Impact of isoflurane anesthesia on D2 receptor occupancy by [18F]fallypride measured by microPET with a modified Logan plot

Abstract

In the previous work, we reported a method that utilized imaging data collected from 60 to 120 min following [(18) F]fallypride administration to estimate the distribution volume ratio DVR' (DVR' ∝ DVR; DVR = 1 + BP(ND) , where BP(ND) is a measure of receptor density, DA D2 in this case). In this work, we use this method to assess the effects of isoflurane anesthesia on [(18) F]fallypride DVR'.

Methods: Rats were injected with [(18) F]fallypride either unconsciously under ∼1.5% isoflurane via the tail vein (Group 1) or consciously via a catheter inserted either in the jugular vein (Group 2) or the tail vein (Group 3). After about 1 h of free access to food and water the rats were anesthetized with 1.5% isoflurane and imaged in a microPET for 60 min. The rats that were injected consciously (Groups 2 and 3) were placed in a rat restrainer during [(18) F]fallypride injection. They were habituated in that restrainer for 3 days prior to the experiment day to minimize restraint-related stress. For comparison, a control group of rats was imaged for 120 min simultaneously with the administration of [(18) F]fallypride i.v. while under 1.5% isoflurane. The DVR' estimates from the 60 min acquisitions were compared with the DVR' from the last 60 min of the 120 min acquisitions (after neglecting the first 60 min). In addition, the striatal time-activity curves were fit with a 2-tissue + plasma compartment model using an arbitrary simulated plasma input function to obtain k(3) /k(4) (≈ BP(ND) ) for the 60 and 120 min acquisitions.

Results: Isoflurane anesthesia caused a significant reduction, up to 22%, in the DVR' estimates, which were 15.7 ± 0.3 (mean ± SE) for the controls, 17.7 ± 0.3 for Group 1, 19.2 ± 0.4 for Group 2, and 18.8 ± 0.7 for Group 3. The compartmental model fit produced similar results, ∼30% reduction in k(3) /k(4) for the 120-min acquisitions compared with the 60-min acquisitions (initial conscious uptake of the radiotracer).

Conclusion: The results of this study demonstrate that isoflurane anesthesia significantly decreases striatal [(18) F]fallypride BP(ND) in rats. Of similar importance, this work demonstrates the effectiveness of delayed scans following radiotracer injection and the implication that different types of studies can be conducted simultaneously with this method, including studies of behavioral and environmental impact on brain receptors.

Figure 1

Time–activity curves (TACs) of the cerebellum and striatum (average of left and right striatum) for rats in Group 2 (n = 6) comparing a 55-min initial conscious uptake period of the radiotracer followed by a 60-min PET scan while under ~1.5% anesthesia to the full 120-min PET scans in which the rats were fully anesthetized with ~1.5% isoflurane from the start of the radiotracer administration through the end of the scan. The TACs are displayed as mean ± SE. SUV: standard uptake value. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Figure 2

Sample Logan plots of a rat injected with [¹⁸F]fallypride via a jugular catheter: (a) 60 min prior to the start of a 60-min dynamic acquisition on the microPET (conscious uptake during the first ~60 min) (DVR′ = 19.1 ± 0.6); (b) 30 s after the start of a 120 min dynamic acquisition (unconscious uptake) (DVR = 15.2 ± 0.8). (c) Logan plot of the last 60 min of the full 120 min data after neglecting the first 60 min (DVR′ = 16.8 ± 1.3). [Color figure can be viewed in the online issue, which is available at www.wileyonlinelibrary.com.]

Figure 3

Statistical display of DVR′ estimates obtained from controls (n = 20): rats imaged for 120 min while under ~1.5% isoflurane anesthesia and DVR′ was measured for the last 60 min of the 120 min data after neglecting the first 60 min. Group 1 (n = 4): Rats were anesthetized and then injected with [¹⁸F]fallypride via the tail vein (TV) and then were allowed to wake up and set free in their cages. Group 2 (n = 14): Rats were restrained and injected with [¹⁸F]fallypride consciously via a jugular catheter (JC) and then set free in their cages. Group 3 (n = 10): Rats were restrained, injected with [¹⁸F]fallypride via the TV consciously and then set free in their cages. Groups 1–3 were fed ad libitum while free in their cages for 55 min and then were anesthetized with ~1.5% isoflurane and imaged in a microPET Focus 220 for 60 min (conscious fallypride uptake for ~60 min + imaging while anesthetized for 60 min).