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All issues Volume 27 / No 3 (June 2022) Wuhan Univ. J. Nat. Sci., 27 3 (2022) 265-272 Full HTML
Open Access
Issue
Wuhan Univ. J. Nat. Sci.
Volume 27, Number 3, June 2022
Page(s) 265 - 272
DOI https://doi.org/10.1051/wujns/2022273265
Published online 24 August 2022

© Wuhan University 2022

Licence Creative CommonsThis is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

0 Introduction

It is claimed that morphine (MOR), an opioid analgesic commonly used in clinical practice, can cause tolerance and even addiction when used for a long time. Addiction includes physical addiction and psychological addiction, the latter of which is more difficult to overcome[1, 2]. It is recognized that the essence of psychological addiction is abnormal and stubborn pathological memory, which is currently called "addiction memory", and it shares a similar neurobiological mechanism with normal learning and memory[1, 2]. The hippocampus is a key brain area for learning and memory, and it has direct circuitry and functional connections with the ventral tegmental area, the nucleus accumbens, and other addiction-related brain areas[2, 3]. Therefore, the hippocampus is also involved in opioid addiction at the genetic, molecular, cellular, synaptic plasticity, and neural circuit levels[1, 2, 4-7].

In previous studies, both acute and chronic administration of MOR have been found to affect the θ or γ power or the frequency of central gravity in the hippocampal electroencephalogram (EEG) power spectrum, but the effects are completely opposite[8, 9]. There was no significant change of EEG power in the dorsal hippocampus (DH) of MOR addicted rats, and the θ or γ bands of the rats decreased after treatment with the opioid receptor antagonist naloxone (NX), suggesting that the changes in the EEG power spectrum may be related to the formation of MOR addicted memories[7]. However, the performance of EEG power spectrum in the extinction of MOR addiction memory has not been reported. The hippocampus is divided into the dorsal hippocampus (DH) and the ventral hippocampus (VH), and have significant differences in terms of circuits and functional characteristics[10]. Hence, in this study, we establish a mouse model of MOR-conditioned place preference (CPP) to explore the EEG power spectrum of DH and VH and the NX processing effect after MOR memory extinction, so as to provide experimental evidence for the research on the neuroelectrophysiological mechanism of opioid addiction withdrawal regulation.

1 Materials and Methods

1.1 Animals

Sixty KM mice (Kunming mice, 30 males) were purchased from Changsheng Biotechnology, Shenyang, China [License: SCXK (Liao) 2015-1]. They were 6 weeks old and 42(±4) g in weight at the beginning of the experiment. The humidity was about 55(±5)%, the temperature was controlled at 22(± 2) ℃, and the light and dark alternated on a 12 h/12 h cycle in the animal room. Animals were kept in groups and their feeding was ad libitum. Before the experiment, the animals adapted to the laboratory room for 1 week, and were gently grasped and touched several times a day to reduce the stress response. The complete experimental process is shown in Fig. 1. All the animal experimental procedures were carried out in accordance with the regulations of Yunnan Province, and were approved by the Biomedical Ethics Committee of Yunnan Normal University.

thumbnail Fig. 1 Timeline of behavioral and EEG experiments after different extinction treatments on the morphine-CPP mice

CPP: conditioned place preference; SAL: saline; MOR: morphine; TE: training extinction; NE: natural extinction; NX: naloxone

1.2 CPP Training

The Acrylic CPP instrument was composed of three boxes (left, middle and right). There were two doors between the three boxes. The left box had inclined stripes and a smooth bottom, and the right box had gray dots and a rough bottom[11]. After each trial, the boxes were wiped with 70% alcohol to eliminate odor interference. The experiment started at 9:00 a.m. every day. The CPP experiment included four stages: habituation, screening, training, and testing, as detailed in Ref.[11]. The time the mice spent in each of the three boxes in a 15 min period was recorded by an animal behavioral video capture system. Each mouse adapted to the CPP procedures once a day for 2 d. The animals with time differences of ≤200 s between the left and right box were selected for the formal experiment.

The selected mice were then divided into MOR group and SAL group, half male and half female. The side with short staying time was the MOR-paired box. The drugs were administered alternately at 24 h intervals (morphine hydrochloride, Shenyang First Pharmaceutical, Shenyang, China) with the dosage increasing (10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, and 30 mg/kg) and the same volumes of saline (SAL) for 10 d. Then, the CPP behaviors were tested (Test 1) in the same way as in the habituation. The staying time in the MOR-paired box (T MOR) and non-paired box (T NON) was recorded. The CPP score = T MOR/(T MOR+T NON)×100%.

The mice with better CPP scores (≥60%) were selected and divided into training extinction (TE) groups and natural extinction (NE) groups (SAL-NE, SAL-TE, MOR-NE and MOR-TE groups, all n = 10, half female) which both received extinction treatment for 5 d. In the TE groups, the animals were placed in the MOR-paired box after SAL injection, and the other operations were consistent with the training period. The test was performed 6 h after the training, once a day. In the NE groups, after MOR-CPP was established, the animals were only injected with SAL and returned to their home cage, and the test phase was repeated 5 d later (Test 2).

1.3 Surgery and EEG Recording

When the CPP experiment was completed, the mice were fixed to the brain stereotaxic instrument under anesthesia (pentobarbital sodium, 60 mg/kg, i.p.). After skin preparation, local anesthesia, and skull exposure, two insulated stainless steel recording electrodes (Φ150 μm, bare tip 300 μm), were inserted into the target brain areas, with the reference electrode above the olfactory bulb. According to a stereotaxic brain atlas[12], the coordinates of recording electrode (unit: mm) were determined with the bregma as coordinate origin [DH: AP-(2.1-2.4), midline(ML) ± 1.5, DV-(1.8-2.0); VH: AP-3.5, ML±(3.2-3.3), DV-4.2]. The EEG signals were recorded by a physiological signal acquisition system (Chengdu Instrument Factory, Chengdu, China). After the signal had stabilized for 10 min (baseline), injected NX (5 mg/kg, i.p), and then recorded for 60 min continuously. EEG data (10 s) were collected from each 10 min segment for analysis. The EEG time series data were transformed into power spectrum data by filtering and fast Fourier transform, and the total power (1-100 Hz), relative total power and the power of six frequency bands (δ (1-4 Hz), θ (4-8 Hz), α (8-12 Hz), β (12-30 Hz), γ1 (30-45 Hz) and γ2 (55-100 Hz) were calculated. Relative power = (absolute power-baseline power)/baseline power×100 %.

1.4 Histology

After the EEG recording, an anode current (DC, 6 V, 10 s) was applied to the target areas via the recording electrodes. Then the animals were sacrificed by overdose anesthetization and perfused with SAL, and fixed with formaldehyde solution (4%, containing 1% potassium ferrocyanide) via the aorta ascendens. The brain was removed and fixed for at least 7 d, and the electrode position was examined by vibrating section (100 μm) and cresyl violet staining.

1.5 Data Analysis

All the data were shown as mean ± standard error of mean (SEM). Paired sample t test was used for intra-group data comparison, and independent sample t test was used for inter-group data comparison. One-way analysis of variance (ANOVA) with multiple comparisons was used for comparison between groups. Two-factor data for time and extinction/NX treatment were compared using repeated measures of two-way analysis of variance (general linear model with repeated measure, GLM-RM). The statistical results were considered statistically significant at P < 0.05.

2 Results

2.1 Histology and CPP Behaviors

The electrode position was shown in Fig. 2(a). Histological examination showed that the electrode position from 8 animals was wrong, and their EEG data were excluded. There was no significant gender difference in CPP scores (independent sample t test, T 30 = 0.987, P =0.332). Therefore, in the following text, gender is no longer differentiated for discussion. Paired sample t test showed that, after 10 d of training, the CPP scores did not change significantly from the baseline in the SAL group (T 15 = 0.820, P = 0.425). But in the MOR group, there was a significant increase compared with its baseline or the SAL group (paired or independent sample t test, both P = 0.000), indicating that the MOR-CPP mouse model was successfully established (Fig. 2(b) and (c)).

thumbnail Fig. 2 Effects of different extinction treaments on the MOR-CPP scores in mice

(a) Photos of the position of the recording electrode tips (coronal slices with cresyl violet staining); (b) training extinction; (c) natural extinction; The arrows indicated the target area in the dorsal or ventral hippocampus; * P < 0.05, ** P < 0.01 (independent-sample t test, vs. SAL); # P < 0.05, ## P < 0.01 (paired-sample t test, vs. baseline)

From the perspective of extinction method, the CPP score of NE group was still higher than the baseline after 5 d of NE treatment (paired sample t test: T 7 = -1.655, P = 0.000), indicating that NE could not cause the complete extinction of MOR-CPP (Fig. 2(c)). However, with the increase of extinction days, the CPP score in the TE group decreased gradually and reached the baseline level after 5 d of training (T 7 = -0.129, P = 0.901 vs. baseline), which was also lower than that in the NE group (independent sample t test, T 14 = 4.259, P = 0.000), suggesting that TE treatment could effectively promote the extinction of MOR-CPP (Fig. 2(b)).

2.2 Total EEG Power

Effects of different extinction treatments and naloxone on the total EEG power in mouse DH and VH are shown in Fig. 3.

thumbnail Fig. 3 Effect of different extinction treatments and naloxone on the total EEG power in mouse dorsal and ventral hippocampus

(a) Absolute lineal power from DH; (b) Relative lineal power from DH; (c) Absolute lineal power from VH; (d) Relative lineal power from VH; * P < 0.05, ** P < 0.01 (ANOVA, significant difference between groups at the same phases after NX injection); BL: baseline

As shown in Fig. 3(a) and (c), ANOVA showed that the baseline level of total power of DH-EEG was similar among all groups (F 3,20 = 0.339, P = 0.798), while the baseline level VH-EEG was different between groups (F 3,20 = 6.848, P = 0.000). Multiple comparisons showed that the difference was mainly affected by extinction methods (NE vs. TE, both P ≤ 0.05; SAL vs. MOR, both P ≥ 0.564). GLM-RM analysis showed that the absolute total power of hippocampal EEG had a time main effect (P = 0.000 for both), suggesting that the total power of EEG in both brain regions increased significantly with time after NX treatment. The time × drug interaction effect was significant (all P ≤ 0.005), suggesting that MOR treatment reduced the growth rate of total EEG power in both brain regions (compared with SAL). The interaction effect of time × extinction was different (DH: F 2.584, 51.670 = 3.320, P = 0.033; VH: F 4.036, 80.727 = 1.230, P = 0.305), which indicated that the increase of total DH-EEG power after NX injection was related to both MOR/SAL treatment and extinction methods, while the increase of VH-EEG was only affected by MOR treatment. GLM-RM analysis showed that the DH-EEG total power between groups was mainly affected by drugs (F 1, 20 = 6.795, P = 0.017) rather than the extinction methods (F 1, 20 = 0.183, P = 0.674); the VH-EEG total power was influenced by the drug and the extinction methods (all F 1,20 ≥ 9.948, P ≤ 0.005). If drug × extinction factors were combined, the difference between the two groups disappeared (F 1, 20 =0.268, P = 0.610), suggesting that drug and extinction method were independent influencing factors.

As shown in Fig. 3(b) and (d), the relative total power excludes the baseline difference. GLM-RM analysis showed that the relative total power of hippocampal EEG was similar to the absolute total power, and there was a time main effect (both P = 0.000), suggesting that the total power of EEG in both brain regions increased significantly with time after NX injection. Different time × drug interaction effects (DH: F 2.480, 31.195 = 5.266, P = 0.006; VH: F 5, 80 = 1.485, P = 0.204) suggest that MOR treatment reduced the growth rate of DH-EEG relative total power, but had nothing to do with the growth rate of VH.

The interaction effect of time × extinction was not significant (all P ≥ 0.132), which showed that the relative total power of EEG in the two brain regions was not affected by extinction methods after NX injection. GLM between groups effects showed that the relative total power of EEG in the two brain regions was mainly caused by MOR treatment (all P ≤ 0.011), while the extinction methods had no significant effect (all P ≥ 0.968).

2.3 EEG Power Spectrum

As shown in Fig. 4, the VH powers of θ, β, γ1 and γ2 were higher than DH powers in SAL-NE or SAL-TE, indicating the different EEG power of the two hippocampal regions in normal mice. Although the total EEG power levels of SAL and MOR were similar, the VH baseline power of γ2 from MOR-TE was higher than that of SAL-TE, while the power of β, γ1 and γ2 from MOR-NE was lower than that of SAL-NE (multiple comparisons, all P < 0.05; Fig. 4(b)). Compared with the NE treatment, the VH power of β, γ1, γ2 (SAL-TE) and γ1 (MOR-TE) was depressed in TE groups (multiple comparisons, P<0.05), suggesting that the lower total power of VH-TE at baseline was mainly caused by the depression of the power of β and γ bands.

thumbnail Fig. 4 Effect of extinction treatments on the hippocampal EEG power spectrum (baseline) in mice

Independent sample t test: * P < 0.05, ** P < 0.01 vs. SAL; # P < 0.05, ## P < 0.01 vs. NE; paired sample t test: & P < 0.05, && P < 0.01 vs. VH

After NX injection, the β, γ1, and γ2 powers of DH and VH in the SAL group increased over time compared with their baseline in both TE and NE treatment (paired sample t test, all P ≤ 0.05), and the δ, θ, and α powers of SAL-DH also increased (all P < 0.05, Fig. 5). In the MOR group, power at most frequency bands had no significant change from baseline (P > 0.05, Fig. 5), except that DH-δ (60 min) and VH-θ (40 min), β (30-60 min) and γ2 (10-40 min, 60 min) were increased by NE treatment (all P < 0.05).

thumbnail Fig. 5 The hippocampal EEG power spectrum changing (Δ/%) after naloxone treatment in mice

BL: baseline; One-way ANOVA: * P < 0.05, ** P < 0.01

In terms of extinction method, the α power of DH/VH treated by SAL-NE after NX injection (DH: 20-60 min; VH: 20-40 min) was higher than that in TE group, but not in MOR group (multiple comparisons: P < 0.05). In addition, the power of some frequency bands (δ: SAL, 60 min, β: MOR, 50 min and γ2: SAL/MOR, 60 min) of DH-NE was higher than that of TE. The power of θ (MOR: 40-60 min), β (SAL/MOR: 30-60 min), γ1 (SAL/MOR: 10-60 min) and γ2 (SAL/MOR: 20-60 min) of VH-NE also increased with time (P < 0.05).

3 Discussion

According to Pavlovian conditioning theory, CPP experiments are used to measure the degree of psychological addiction of animals to reward substances under certain circumstances[13]. In this study, the CPP scores of KM mice were significantly higher than those of SAL group and its own baseline after 10 d of treatment with MOR by increasing the dose of MOR every other day, indicating that the establishment of MOR-CPP was successful. On this basis, the effects of TE and NE were detected, and the results showed that, after 5 d of treatment, the CPP scores of the TE group had dropped to the baseline level, while the CPP scores of the NE group were still high (see Fig. 2(b) and (c)). This result is similar to the results obtained from research on mice of Ref.[14], and rats by using constant doses (10 mg/kg) for CPP modeling and TE treatment[15-17], proving that TE treatment can completely extinguish MOR-CPP in a shorter time than NE treatment.

EEG power spectrum is widely used to study the functional state of the brain. Previous studies using wireless telemetry have found that the context of the drug-paired box during the extinction period of opioid CPP was accompanied by the decrease of δ+θ power of the nucleus accumbens shell region and the increase of β power[18], as well as the decrease of θ power in the prefrontal infralimbic area[19]. Studies have also shown that chronic MOR treatment can increase DH-θ and γ power in mice and rats[8, 9]. The total power of DH-EEG and the δ, θ and α bands power of rats with established MOR-CPP showed an increasing trend[7]. In this study, it was found that the total power of DH-EEG of MOR-CPP animals was similar to that of SAL group, regardless of TE or NE treatment, after 5 days of extinction treatment (Fig. 3(a)), which was the same as that of other brain regions in the extinction phase and DH in the non-extinction phase. However, the total power of VH-EEG in TE treatment was significantly lower than that in NE treatment (in SAL group or MOR group, Fig. 3(c)), suggesting that the change of total power of VH-EEG was mainly related to the extinction method, rather than MOR drug, and TE treatment could selectively reduce the total power of VH-EEG.

Power spectrum analysis showed that the baseline power of γ1, γ2 and β in SAL-VH area was decreased by TE treatment compared with NE treatment. The baseline power of β, γ1 and γ2 in MOR-VH treated by NE was lower than that in SAL group. It is worth noting that the baseline γ2 power of MOR-VH treated by TE was higher than that of SAL, while only γ1 power of MOR-VH treated by NE was higher than that of TE (Fig. 4). These results indicate that MOR, NE and TE treatments have different effects on the EEG power spectrum of the hippocampus (DH or VH), and mainly affect the β and γ bands of VH. The VH-EEG power spectrum was better than DH to reflect the behavioral changes of MOR-CPP extinction. However, although TE can promote the extinction of MOR-CPP, the hippocampal EEG of animals with MOR addiction extinction is still different from that of normal animals, which may be related to the relapse of drug addiction. As an important brain region associated with cognitive function, hippocampus EEG-θ, γ and θ-γ co-oscillations are closely associated with cognitive functions such as learning and memory and MOR addiction memory[7, 20, 21]. DH and VH differ greatly in development, anatomy, circuitry, molecular characteristics, synaptic plasticity, and function[10, 22]. Although both are involved in the memory process of MOR addiction, several studies in recent years have suggested that VH plays an important role in the mechanisms of nicotine[22], cocaine[23] and opioid addiction[6, 7, 11, 24]. The present study further proved that the change of VH-β and γ band power is directly related to the extinction of opioid addiction and the extinction method.

Opioid receptor antagonist NX can stimulate the central nervous system, promote arousal and recovery of consciousness, and is mainly used for opioid detoxification first aid and relapse prevention in clinical settings[25]. In this study, it was found that NX injection could increase the total power of EEG in DH and VH in SAL mice and its multiple power spectrum components, especially the high-frequency fast wave power (such as β, γ1 and γ2), which is similar to previous reports[26]. However, the EEG power of MOR mice did not increase significantly, and was lower than that of SAL group. The θ, β and γ2 power of MOR-VH treated with NE only increased (Fig. 4). The increased power of high-frequency fast waves, such as β and γ, indicates that the animals' cerebral cortex activity is more desynchronized, suggesting that NX does play a role in promoting arousal. On the one hand, the significant difference in EEG power spectrum between the MOR-CPP extinct mice and the SAL group indicates that MOR addiction has a profound effect on hippocampal function, and this effect is difficult to eliminate by extinction treatment only for a few days. This may be related to the damage of gene expression and molecules, and plasticity of neurons caused by opioid addiction[27-30]. On the other hand, since the MOR-CPP of NE treated animals did not actually extinguish to the baseline level during EEG recording and still had a higher CPP score, the difference in VH-EEG power spectrum between TE and NE treatment may only reflect the degree of hippocampal CPP memory extinction.

4 Conclusion

This study firstly found that the total power and power spectrum of dorsal hippocampal EEG of MOR-CPP extinction mice are similar to those of normal mice, but the correlation between the power spectrum of ventral hippocampal EEG, especially the power of β and γ bands, and the extinction methods are higher. Opioid receptor antagonist NX can improve the total EEG power and β and γ frequencies of DH-VH in normal animals, but the effect of promoting the EEG power of MOR-CPP extinction animals is limited. The role of the hippocampus in opioid addiction-extinction and the mechanism of opioid receptors remain to be further investigated.

Acknowledgments

We are grateful to FU Zhichao, WANG Xia, LIU Yingqing, YAO Linghong, and ZHOU Ying from the Yunnan Normal University for their assistance in animal behavioral experiment.

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All Figures

thumbnail Fig. 1 Timeline of behavioral and EEG experiments after different extinction treatments on the morphine-CPP mice

CPP: conditioned place preference; SAL: saline; MOR: morphine; TE: training extinction; NE: natural extinction; NX: naloxone
In the text
thumbnail Fig. 2 Effects of different extinction treaments on the MOR-CPP scores in mice

(a) Photos of the position of the recording electrode tips (coronal slices with cresyl violet staining); (b) training extinction; (c) natural extinction; The arrows indicated the target area in the dorsal or ventral hippocampus; * P < 0.05, ** P < 0.01 (independent-sample t test, vs. SAL); # P < 0.05, ## P < 0.01 (paired-sample t test, vs. baseline)
In the text
thumbnail Fig. 3 Effect of different extinction treatments and naloxone on the total EEG power in mouse dorsal and ventral hippocampus

(a) Absolute lineal power from DH; (b) Relative lineal power from DH; (c) Absolute lineal power from VH; (d) Relative lineal power from VH; * P < 0.05, ** P < 0.01 (ANOVA, significant difference between groups at the same phases after NX injection); BL: baseline
In the text
thumbnail Fig. 4 Effect of extinction treatments on the hippocampal EEG power spectrum (baseline) in mice

Independent sample t test: * P < 0.05, ** P < 0.01 vs. SAL; # P < 0.05, ## P < 0.01 vs. NE; paired sample t test: & P < 0.05, && P < 0.01 vs. VH
In the text
thumbnail Fig. 5 The hippocampal EEG power spectrum changing (Δ/%) after naloxone treatment in mice

BL: baseline; One-way ANOVA: * P < 0.05, ** P < 0.01
In the text

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