# Presentation: 012325

## Recent Imaging Approaches to Studying Pharmacokinetics of Solvents 

**Translational Neuroimaging: [****11****C]raclopride**

***Recent Imaging Approaches to Studying Pharmacokinetics of Solvents***** **

- Stephen L. Dewey and Wynne K. Schiffer

## Neuroimaging approaches:

- Positron Emission Tomography (PET)
- microPET
- Magnetic Resonance Imaging (MRI)
- Functional MRI
- High Field MRI and fMRI (9.4 T)
- Optical Imaging
- microCT

##  PET

**Medical Imaging at BNL**

**Function**

## Positron labeled inhalants used for primate PET and rodent microPET studies

**Future development**
**11****C-TCE**
**11****C-Carbon-tetrachloride**
**11****C-Xylene **
**11****C-Propane**

## [11C]-Toluene

## Time course of toluene in the brain

- 5 minutes after [11C]toluene

- 25 minutes after [11C]toluene

**Might contribute to the leukoencephalopathy observed in toluene abusers ***(Filley, 2004)*

## [11C]-Acetone

**[****11****C]-Acetone**

## Inhaled [11C]-Butane

## How do other inhalants compare to toluene?

- striatum

- white matter

## Impact of conditioned place preference (CPP) to 5000 ppm of inhaled toluene on 18FDG uptake in the same animal over time

- 1 day after last exposure
** ****Day 40**

- Volumetric renderings created with Amide software and corrected for the injected dose (ID) of 18FDG and animal weight

- 3 wks into conditioning, 30m after tol
** ****Day 25**

- Pre- conditioning scan
** ****Day 0**

- 14 days after last exposure
** ****Day 54**

- 45 days after last exposure
** ****Day 99**

## Toluene-induced changes in white matter measured with high field (9.4 T)  μMRI

**Animal 2**
**Prior to toluene**

**Animal 2**
**After 20 days 5000 ppm inhaled toluene**

## Toluene-induced changes in white matter (WM)

**before toluene**

**after toluene**

***Correlation with changes in metabolic function?***

***Could [******11******C]-toluene be a WM ligand?***

## Does toluene alter synaptic dopamine?

- Use toluene-induced displacement of 11C-raclopride as an assay of synaptic DA
- IV toluene (20 mg/kg in beta cyclodextrin)
- Anesthetized animals

## Small Animal Imaging with 11C-Raclopride

**Small Animal Imaging with**** ****11****C-Raclopride**

**Small animal tomograph**

**11****C-raclopride competes with endogenous DA at D****2****R**

**11****C-raclopride**

**Radioactivity Distribution**

## IV toluene increases synaptic DA and displaces 11C-raclopride

| Animal | BP baseline | BP challenge | % change |
| --- | --- | --- | --- |
| Rodent #1 | 2.55 | 2.29 | -10.19 |
| Rodent #2 | 2.03 | 1.87 | -7.89 |
| Rodent #3 | 2.21 | 1.76 | -20.36 |
| Average | 2.26 ± 0.15 | 1.97 ± 0.16 | -12.81 ± 3.83 |

- Baseline

- Toluene Challenge

## The Volatile Operant Conditioning Chamber for Inhalants (VOCCI)

**Generation** **of** toluene vapors

- Mixture** **of toluene & air metered with mass flow controller

- On-line measurement using flame ionization detector (FID)

- 3 chamber CPP apparatus with IR photocell recording of time spent in chambers.

**Notes:**
Compressed air coming into a round bottom flask and the outlet takes volitle toluene through a flame ionization detector which moderates the flow with air thorugh the valve to a tube in the side of the CPP chamber. What’s going out of the opening is set at the flame ionization detector.  Heated to get more toluene off 

## Conditioning Protocol

- 4 animals paired to black side, 4 to white side, 8 controls for air exposure only
- Cage-mates were exposed to toluene or air in pairs
- Pairing sessions: 12 days, 6 pairings for each treatment session, 30 min duration
- Test session: 5 min acclamation, 15 min free access, no drug exposure on the test day

## Toluene produces conditioned place preference in Sprague-Dawley rats

- Average time spent in the white or black box (control, A) and in toluene or air-paired side (B). Test animals were conditioned using 2,000 ppm of toluene vapors (toluene-paired side).  Data are means  S.E.M. **, P<0.01
- 						Gerasimov et al., 2002

## Different reinforcing effects of toluene and acetone reflect pharmacokinetics

*****

*****

- Preference for toluene-paired chamber

- Preference for acetone chamber

*Consistent with the pharmacokinetics, conditioned place preference to acetone requires much longer pairings (90 min) as opposed to toluene, which only requires 30 minute pairings.*

## Behavioral Neuroimaging: Is there a metabolic signature of drug craving?

**Behavioral Neuroimaging: ****Is there a metabolic signature of drug craving?**

- 18FDG uptake during the expression of place preference to inhaled toluene

- Images represent SPM t-maps of the brain areas where increases in 18FDG uptake correlate with increases in conditioning score (time spent in the toluene-paired chamber).

## Can we block the effects of toluene on brain chemistry and behavior?

- Vigabatrin (GVG, Sabril) blocks the biochemical and behavioral effects of cocaine, methamphetamine, amphetamine, alcohol, heroin, morphine, and nicotine and their combinations.
- Completed 2 small open label clinical trials in Mexico in cocaine and methamphetamine-dependent subjects.

## Effects of GVG on the expression of toluene-induced CPP

- Significant difference from toluene chamber, **p < 0.05; ***p < 0.001 – student’s t-test

## GVG blocks the expression of conditioned place preference to toluene - presence of aversion?

## GVG blocks Toluene-induced increases in brain dopamine

- Control

- Toluene pretreat.

- GVG/Toluene

## Conclusion

- The rewarding effects of inhaled toluene are mediated, at least in part, by DA.  Thus, these effects are subject to GABAergic modulation by GVG.
- Toluene produces persistent and profound decreases in 18FDG uptake that appear to partially recover over time.

## Acknowledgments

- This project was funded by the United States Department of Energy/ Office of Biological and Environmental Research (USDOE/OBER DE-AC02-98CH10886) and NIH DA017349, DA15874, DA015041.