title: Dissociation of metabolic and hemodynamic levodopa responses in the 6-hydroxydopamine rat model.
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 sequential15O-water (H215O) and18F-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.
authors.affiliation: Center for Neurosciences, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA. Electronic address: rlerner@nshs.edu.
authors.forename: Renata P
authors.initials: RP
authors.lastname: Lerner
authors.affiliation: Basal Ganglia Pathophysiology Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden. Electronic address: zisis.bimpisidis@med.lu.se.
authors.forename: Zisis
authors.initials: Z
authors.lastname: Bimpisidis
authors.affiliation: Center for Neurosciences, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA. Electronic address: sagorastos1@gmail.com.
authors.forename: Stergiani
authors.initials: S
authors.lastname: Agorastos
authors.affiliation: Center for Neurosciences, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA. Electronic address: sassyhippy76@gmail.com.
authors.forename: Sandra
authors.initials: S
authors.lastname: Scherrer
authors.affiliation: Center for Neurosciences, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA. Electronic address: sdewey@nshs.edu.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Dewey
authors.affiliation: Basal Ganglia Pathophysiology Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden. Electronic address: angela.cenci_nilsson@med.lu.se.
authors.forename: M Angela
authors.initials: MA
authors.lastname: Cenci
authors.affiliation: Center for Neurosciences, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA. Electronic address: david1@nshs.edu.
authors.forename: David
authors.initials: D
authors.lastname: Eidelberg
mesh_terms: D000700:Analgesics / Q000627:therapeutic use; D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics; D006439:Hemodynamics / Q000187:drug effects*; D007530:Isoflurane / Q000627:therapeutic use; D007649:Ketamine / Q000627:therapeutic use; D007980:Levodopa / Q000627:therapeutic use*; D016627:Oxidopamine / Q000633:toxicity*; D010300:Parkinson Disease / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D049268:Positron-Emission Tomography; D051381:Rats; D017207:Rats, Sprague-Dawley; D013565:Sympatholytics / Q000633:toxicity*
chemical_list: D000700:Analgesics; D000978:Antiparkinson Agents; D013565:Sympatholytics; D019788:Fluorodeoxyglucose F18; D007980:Levodopa; D007649:Ketamine; D016627:Oxidopamine; D007530:Isoflurane
keywords: Cerebral blood flow; Glucose metabolism; Levodopa treatment; MicroPET; Parkinson's disease