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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

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Abstract

Purpose

Using positron emission tomography in isoflurane-anaesthetised cat, we recently demonstrated that the effect of d-amphetamine (AMPH) was greater on the binding potential (BPND) of the agonist dopamine D2/D3 radiotracer (+)-4-[11C]propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1, 4]oxazin-9-ol ([11C]-(+)-PHNO) than on that of the antagonist [11C]-raclopride, a finding that we were unable to replicate in conscious rat. Herein we tested whether isoflurane differentially affects the AMPH sensitivity of [11C]-(+)-PHNO and [3H]-raclopride.

Procedures

Conscious or isoflurane-anaesthetised rats pretreated intravenously (i.v.) with saline or 4 mg/kg AMPH were co-injected i.v. with [11C]-(+)-PHNO/[3H]-raclopride or [3H]-(+)-PHNO/[11C]-(−)-N-propyl-norapomorphine ([11C]-(−)-NPA) and euthanised 2, 10, 20, 30, 40 or 60 min following [11C]-(+)-PHNO/[3H]-raclopride or 60 min following [3H]-(+)-PHNO/[11C]-(−)-NPA. Striatal binding at 60 min, estimated by the specific binding ratio (SBR) and the binding potential with respect to non-displaceable binding (BPND) for pseudodynamic data, was calculated using the simplified reference tissue model.

Results

Isoflurane increased [11C]-(+)-PHNO, [3H]-(+)-PHNO and [11C]-(−)-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 [3H]-raclopride SBR. Similar results were observed for [11C]-(+)-PHNO and [3H]-raclopride BPND.

Conclusions

Isoflurane differentially increases the binding and AMPH sensitivity of [11C]-(+)-PHNO and [11C]-(−)-NPA relative to [3H]-raclopride, suggesting that agonist radiotracers will prove no more effective for imaging dopaminergic activity in human than antagonist radiotracers.

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Abbreviations

AMPH:

d-Amphetamine

B max :

Total density of specific binding sites

BP:

Binding potential

BPF :

Binding potential with respect to free radiotracer in plasma

BPND :

Binding potential with respect to non-displaceable binding

DAT:

Dopamine transporter

%ID/g:

Percent of injected dose per gram wet tissue weight

K D :

Equilibrium dissociation constant

l-DOPA:

3,4-dihydroxy-L-phenylalanine

MNPA:

2-Methoxy-N-propyl-norapomorphine

(−)-NPA:

(−)-N-propyl-norapomorphine

PET:

Positron emission tomography

(+)-PHNO:

(+)-4-Propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1, 4]oxazin-9-ol

SBR:

Specific binding ratio

SUV:

Standard uptake value

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Acknowledgments

The authors would like to thank Armando Garcia and Winston Stableford for radiochemical synthesis of [11C]-(+)-PHNO and [11C]-(−)-NPA and Jun Parkes and Neil Vasdev for their assistance with the animal experiments. The work in this study was financially supported the Canadian Institutes of Health Research (MOP 74702).

Conflict of Interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Institute of Medical Science, University of Toronto, Toronto, ON, Canada, M5S 1A8

    Patrick Neil McCormick & Alan A. Wilson

  2. PET Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, Canada, M5T 1R8

    Patrick Neil McCormick, Nathalie Ginovart & Alan A. Wilson

  3. Department of Psychiatry, University of Toronto, Toronto, ON, Canada, M5S 1A8

    Alan A. Wilson

  4. University Department of Psychiatry, Neuroimaging Unit, University of Geneva, Geneva, Switzerland

    Nathalie Ginovart

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  1. Patrick Neil McCormick
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Correspondence to Patrick Neil McCormick.

Additional information

Significance: This article provides direct evidence that the elevated d-amphetamine sensitivity of the dopamine D2/D3 receptor agonist radiotracers [11C]-(+)-PHNO and [11C]-(−)-NPA (relative to the antagonist radiotracer [11C]-raclopride) is due to the confounding effects of isoflurane anaesthesia, rather than to considerations of the affinity state of the radiotracers’ binding sites as has been argued elsewhere (vide infra).

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McCormick, P.N., Ginovart, N. & Wilson, A.A. 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. Mol Imaging Biol 13, 737–746 (2011). https://doi.org/10.1007/s11307-010-0380-3

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  • DOI: https://doi.org/10.1007/s11307-010-0380-3

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