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

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.

Within-Subject Comparison of [11C]-( + )-PHNO and [11C]raclopride Sensitivity to Acute Amphetamine Challenge in Healthy Humans

“…Recently published data in awake and anaesthetised rodents implied that the greater sensitivity of agonists to amphetamine-induced dopamine release is a side effect of anaesthesia, which may not be present in conscious humans (McCormick et al, 2011). In our study, a direct within-subject comparison of agonist and antagonist ligands contradicts this speculation.…”

“…In a follow-up study by the same group, the effect of amphetamine on the binding of the agonists ( + )-PHNO and NPA was greater than that on the binding of the antagonist raclopride, in rats anaesthetised with isoflurane, but of similar magnitude in conscious rats (McCormick et al, 2011). Although these data implicate the effects of anaesthesia in the increased sensitivity of agonist radioligands, we do not believe them to be a major factor, because the increased sensitivities of both […”

Amphetamine challenge decreases yohimbine binding to α2 adrenoceptors in Landrace pig brain

“…A separate study of the effect of anesthesia in pigs (Alstrup et al 2010) using isoflurane and propofol demonstrated the relative insensitivity of yohimbine to the effects of anesthesia compared to the binding of another tracer, SCH23390. However, anesthesia may potentiate the effect of amphetamine, as it has been shown that inhalation anesthetics including isoflurane increase monoamine release (Ginovart et al 2002;McCormick et al 2011), potentially leading to an overestimation of the effect of the stimulant in our study compared to the awake condition.…”

“…Anesthetics play an important role in the interpretation of binding data and even more in that of pharmacological challenges (Ginovart et al 2002;Hassoun et al 2003;McCormick et al 2011;Tsukada et al 1999). A separate study of the effect of anesthesia in pigs (Alstrup et al 2010) using isoflurane and propofol demonstrated the relative insensitivity of yohimbine to the effects of anesthesia compared to the binding of another tracer, SCH23390.…”

How Relevant Are Imaging Findings in Animal Models of Movement Disorders to Human Disease?

“…While many techniques are being actively developed to permit awake imaging [3,32,52], they are still relatively rare and some require extensive training of subjects, possibly introducing population bias. To date, most animal studies are performed under anesthesia resulting in variable effects on the binding of the tracers used [1,36,63], influencing the MRI or MRS sequences considered [32,72], and the anatomical or functional nature of the study.…”