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Dissociation of metabolic and hemodynamic levodopa responses in the 6-hydroxydopamine rat model

Lerner, Renata P.; Bimpisidis, Zisis LU ; Agorastos, Stergiani; Scherrer, Sandra; Dewey, Stephen L.; Cenci Nilsson, Angela LU and Eidelberg, David (2016) In Neurobiology of Disease 96. p.31-37
Abstract

Dissociation of vasomotor and metabolic responses to levodopa has been observed in human subjects with Parkinson's disease (PD) studied with PET and in autoradiograms from 6-hydroxydopamine (6-OHDA) rat. In both species, acute levodopa administration was associated with increases in basal ganglia cerebral blood flow (CBF) with concurrent reductions in cerebral metabolic rate (CMR) for glucose in the same brain regions. In this study, we used a novel dual-tracer microPET technique to measure CBF and CMR levodopa responses in the same animal. Rats with unilateral 6-OHDA or sham lesion underwent sequential 15O-water (H2 15O) and 18F-fluorodeoxyglucose (FDG) microPET to map CBF and CMR following... (More)

Dissociation of vasomotor and metabolic responses to levodopa has been observed in human subjects with Parkinson's disease (PD) studied with PET and in autoradiograms from 6-hydroxydopamine (6-OHDA) rat. In both species, acute levodopa administration was associated with increases in basal ganglia cerebral blood flow (CBF) with concurrent reductions in cerebral metabolic rate (CMR) for glucose in the same brain regions. In this study, we used a novel dual-tracer microPET technique to measure CBF and CMR levodopa responses in the same animal. Rats with unilateral 6-OHDA or sham lesion underwent sequential 15O-water (H2 15O) and 18F-fluorodeoxyglucose (FDG) microPET to map CBF and CMR following the injection of levodopa or saline. A subset of animals was separately scanned under ketamine/xylazine and isoflurane to compare the effects of these anesthetics. Regardless of anesthetic agent, 6-OHDA animals exhibited significant dissociation of vasomotor (ΔCBF) and metabolic (ΔCMR) responses to levodopa, with stereotyped increases in CBF and reductions in CMR in the basal ganglia ipsilateral to the dopamine lesion. No significant changes were seen in sham-lesioned animals. These data faithfully recapitulate analogous dissociation effects observed previously in human PD subjects scanned sequentially during levodopa infusion. This approach may have utility in the assessment of new drugs targeting the exaggerated regional vasomotor responses seen in human PD and in experimental models of levodopa-induced dyskinesia.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Cerebral blood flow, Glucose metabolism, Levodopa treatment, MicroPET, Parkinson's disease
in
Neurobiology of Disease
volume
96
pages
7 pages
publisher
Elsevier
external identifiers
  • Scopus:84983378556
ISSN
0969-9961
DOI
10.1016/j.nbd.2016.08.010
language
English
LU publication?
yes
id
ac86c839-f313-4090-8b38-f12e1f94f027
date added to LUP
2016-10-12 13:00:14
date last changed
2016-10-13 03:00:02
@misc{ac86c839-f313-4090-8b38-f12e1f94f027,
  abstract     = {<p>Dissociation of vasomotor and metabolic responses to levodopa has been observed in human subjects with Parkinson's disease (PD) studied with PET and in autoradiograms from 6-hydroxydopamine (6-OHDA) rat. In both species, acute levodopa administration was associated with increases in basal ganglia cerebral blood flow (CBF) with concurrent reductions in cerebral metabolic rate (CMR) for glucose in the same brain regions. In this study, we used a novel dual-tracer microPET technique to measure CBF and CMR levodopa responses in the same animal. Rats with unilateral 6-OHDA or sham lesion underwent sequential <sup>15</sup>O-water (H<sub>2</sub> <sup>15</sup>O) and <sup>18</sup>F-fluorodeoxyglucose (FDG) microPET to map CBF and CMR following the injection of levodopa or saline. A subset of animals was separately scanned under ketamine/xylazine and isoflurane to compare the effects of these anesthetics. Regardless of anesthetic agent, 6-OHDA animals exhibited significant dissociation of vasomotor (ΔCBF) and metabolic (ΔCMR) responses to levodopa, with stereotyped increases in CBF and reductions in CMR in the basal ganglia ipsilateral to the dopamine lesion. No significant changes were seen in sham-lesioned animals. These data faithfully recapitulate analogous dissociation effects observed previously in human PD subjects scanned sequentially during levodopa infusion. This approach may have utility in the assessment of new drugs targeting the exaggerated regional vasomotor responses seen in human PD and in experimental models of levodopa-induced dyskinesia.</p>},
  author       = {Lerner, Renata P. and Bimpisidis, Zisis and Agorastos, Stergiani and Scherrer, Sandra and Dewey, Stephen L. and Cenci Nilsson, Angela and Eidelberg, David},
  issn         = {0969-9961},
  keyword      = {Cerebral blood flow,Glucose metabolism,Levodopa treatment,MicroPET,Parkinson's disease},
  language     = {eng},
  month        = {12},
  pages        = {31--37},
  publisher    = {ARRAY(0x8396020)},
  series       = {Neurobiology of Disease},
  title        = {Dissociation of metabolic and hemodynamic levodopa responses in the 6-hydroxydopamine rat model},
  url          = {http://dx.doi.org/10.1016/j.nbd.2016.08.010},
  volume       = {96},
  year         = {2016},
}