We investigated an imaging strategy that provides simultaneous measurements of radiotracer binding and behavior in awake, freely moving animals. In this strategy, animals are injected intravenously (i.v.) through a catheterized line and permitted to move freely for 30 min during uptake of the imaging agent, in this case 11C-raclopride. After this Awake Uptake period, animals are anesthetized and scanned for 25 min. We tested the utility of this strategy for measuring changes in striatal 11C-raclopride binding under control conditions (awake and freely moving in the home cage) and with several drug challenges: a loading dose of unlabeled raclopride, pretreatment with methamphetamine (METH) or pretreatment with γ-vinyl-GABA [S(+)-GVG] followed by METH. An additional group of animals underwent a stress paradigm that we have previously shown increases brain dopamine. For drug challenge experiments, the change in 11C-raclopride binding was compared to data from animals that were anesthetized for the uptake period ("Anesthetized Uptake") and full time activity curves were used to calculate 11C-raclopride binding. Regardless of the drug treatment protocol, there was no difference in 11C-raclopride striatum to cerebellum ratio between the Awake versus the Anesthetized Uptake conditions. Awake and Anesthetized groups demonstrated over 90% occupancy of dopamine receptors with a loading dose of cold raclopride, both groups demonstrated a ~ 30% reduction in 11C-raclopride binding from METH pretreatment and this effect was modulated to the same degree by GVG under both uptake conditions. Restraint during Awake Uptake decreased 11C-raclopride binding by 29%. These studies support a unique molecular imaging strategy in which radiotracer uptake occurs in freely moving animals, after which they are anesthetized and scanned. This imaging strategy extends the applicability of small animal PET to include functional neurotransmitter imaging and the neurochemical correlates of behavioral tasks.
Bibliographical noteFunding Information:
This work was carried out at Brookhaven National Laboratory under Contract No. DE-AC02-98CH10886 with the U.S. Department of Energy and supported by its Office of Biological and Environmental Research. Additional funds were provided by the NIH (DA15041 and DA22346 to SLD). We are grateful for discussions with Drs. Joanna Fowler, Jean Logan and Nora Volkow. We appreciate the efforts of Colleen Shea, Lisa Muench and Youwen Xu, technical assistance from James Anselmini and Barry Laffler in the BNL Chemistry Department, and Health Physics support from Kimberly Wehunt and Cheryl Burns.
- Gamma-vinyl GABA (GVG)
- Positron Emission Tomography (PET)