Abstract
BackgroundAccumulating evidence indicates that neuroinflammation (NI) significantly contributes to drug addiction, but the conversion of NI after drug withdrawal is not clear. Here, we conducted 18F-flutriciclamide (GE180) positron emission tomography (PET) imaging to investigate the conversion of NI during drug withdrawal and conditioning-induced aversion by measuring the change in microglial activation with 18F-GE180.MethodsTwelve male adult Sprague–Dawley rats were subjected to morphine withdrawal by the administration of naloxone, and six of them were used to model conditioned place aversion (CPA). 18F-GE180 PET imaging was performed for 11 rats on the last day of the morphine treatment phase and for 10 rats on the response assessment phase of the behavior conditioning procedure. A 18F-GE180 template was established for spatial normalization of each individual image, and the differential 18F-GE180 uptakes between the drug withdrawal (DW) group and the drug addiction (DA) group, the CPA group and the DA group, and the CPA group and the DW group were compared by a voxel-wise two-sample t test using SPM8.ResultsBoth the DW group and the CPA group spent less time in the conditioning cage during the post-test phase compared with the pretest phase, but only the difference in the CPA group was significant (63.2 ± 34.6 vs. − 159.53 ± 22.02, P < 0.005). Compared with the DA group, the uptake of 18F-GE180 increased mainly in the hippocampus, visual cortex, thalamus and midbrain regions and decreased mainly in the sensory-related cortices after the administration of naloxone in both the DW and CPA groups. Increased 18F-GE180 uptake was only observed in the mesolimbic regions after conditioned aversion compared with the DW group.ConclusionIn morphine-dependent rats, Neuroinflammation (NI) became more severe in the addiction-involved brain regions but remitted in the sensory-related brain regions after the administration of naloxone, and this NI induced by withdrawal was further aggravated after conditioned aversion formation thus may help to consolidate the withdrawal memory.
Highlights
Accumulating evidence indicates that neuroinflammation (NI) significantly contributes to drug addiction, but the conversion of NI after drug withdrawal is not clear
After the administration of naloxone, the drug withdrawal (DW) group displayed increased 18F-GE180 uptake in the bilateral visual and cingulate cortices, right hippocampus, thalamus and midbrain as well as decreased 18F-GE180 uptake in the bilateral sensory, insular and piriform cortices, optic chiasm, left hippocampus and pons compared with the drug addiction (DA) group (Fig. 4A)
The Conditioned place aversion (CPA) group displayed increased 18F-GE180 uptake in the bilateral visual cortex, left entorhinal cortex, left septal nucleus, bilateral caudate putamen, bilateral hippocampus, thalamus, midbrain and cerebellum and decreased uptake of 18F-GE180 in the bilateral sensory, insular and piriform cortices, left caudate putamen, optic chiasm, olfactory and medulla compared with the DA group
Summary
Accumulating evidence indicates that neuroinflammation (NI) significantly contributes to drug addiction, but the conversion of NI after drug withdrawal is not clear. We conducted 18F-flutriciclamide (GE180) positron emission tomography (PET) imaging to investigate the conversion of NI during drug withdrawal and conditioning-induced aversion by measuring the change in microglial activation with 18F-GE180. Accumulating evidence has indicated that glial activation, including microglia and astrocytes, and the associated neuroinflammatory signals significantly contribute to drug addiction [1, 2], while modulation of glial activation shows some drug withdrawal symptoms [3]. Place conditioning is commonly used in cue-elicited drug craving and the treatment of addiction since the rewarding/aversive effects of the drug administered with the environment play a key role in addiction treatment [4]. Conditioned place aversion (CPA) was more commonly used in investigating the mechanism of withdrawal. The effect of CPA training on NI is less investigated
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