated with DTBZ (r(S) = -0.85), CFT (r(S) = -0.87), and FD (r(S) = -0.85) specific uptake in nucleus accumbens (NAcc,) and dopaminergic cell counts in ventral tegmental area (VTA, r(S) = -0.80). Dopaminergic cell loss in VTA provided significant predictive power for apathy scores after controlling for the influence of cell loss in SN. Additionally, forward step-wise regression analyses indicated that neuropathological changes in the VTA-NAcc pathway predict apathetic behavior better than motor impairment or neuropathological changes in the nigrostriatal network. Our findings suggest that dopaminergic dysfunction within the VTA-NAcc pathway plays a role in the manifestation of apathetic behaviors in MPTP-lesioned primates. Similar changes in people with PD may contribute to apathy.

Figure 1

Region of interests drawn on T1-weighted MR image with the nucleus accumbens ROIs indicated by arrows. ROIs extended two slices anteriorly and posteriorly from the slice shown.

Figure 2

VTA and SN as outlined in the current study on TH-immunostained transverse slices. The 3^rd cranial nerve fibers are indicated by arrows. The scale bar (bottom right) is 1000μm.

Figure 3

The relationship between MPTP dose and apathy score revealed a linear dose-response with apathy scores increasing as MPTP dose increased. Higher apathy scores indicate greater impairment. Each data point reflects the post/pre-MPTP apathy score for a single subject, and the line is the linear fit of the data.

Figure 4

The relationship between DTBZ (□), CFT (◇), and FD (△) specific uptake in the NAcc (top) and VTA cell counts (+, bottom) with MPTP dose. Specific tracer uptake in the NAcc decreased at a greater rate than VTA cell counts as MPTP dose increased. Each data point reflects the post-MPTP injected/control side ratio for an individual subject.

Figure 5

The relationship between VTA cell counts and DTBZ (□), CFT (◇), and FD (△) specific uptake in the NAcc. NAcc striatal uptake decreased linearly with cell counts in the VTA, and showed greater decrease than cell counts following MPTP injection. Each data point reflects the post-MPTP injected/control side BP or K_occ ratio for an individual subject, and the line is the linear fit of the data.

Figure 6

The relationship between apathy scores and DTBZ (□), CFT (◇), and FD (△) specific uptake (top), and VTA cell counts (X, bottom). Apathy scores showed an inverse relationship to both NAcc tracer uptake and cell counts following MPTP. Each point represents the post/pre-MPTP apathy score and post-MPTP injected/control side measures for an individual subject, and each line is the linear fit of the data.