Alteration of Neuroinflammation Detected by 18F-GE180 PET Imaging in Place-Conditioned Rats with Morphine Withdrawal

doi:10.21203/rs.3.rs-621858/v1

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Alteration of Neuroinflammation Detected by ¹⁸F-GE180 PET Imaging in Place-Conditioned Rats with Morphine Withdrawal

https://doi.org/10.21203/rs.3.rs-621858/v1

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Background: Accumulating evidence indicates that neuroinflammation significantly contributes to drug addiction, but the conversion of neuroinflammation after drug withdrawal is not clear. Here, we conducted ¹⁸F-flutriciclamide (GE180) positron emission tomography (PET) imaging to investigate the conversion of neuroinflammation during drug withdrawal and conditioning-induced aversion by measuring the change in microglial activation with ¹⁸F-GE180.

Methods: Twelve 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 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.

Results: Both the DW group and the CPA group spent less time in the conditioning cage during the posttest 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.

Conclusion: In morphine-dependent rats, neuroinflammation became more severe in the addiction-involved brain regions but remitted in the sensory-related brain regions after the administration of naloxone, and this neuroinflammation induced by withdrawal was further aggravated after conditioned aversion formation thus may help to consolidate the withdrawal memory.

Nuclear Medicine & Medical Imaging

Drug addiction

Neuroinflammation

Conditioned place aversion

Translocator protein 18 kDa

Positron emission tomography

Drug addiction is mainly characterized by the repeated use of addictive drugs. Recently, 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]. However, the evolution of neuroinflammation after drug withdrawal is not clear.

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]. Steven et al. conducted a conditioned place preference (CPP) assay to detect the efficacy of dexamethasone in attenuating the augmentation of the behavioral response to cocaine and suggested that anti-inflammatory agents may be effective in normalizing the rewarding effects of cocaine[5]. Conditioned place aversion (CPA) was more commonly used in investigating the mechanism of withdrawal. Indeed, CPA induces several brain function changes such as learning-induced synaptic plasticity[6], brain derived neurotrophic factor (BDNF) and immediate early genes (IEGs) expression[7], protein kinase A (PKA) and kappa opioid receptor (KOR) changes[8]. But the effect of CPA training on neuroinflammation is less investigated.

Translocator protein 18 kDa (TSPO), formerly known as the peripheral benzodiazepine receptor, is highly expressed in phagocytic cells of the immune system, such as microglia and macrophages[9]. The radioligands of TSPO for positron emission tomography (PET) can detect neuroinflammation, mainly microglial activation and proliferation, in vivo[10]. The development of ¹¹C-PK11195 as the first-generation TSPO PET ligand made TSPO a surrogate marker of neuroinflammation[11,12]. However, the short half-life of ¹¹C, poor signal-to-noise ratio due to high nonspecific binding and rather problematic radiochemistry limit its clinical application[12]. Due to the issues of ¹¹C-PK11195 and the increased interest in neuroinflammation, improved Fluorine labeled TSPO PET tracers, such as ¹⁸F-DPA-714 and ¹⁸F-GE180, have been developed[13,14]. These second-generation tracers possessed improved binding affinity and better kinetics. Here, we chose ¹⁸F-GE180 (Flutriciclamide) to detect the neuroinflammation in conditioned behavior in vivo for better understanding of the mechanism of neuroinflammation in drug addiction and aid in the search for treatments for addiction.

In this study, we constructed a digital ¹⁸F-GE180 template for automated whole-brain analysis of ¹⁸F-GE180 PET images. Then, we aimed to measure the change in neuroinflammation after naloxone treatment for morphine addiction and naloxone-CPA using ¹⁸F-GE180 PET imaging with a new digital ¹⁸F-GE180 template. We hypothesized that naloxone-induced morphine-withdrawal will arise neuroinflammation which account for aversion effects, and CPA training may aggravate the neuroinflammation thus help to consolidate withdrawal memory.

Animals and radiopharmaceuticals

Twelve male adult Sprague-Dawley rats (220-250 g) were housed singly in a 12 h light/dark cycle with free access to water and food and controlled temperature and humidity. All experimental procedures were performed according to protocols approved by Fudan University, Shanghai, China, and followed the guidelines of the National Institutes of Health Guide for the Care and Use of Laboratory Animals as well as the ARRIVE guidelines, original version. All efforts were made to minimize animal suffering and reduce the number of animals use. ¹⁸F-GE180 was prepared at the PET Center, Huashan Hospital, Fudan University, under the requirement of GMP.

Chronic morphine treatment

Male adult Sprague-Dawley rats were treated with morphine according to procedures described previously[15]. Briefly, morphine dependence was induced in rats by repeated intraperitoneal (i.p.) injections of morphine twice daily at 8:00 A.M. and 7:00 P.M. The morphine dose was progressively increased from 10 mg/kg to 40 mg/kg: day 1, 2 × 10 mg/kg; day 2, 2 × 20 mg/kg; day 3, 2 × 30 mg/kg; and days 4 and 5, 2 × 40 mg/kg. Control rats were treated with saline following the same procedure.

Conditioned place aversion

The procedure for CPA was similar to that described previously[16,17]. CPA took place in a three-compartment place conditioning apparatus (Med Associates, United States) with distinct visual and tactile contexts, which are readily discriminated by rats. The CPA procedure consisted of three phases: preconditioning, drug treatment, and conditioning phases. In the preconditioning phase (Day 1), rats were given an initial assessment of their baseline preference to determine whether rats had a preexisting preference for any of the three compartments. They were placed in the central neutral area of the apparatus for 2 min and allowed to freely explore the apparatus for 15 min. Rats showing strong unconditioned aversion or preference for any compartment were eliminated (i.e., ＜20% or ≥ 80% of the session time, the number of excluded rats did not exceed 10% of the sample). During the drug treatment phase (days 2-6), rats were treated with morphine for 5 consecutive days as described in the “Chronic morphine treatment” section and assigned to the drug addiction (DA) group. In the conditioning phase (days 7-10), rats were divided into drug withdrawal (DW) group and CPA group randomly. The CPA group received a naloxone injection (0.3 mg/kg) (to precipitate morphine withdrawal) after a morphine injection (40 mg/kg) before being placed in the minor preference compartment on days 7 and 9, and on the alternate days (days 8 and 10), they received a saline injection after a morphine injection (40 mg/kg) before being placed in the opposite compartment. To distinguish conditioned responses, rats in the withdrawal group received a naloxone injection (0.3 mg/kg) after a morphine injection (40 mg/kg) in the home cage on days 7 and 9 and a saline injection after a morphine injection (40 mg/kg) in the home cage on days 8 and 10. After one day of retrieval since the conditioning phase, each rat was placed blind in the same apparatus for 15 min to assess the place aversion response on day 12 (the response-assess phase). The time that rats spent in the compartment on the preconditioning phase was recorded as the pretest time, and that on the response-assess phase was recorded as the posttest time. The CPA score was defined as the time in the minor preference compartment minus the time in the opposite compartment. Since withdrawal/aversion conditioning was performed in the minor preference compartment, the opposite compartment became a more preferred compartment at retrieval after conditioning in the conditioned withdrawal/aversion group. Therefore, the CPA score was positive in the pretest session but was negative at retrieval in the conditioned withdrawal group.

PET scanning

Micro-PET/CT imaging was conducted as described previously using a micro-PET/CT scanner (Siemens Inc., United States)[18,19]. Briefly, static PET/CT imaging was collected for 20 min at 40 min post intravenous injection[14] of ¹⁸F-GE180 (296-444 MBq/kg body weight) and at 50 min post intravenous injection of ¹⁸F-FDG (370-555 MBq/kg body weight). Then, the rats were positioned in a spread-supine position on the imaging bed and anesthetized by 2–3% isoflurane in medical oxygen (1-2 L/min) at room temperature with an isoflurane vaporizer (Molecular Imaging Products Company, United States) during the PET/CT procedure. PET/CT images were reconstructed using the ordered subsets expectation maximization 3D algorithm, and data were reviewed using Inveon Research Workplace software (Siemens). GE180 imaging was performed on the last day of the drug treatment phase (day 6, defined as the drug addiction group) and the response assessment phase (day 12), while FDG imaging was only performed on day 6 to assist in the establishment of the GE180 template. One animal died during the GE180 imaging on day 6, and one died during CPA training, so the final sample size of DA, DW and CPA groups was 11, 6 and 5, respectively.

Construction of the ¹⁸F-GE180 PET template

The rat ¹⁸F-GE180 PET template was reconstructed by a method described previously using SPM8 (Welcome Trust Centre for Neuroimaging, London, UK; http://www.fil.ion.ucl.ac.uk/sp)[20,21]. Briefly, we first coregistered all of the GE180 images to their individual FDG images obtained on day 6 due to the low cerebral uptake of GE180. Then, the individual FDG images were normalized to a rat FDG template of a toolbox of SPM8 named spmtatHEP[22], and the transformation parameters were used for the normalization of all of the individual GE180 images. After that, the matrix value of the normalized GE180 images was rescaled to [0 255]. Finally, the normalized GE180 images were arithmetically averaged to create the template (Fig. 1). Since the averaged image after multiple iterations was distorted, all of the steps, including chorister, spatial normalization, and arithmetic average, were repeated only once.

Statistical analysis

Statistical analysis was conducted by GraphPad Prism 8. The normality of the distribution of the CPA scores were tested by Shapiro-Wilk normality test and Kolmogorov-Smirnov normality test. The difference of the CPA scores between multi-groups were analyzed by one-way ANOVA following by Bonferroni post hoc analysis, statistical significance was determined as p < 0.05.

To detect the change in the activation of glia after morphine withdrawal and CPA training, a voxel-wise two-sample t-test was performed by SPM8 with global mean intensity calculation to compare the different ¹⁸F-GE180 uptake between the DW group, the DA group and the CPA group in pairs using the toolbox spmtatHEP. A significance threshold was set as P < 0.001 with nonmultiple correction, and K > 20 voxels was set as the cluster extent threshold.

Construction of the ¹⁸F-GE180 template in rats

A ¹⁸F-GE180 template was established (Fig. 2) for the spatial normalization of each individual image, and the coordinate of the template fitted the atlas image in Paxinos & Watson space[23]. The uptake of GE180 was mainly concentrated in the area around the ventricle and was low in the cortex area, which was consistent with previous research[24].

Establishment of the CPA animal model

As shown in Fig, 3B. After CPA training, the CPA score in the CPA group rats was significantly decreased compared with that in the withdrawal group (CPA score, -159.53 ± 22.02 vs. 30.18 ± 28.89, P < 0.0001). The difference in the CPA group between the pretest and posttest was also statistically significant (CPA score, 63.2 ± 34.6 vs. -159.53 ± 22.02, P < 0.005).

Alternation of the brain uptake in different rats

Change in ¹⁸F-GE180 uptake after the administration of naloxone and conditioning training

The primary analysis investigated the change in the activation of glia after drug withdrawal and conditioning training (Fig. 4). After the administration of naloxone, the 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 DA group (Fig. 4A). Similar but wider results were found in the CPA group than in the DA group, as shown in Fig. 4B. The 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.

Increased ¹⁸F-GE180 uptake in the CPA group compared with the withdrawal group

Additional analysis aimed to investigate the conversion of neuroinflammation caused by withdrawal after conditioning training. Fig. 5 indicates aggravated neuroinflammation after conditioning training since only increased ¹⁸F-GE180 uptake was obtained in the right sensory cortex, right medial entorhinal cortex, left hippocampus, left caudate putamen, left hypothalamus, and midbrain regions in the CPA group compared with the withdrawal group.

In addition to numerous studies illustrating the contribution of neuroinflammation to drug addiction, we established a ¹⁸F-GE180 PET template and further investigated the change in microglial activation during drug withdrawal and conditioning-induced aversion in a rodent model. This is the first study to set up a ¹⁸F-GE180 PET template for small animals, although we did not perform any validation in the statistical analysis with this small sample size, we provided a method to set up a ¹⁸F-GE180 PET template for small animals.

Previous studies found that microglial activation accounts for withdrawal symptoms, and blocking the activation of microglial cells can alleviate this symptom[25,26]. An in vitro experiment also revealed that the administration of naloxone resulted in increased expression of inflammatory mediators, including tissue necrosis factor-alpha (TNF-α), interleukin-1-beta (IL-1β), interleukin-6 (IL-6), and interleukin-10 (IL-10), in brain tissues of morphine-dependent mice[27]. Both in vivo and ex vivo studies have demonstrated that TSPO was well parallel with the microglial activation[28,29], and PET imaging using TSPO ligands is a promising tool to visualize neuroinflammation induced by the activated microglial[30-32]. In our in vivo study, despite the wider regions the CPA group exhibited than the DW group in comparison with the DA group, both groups presented overexpression of ¹⁸F-GE180 mainly in the hippocampus, visual cortex, thalamus, and midbrain. Similar results were reported in a methadone maintenance treatment of heroin-related addiction by fMRI that the protracted abstinence patients demonstrated significantly higher brain responses in mesolimbic regions and visuospatial-attention regions[33]. The hippocampus plays an important role in memory, and morphine exposure, regardless of acute or chronic exposure, impairs hippocampus-dependent spatial learning and memory[34,35]. The visual cortex has been demonstrated to be impacted by different behavior contexts[36] and was found to be activated during drug-cue-induced craving[37]. The thalamus, which is a vital sensory center, was found to be involved in the reinstatement, extinction, and expression of drug-seeking behaviors[38,39]. The midbrain is necessary for locomotion[40], and it has been reported that heightened midbrain activations may reduce the approach motivation for cocaine[41]. All of these findings suggested that addiction-involved regions may be vulnerable to neuroinflammation during the withdrawal stage.

More importantly, after CPA training, microglial activation was increased compared with that in the DW group. The regions mainly include the mesolimbic regions (right medial entorhinal cortex, left hippocampus, left caudate putamen, left hypothalamus, and midbrain). The reduced CPA score also supported this imaging result: after conditioning training, rodents were even less willing to stay in the compartment where they received naloxone injection. Furthermore, the medial entorhinal cortex could connect with the hippocampus for episodic memory transfer[42]. Hence, we considered that the aggravated neuroinflammation that occurred in the hippocampus and midbrain after CPA training may account for the reinforcement of withdrawal memory and escape behavior.

We also detected reduced ¹⁸F-GE180 uptake mainly in the sensory-related cortices (the sensory, insular and piriform cortices) in both the DW and CPA group rats compared with the DA group. There are two possible reasons for this result. One is that naloxone might not only cause neuroinflammation but also have an antagonistic effect on morphine[43], and previous reports have verified naloxone can reduce the activation of microglia by different manners[44,45]. We hypothesized that the reduced microglia activation observed in this study might be due to the antagonistic effect on morphine. The second is that the specificity of TSPO for neuroinflammation and glial cells is not exclusive. TSPO is also expressed by endothelial cells[46]; in addition, the expression of TSPO may indicate the denseness of microglial cells instead of activation[28]. Further in vitro and longitudinal studies are needed to validate these hypotheses.

There are also some limitations in this study. First is that we only enrolled male rats in order to eliminate the differences in behavior and neurobiology of drug addiction caused by sex[47,48], but how the neuroinflammation is affected by drug addiction/withdrawal in female animals still needs to be illustrated in further research. Second is that in this animal experiment, we did not measure the affinity of brain microglia to GE180, because there is no significant difference in the affinity of brain microglia in rats. However, when applied in clinical practice, we consider that microglia with different affinities in human brain will have an impact on the uptake of GE180, which should be taken into account.

In this rodent study, we set up a ¹⁸F-GE180 template to investigate the conversion of neuroinflammation by detecting changes in glial activation in the brains of naloxone-induced morphine withdrawal rats and CPA model rats. Specifically, after naloxone treatment, neuroinflammation became more severe in the addiction-involved regions but remitted in the sensory-related regions, and this neuroinflammation induced by withdrawal was further aggravated after conditioned aversion formation thus may help to consolidate the withdrawal memory. TSPO PET can well monitor the change of neuroinflammation during morphine withdrawal course.

CPP: conditioned place preference

CPA: conditioned place aversion

DA: drug addiction

DW: drug withdrawal

GE180: ¹⁸F-Flutriciclamide

TSPO: translocator protein 18 kDa

Ethics approval and consent to participate

All experimental procedures were performed according to protocols approved by Fudan University, Shanghai, China, and followed the guidelines of the National Institutes of Health Guide for the Care and Use of Laboratory Animals as well as the ARRIVE guidelines, original version.

Consent for publication

Written informed consent for publication was obtained from all participants.

Availability of data and material

All the raw data of this study, including PET images and behavior data, can be obtained through the corresponding authors on reasonable request.

Competing interest

The authors declare no competing interest in this article.

Funding

This research was sponsored by the National Science Foundation of China (82071962, 82001143), the Shanghai Sailing Program (19YF1405300, 20YF1404400), the Shanghai Municipal Science and Technology Major Project and ZJLab (No. 2018SHZDZX01), and the Shanghai Municipal Key Clinical Specialty (shslczdzk03402).

Author contributions

JL and FX contributed to the conception and design of the study. DS and DJ designed and performed the animal experiments. FX produced the radiotracers. JL collected the PET/CT data. JL and QH contributed to the analysis and interpretation of the data. JL wrote the draft of this manuscript. YG and BL reviewed the study design and helped to redesign this study. FX, FH and JZ contributed to critical review and revision of the manuscript for this article.

Acknowledgements

The authors want to thank Jianfei Xiao, Yue Qian, and Zhiwei Pan for their generous assistance with this study.

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08 Jun, 2021

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Alteration of Neuroinflammation Detected by ¹⁸F-GE180 PET Imaging in Place-Conditioned Rats with Morphine Withdrawal

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