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 [11C]-dihydrotetrabenazine (DTBZ), [11C]-2β-3β-4-fluorophenyltropane (CFT), and [18F]-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 (rS = −0.85), CFT (rS = −0.87), and FD (rS = −0.85) specific uptake in nucleus accumbens (NAcc,) and dopaminergic cell counts in ventral tegmental area (VTA, rS = −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.

Left nucleus accumbens atrophy in deficit schizophrenia: A preliminary study

“…It should, however, be noted that in our NDSZ sample the association between age/duration of illness and left nucleus accumbens volume shows a similar but non significant trend. Furthermore, avolition/apathy is strongly associated with poor outcome in schizophrenia patients in general (Strauss et al, 2013) and with structural and functional alterations of the meso-cortico-limbic pathway, which includes the nucleus accumbens in various subsets of neuropsychiatric disorders and in animal and lesion models (Paul et al, 2005;Levy and Dubois, 2006;Brown et al, 2012;Barnes et al, 2013). Longitudinal studies describing volume or shape trajectories of sub-cortical structures in adults are still lacking.…”

In vivo measures of nigrostriatal neuronal response to unilateral MPTP treatment

“…Detailed descriptions of the approaches have been published earlier (Brown et al, 2012; Karimi et al, 2013; Tabbal et al, 2012; Tian et al, 2012). The following is a short overview.…”

“…A blinded reviewer rated parkinsonism on video recordings using validated scales, and the final parkinsonism score was used for analysis, as motor impairment was stable for at least 4–5 weeks prior to euthanasia (Tabbal et al, 2012; Tabbal et al, 2006; Perlmutter et al, 1997). Images were processed as previously described (Brown et al, 2012; Tabbal et al, 2006; Karimi et al, 2013). A reviewer unaware of MPTP dose manually placed the region of interests (ROIs) on the dorsal caudate nucleus and dorsal putamen on the T1-weighted magnetization prepared rapid gradient echo (MPRAGE) scan for each animal (Fig 8).…”

“…These newly measured variables were compared with previously published data from the same animals of in vivo PET, quantified autoradiography, striatal dopamine, nigral cell counts and motor ratings of parkinsonism (Brown et al, 2012; Karimi et al, 2013; Tabbal et al, 2012; Tian et al, 2012). This allows us to investigate whether the measures of axonal fibers fall in between the striatal terminal field and nigral cell body measures in relative to motor parkinsonism.…”

Apathy is associated with white matter abnormalities in anterior, medial brain regions in persons with HIV infection

“…In one structural MRI study of 12 asymptomatic HIV+ individuals, Paul and colleagues (2005) reported a significant correlation, independent of depression and disease duration, between apathy and reduced volume in the nucleus accumbens, a structure whose damage in humans and monkeys has been associated with apathy (Brown et al, 2012; Phillips et al, 1987). Volume of the caudate nucleus, which plays a critical role in the dorsolateral and orbitofrontal circuits, was not significantly associated with apathy ratings (Paul et al, 2005).…”