TY - JOUR
T1 - Dopamine pathway loss in nucleus accumbens and ventral tegmental area predicts apathetic behavior in MPTP-lesioned monkeys
AU - Brown, C. A.
AU - Campbell, M. C.
AU - Karimi, M.
AU - Tabbal, S. D.
AU - Loftin, S. K.
AU - Tian, L. L.
AU - Moerlein, S. M.
AU - Perlmutter, J. S.
N1 - Funding Information:
This study was funded by NIH ( NS050425 , NS058714 , NS41509 , and NS075321 ); Michael J Fox Foundation ; Murphy Fund ; American Parkinson Disease Association (APDA) Center for Advanced PD Research at Washington University ; Greater St. Louis Chapter of the APDA ; McDonnell Center for Higher Brain Function ; Hartke Fund ; Howard Hughes Medical Institute ; Parkinson's Disease Foundation ; and Barnes-Jewish Hospital Foundation (Elliot H. Stein Family Fund and PD Research Fund) . We thank Hugh Flores, Christina Zukas, Darryl Craig, Cedric Huchuan Xia, Iboro Umana, and Terry Anderson for expert technical assistance. All authors report no financial interests or potential conflicts of interest.
PY - 2012/7
Y1 - 2012/7
N2 - 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 8weeks 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.
AB - 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 8weeks 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.
KW - Apathy
KW - DTBZ
KW - Limbic pathway
KW - Nigrostriatal
KW - Parkinsonism
KW - Ventral striatum
UR - http://www.scopus.com/inward/record.url?scp=84861657617&partnerID=8YFLogxK
U2 - 10.1016/j.expneurol.2012.04.025
DO - 10.1016/j.expneurol.2012.04.025
M3 - Article
C2 - 22579525
AN - SCOPUS:84861657617
SN - 0014-4886
VL - 236
SP - 190
EP - 197
JO - Experimental Neurology
JF - Experimental Neurology
IS - 1
ER -