Patterns of brain activation associated with conditioned place preference in rats

Abstract

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Objectives: Human PET studies have identified a metabolic signature of drug craving in dependent subjects presented with drug-associated cues. We tested the hypothesis that cue-elicited craving in rats, when modeled with the conditioned place preference (CPP) paradigm, results in a similar pattern of brain activation. Specifically, we developed a behavioral neuroimaging strategy by testing both Forced Exposure (FE; during FDG uptake, animals are placed in a distinct environment where they received methamphetamine, METH) and Free Choice exposure (FC; animals are given a choice of chambers during FDG uptake).

Methods: PET FDG scanning in male Sprague Dawley rodents was performed during the CPP pre-test. Animals were treated with METH (n = 10; 1.0 mg/kg) then saline in separate chambers for 10 alternating days (20 total). On the day of the CPP test, animals received only FDG prior to being placed in the METH-paired chamber (FE) or in the neutral chamber (FC). The extent of locomotor activity in the drug-paired chamber was recorded on videotape and rated with a computerized automated scoring system (TopScan, CleverSync). In the FC protocol, sec in each was also assessed. Animals were anesthetized after 45 min of uptake and scanned for 10 min. FDG data were normalized to stereotaxic space and proportionally scaled to the global mean. Voxel-wise analysis was implemented in SPM2 and verified by Region of Interest (ROI) regression analysis performed using PMOD. The main factor of interest was locomotor activity in the drug paired chamber (distance, in mm) and where possible, preference (time in drug-paired minus time in saline-paired chamber).

Results: Compared to the baseline scan, both conditions produced significant bilateral activations of the amygdala, thalamus, motor cortex, anterior cingulate gyrus and cerebellum. In the FC protocol, there were significant bilateral increases in FDG uptake in the medial forebrain bundle and striatum that were not evident in the FE protocol. However, FE significantly activated the amygdala and sensory cortex where FC did not. Patterns of activation detected by SPM were substantiated by ROI analysis, where brain activity from the FC striatal and orbitofrontal ROIs (including the medial forebrain bundle) was positively correlated with conditioning score (R²=0.57, p<0.001).

Conclusions: These studies suggest that the FC approach most closely mimics the brain activation documented in human subjects, where common areas of increased metabolism were the amygdala, orbitofrontal cortex and ventral striatum. Our studies support an experimental protocol where FDG is injected away from the tomograph and with minimal impact on behavior.

Research Support (if any): NIH DA15082, DA16025, DA15041 and performed under BSA DOE DE-AC02-98CH10886