title: Isoflurane anaesthesia differentially affects the amphetamine sensitivity of agonist and antagonist D2/D3 positron emission tomography radiotracers: implications for in vivo imaging of dopamine release.
abstract: OBJECTIVE
  Using positron emission tomography in isoflurane-anaesthetised cat, we recently demonstrated that the effect of D-amphetamine (AMPH) was greater on the binding potential (BP(ND)) of the agonist dopamine D2/D3 radiotracer (+)-4-[(11)C]propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1, 4]oxazin-9-ol ([(11)C]-(+)-PHNO) than on that of the antagonist [(11)C]-raclopride, a finding that we were unable to replicate in conscious rat. Herein we tested whether isoflurane differentially affects the AMPH sensitivity of [(11)C]-(+)-PHNO and [(3)H]-raclopride.
  
  
  METHODS
  Conscious or isoflurane-anaesthetised rats pretreated intravenously (i.v.) with saline or 4 mg/kg AMPH were co-injected i.v. with [(11)C]-(+)-PHNO/[(3)H]-raclopride or [(3)H]-(+)-PHNO/[(11)C]-(-)-N-propyl-norapomorphine ([(11)C]-(-)-NPA) and euthanised 2, 10, 20, 30, 40 or 60 min following [(11)C]-(+)-PHNO/[(3)H]-raclopride or 60 min following [(3)H]-(+)-PHNO/[(11)C]-(-)-NPA. Striatal binding at 60 min, estimated by the specific binding ratio (SBR) and the binding potential with respect to non-displaceable binding (BP(ND)) for pseudodynamic data, was calculated using the simplified reference tissue model.
  
  
  RESULTS
  Isoflurane increased [(11)C]-(+)-PHNO, [(3)H]-(+)-PHNO and [(11)C]-(-)-NPA SBR (mean ± SD) by 80 ± 30%, 170 ± 50% and 120 ± 40%, and doubled the effect of AMPH on the SBR of these radiotracers to -61 ± 9%, -69 ± 12% and -60 ± 12%, respectively. Neither effect was seen for [(3)H]-raclopride SBR. Similar results were observed for [(11)C]-(+)-PHNO and [(3)H]-raclopride BP(ND).
  
  
  CONCLUSIONS
  Isoflurane differentially increases the binding and AMPH sensitivity of [(11)C]-(+)-PHNO and [(11)C]-(-)-NPA relative to [(3)H]-raclopride, suggesting that agonist radiotracers will prove no more effective for imaging dopaminergic activity in human than antagonist radiotracers.
authors.affiliation: Institute of Medical Science, University of Toronto, Toronto, ON, Canada. patrick.mccormick@camhpet.ca
authors.forename: Patrick Neil
authors.initials: PN
authors.lastname: McCormick
authors.forename: Nathalie
authors.initials: N
authors.lastname: Ginovart
authors.forename: Alan A
authors.initials: AA
authors.lastname: Wilson
mesh_terms: D000661:Amphetamine / Q000494:pharmacology*; D000758:Anesthesia; D000818:Animals; D002415:Cats; D002531:Cerebellum / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D065127:Dopamine D2 Receptor Antagonists; D007530:Isoflurane / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D017072:Neostriatum / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D010078:Oxazines / Q000493:pharmacokinetics / Q000494:pharmacology; D049268:Positron-Emission Tomography / Q000379:methods*; D020891:Raclopride / Q000493:pharmacokinetics / Q000494:pharmacology; D011868:Radioisotopes / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000819:agonists; D050637:Receptors, Dopamine D3 / Q000819:agonists / Q000037:antagonists & inhibitors; D013997:Time Factors
chemical_list: D065127:Dopamine D2 Receptor Antagonists; D010078:Oxazines; D011868:Radioisotopes; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C042631:naxagolide; D020891:Raclopride; D000661:Amphetamine; D007530:Isoflurane; D004298:Dopamine