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

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. 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. 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). 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.