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.
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.
McCormick
Patrick Neil
PN
Institute of Medical Science, University of Toronto, Toronto, ON, Canada. patrick.mccormick@camhpet.ca
Ginovart
Nathalie
N
Wilson
Alan A
AA
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
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