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Journal of Diabetes and Metabolic Disorders logoLink to Journal of Diabetes and Metabolic Disorders
. 2022 Nov 17;22(1):275–285. doi: 10.1007/s40200-022-01129-6

Modulation of social and depression behaviors in cholestatic and drug-dependent mice: possible role of opioid receptors

Fatemeh Khakpai 1, Niloofar Rezaei 2, Yasaman Issazadeh 2, Mohammad-Reza Zarrindast 2,3,4,✉
PMCID: PMC10225439  PMID: 37255824

Abstract

Objectives

Social behavior, a set of motivating activities critical for survival, is disturbed in cholestasis conditions and many substance abusers as well as psychiatric disorders. The documented loss of social interest in cholestatic patients may be associated with depressive symptoms. Interestingly, the endogenous opioid system is involved in the modulation of depression.

Methods in this research

, we assessed the effect of cholestasis and drug dependence on social and depression behaviors using the Three-Chamber Paradigm Test, Forced Swim Test (FST), and Tail Suspension Test (TST) as well as Open Field Test (OFT) in male NMRI mice.

Results

The results indicated that alone administration of morphine and tramadol, as well as co-administration of them, increased social motivation and novelty but decreased depression in bile duct ligated mice. Whereas, alone administration of naloxone (a µ-opioid receptor antagonist) and co-administration of it along with morphine and tramadol decreased social motivation and novelty while enhanced depression in the sham-operated and bile duct ligated mice. These administrations of drugs did not change locomotor activity compared to the control group.

Conclusion

In conclusion, it appears that (i) both cholestasis and drug dependence impaired social motivation behavior, as well as induced depression-like behavior in the bile duct, ligated mice, (ii) alone administration of morphine and tramadol as well as co-treatment of them may protect against cholestasis and drug dependence induced abnormal behaviors, (iii) µ-opioid receptors play an important role in modulation of social motivation and depression behaviors in mice.

Keywords: Cholestasis, Drug dependence, Social behaviors, Depression, Opioid, Mice

Introduction

Obstructive cholestasis is induced through common bile duct ligation during surgical laparotomy. It is described clinically via pruritus, jaundice, discolored urine, and pale stools [1, 2]. Moreover, it causes bile duct obstruction, hepatitis, biliary cirrhosis, cholangiocarcinoma, portal hypertension, and depression as well as a loss of social behaviors [3–5]. Similarly, clinical studies revealed that a loss of social interest is frequently observed by health care providers of patients with Primary Biliary Cirrhosis [6]. There is evidence that cholestasis influenced the activity of the central nervous system (CNS) [7]. So, enhanced opioidergic neurotransmission in the brain has been assumed to be a component of the pathophysiology of cholestasis which is involved in pruritus, hypotension, and encephalopathy of cholestasis [8]. Documents supporting this increased opioidergic tone include the involvement of opioid withdrawal syndrome via application of an opioid antagonist, both in cholestatic patients and in a mouse model of cholestasis [9]. Furthermore, it has been reported global down-regulation of µ-opioid receptors in the brain of rodents with cholestasis [10, 11]. Symptoms related to the cholestasis are reversed or somewhat ameliorated through µ-opioid receptor antagonists. Opioid receptor antagonists have been revealed to relieve several symptoms, except for pruritus, and recover liver function as revealed in experimental cholestasis [12, 13].

Drug dependence is described as the need for sustained drug exposure to evade a withdrawal syndrome, which is determined through physical and motivational disturbances when the drug is withdrawn [14, 15]. The molecular basis for the action of opiates is recognized as being through interaction with a family of receptors (µ, γ, κ, ε, δ) of which the µ-receptor is possibly primarily responsible for the functions of morphine and the other abused opiate drugs [16, 17]. Morphine dependence is usually determined via serious affective and physical disorders, for example, irritability, anxiety, nausea, chills, sweating, diarrhea, sneezing, muscular and abdominal pain, depression as well as social behavior deficiency [18–21]. In addition, tramadol abuse and dependency have been enhanced recently. Tramadol exerts a weak agonist influence via binding to µ- and κ-opioid receptors. It also influences monoamine systems, where it inhibits the uptake of norepinephrine and serotonin, thereby reducing pain transmission in the spinal cord [22, 23]. Studies revealed that endogenous opioids via µ-receptors are involved in depressed mood [24], and social bonding as well as affiliative behaviors [25–27].

Having and preserving close social bonds is necessary for health, well-being, and normal activities [28]. However, chronic cholestasis causes a loss of social interest and anhedonia [29]. On the other hand, opioid system function increased in cholestasis disease [8]. Biotransformation of most opioids is performed in the liver, so the disposition of opioids may be affected in cholestasis diseases [30]. Considering the above, we decided to evaluate the effect of cholestasis and drug dependence on social behaviors and depression in mice.

Materials and methods

Animals

Male NMRI mice weighing 25–30 g were obtained from the Tehran University of Medical Sciences, Tehran, Iran. Mice were housed in groups of 8 in Plexiglas cages at a steady room temperature (22 ± 2 ◦C) with a 12 h light/dark cycle. Mice had been fed with a standard balanced diet and tap water except during the limited time of tests. Behavioral tests were performed during the light phase of the light/dark cycle. Eight mice were used in each group and each mouse was used once only. All experimental procedures and animal use were confirmed by the Research and Ethics Committee of the Tehran University of Medical Sciences and were performed under institutional guidelines for the care and use of laboratory animals (NIH publications no. 80 − 23; revised 1996).

Surgical laparotomy

Two experimental groups including sham and bile duct ligation were used in experimental groups. These groups underwent laparotomies, which were done under general anesthesia induced via intra-peritoneal (i.p.) administration of a mixture of ketamine/xylazine (50 and 5 mg/kg, respectively). The sham operation group consisted of laparotomy, bile duct determination, and manipulation however without ligation. In the bile duct ligation group, the common bile duct was completely exposed, ligated at two points about 5 mm apart, and transected at midpoint among the ligatures. After the closure of the abdominal wound, the mice received 1 ml of saline (i.p.) and were conveyed to a clean box until complete recovery. Mortality due to operation was under 5% during and/or after surgery.

Induction of dependence

5–7 days after bile duct ligation surgery, animals were rendered dependent on morphine (morphine-dependent group) and tramadol (tramadol dependent group) as well as morphine + tramadol (morphine + tramadol dependent group), based on the protocol performed previously [31]. Morphine sulfate was administrated subcutaneously (s.c.) and tramadol was administrated i.p. Administration of drugs was performed three times daily at 8, 12, and 16 h on the doses of 25, 50, and 75 mg/kg, respectively. The highest dose of the third daily application was used to reduce any overnight withdrawal (acute administration). Morphine or tramadol administration was performed over a maximum of 3 days for any group of animals (chronic administration). A dose of 50 mg/kg of morphine sulfate or tramadol was also injected on the 4th day (2 h before to naloxone administration). Loss of weight (5–8%) and death (1%) was detected with a chronic application of morphine sulfate or tramadol. Dependence was proven by s.c. injection of naloxone (2 mg/kg). Withdrawal symptoms such as jumping, wet-dog shakes, diarrhea, and urination were recorded 5 min after naloxone injection for 30 min.

Drugs

The drugs which have been used in the experiment were morphine sulfate (Temad, Iran), Tramadol hydrochloride (Tehran-Daru, Iran), and naloxone hydrochloride ampoules (Daru-Pakhsh, Iran). All drugs were dissolved in a sterile physiological solution. Morphine and naloxone were injected s.c. but tramadol was injected i.p. at a volume of 10 ml/kg. The control group received saline.

Three-Chamber paradigm test

Three-chamber paradigm test performed based on our previous research [32]. Three-chamber paradigm test used for evaluation of social communication skills. In order to evaluate Three-Chamber Paradigm Test, there were 3 important phases including habituation phase (5 min), social affiliation and sociability phase (or session I, 10 min), and social novelty/preference and social memory phase (session II, 10 min).

Forced swim test (FST)

Mice were individually located within glass cylinders (height: 25 cm and diameter: 10 cm) containing 19 cm of water and kept at 25 °C. Mice were left in the cylinder for 6 min. After the first 2 min, the total period of immobility was recorded during a 4 min test. The mouse was judged to be immobile when it stayed floating passively [33].

Tail suspension test (TST)

The total time of immobility produced by tail suspension was measured according to the previous study [33]. In this method, mice both acoustically and visually isolated were suspended 0.5 m above the floor through adhesive tape placed about 1 cm from the tip of the tail. Immobility time was recorded during a 6 min period of the TST.

The Open Field Test (OFT)

All mice were studied by the open field test. All tests were carried out in a room with poor lighting in silence and without any preceding habituation. Mice were kept in the test room for 15 min previous to the trial for adaptation. The Test chamber was black, and square, with sizes of 50 × 50 cm and 40 cm in height walls. The floor of the test chamber was divided into 16 squares. The locomotor activity of mice was measured for 6 min in the open field test. Line passage frequency with which mice go across one of the lines with all 4 paws was measured through the camera and manually observed and recorded. The open-field test was done according to the previously described procedure [33].

Experimental design

The current research consisted of 3 experiments. In experiments 1 and 3, eight mice were used in each experimental group. In experiment 2, ten mice were used in each experimental group. Eight mice were used for the behavioral test (data recording) and two mice were used as partners (i.e. strangers I and II). Stranger I or II were always the same. The relationship between eight mice of each experimental group which changed in each experiment and partners (i.e. strangers I and II) who were continually similar, were recorded.

In experiment 1, the effects of acute and chronic administration of morphine (50 mg/kg) and tramadol (50 mg/kg) as well as morphine (50 mg/kg) + tramadol (50 mg/kg) on the withdrawal symptom (jumping) induced by naloxone (2 mg/kg) were investigated in sham-operated and bile duct ligated mice. In experiment 2, the effects of saline (10 ml/kg), naloxone (2 mg/kg), morphine (50 mg/kg), tramadol (50 mg/kg), morphine (50 mg/kg) + tramadol (50 mg/kg), morphine (50 mg/kg) + naloxone (2 mg/kg), tramadol (50 mg/kg) + naloxone (2 mg/kg) and morphine (50 mg/kg) + tramadol (50 mg/kg) + naloxone (2 mg/kg) on social behaviors were investigated in sham-operated and bile duct ligated mice. In experiment 3, the effects of mentioned doses of drugs on the performance of mice in the FST, TST and OFT were examined Fig. 1 indicated the experimental procedure.

Fig. 1.

Fig. 1

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Experimental procedure

Statistical analyses

All obtained results are expressed as mean ± standard error of the mean (S.E.M.). The student’s t-test was used to assess social behaviors in Three-Chamber Paradigm Test. Statistical significances in the FST, TST and OFT were evaluated through the use of one-way analysis of variance (ANOVA) followed by Post-hoc multiple comparisons to analyze opioid drugs action, or two-way ANOVA was performed to analyze the interactions between the drug combination compared to the individual treatment in sham-operated and bile duct ligation groups. In addition following a significant F-value, Post-hoc analysis was used to evaluate differences between groups. Significant differences were considered at P < 0.05.

Histology

At the end of tests, liver tissues were inspected. These tissues assessed for confirmation of bile duct ligation surgery. For this, the liver tissues were fixed in 10% formalin for 7–10 days. Liver tissue preparation was made by routine histological procedures. Using the hematoxylin-eosin technique, histological Sect. (4 μm) were stained for morphological assessment (Fig. 2) [34].

Fig. 2.

Fig. 2

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Histological sections of liver tissue in sham-operated and bile duct ligated mice

Results

The effects of acute and chronic administration of opioid agonists on the withdrawal symptom (jumping)

Figure 3 is indicated that administration of morphine or tramadol and co-injection of them on the administration of naloxone alone induced jumping behavior in sham-operated and bile duct ligated mice. Both groups received morphine, tramadol, and morphine along with tramadol (as described in the induction of dependence section) to induce drug dependence as well as naloxone (2 h after opioid agonists injection) to confirm drug dependence by assessing withdrawal symptoms such as jumping. Two-way ANOVA followed by LSD test (shown in Fig. 3 A) revealed a significant effect of treatment [F (1, 42) = 21.30, P = 0.000], and dose-effect [F (2, 42) = 3.682, P = 0.031] but no significant effect of treatment × dose interaction [F (2, 42) = 0.271, P = 0.764] on jumping in acute treatment-vs. chronic treatment of sham-operated animals. As shown in Fig. 3B two-way ANOVA followed by LSD test indicated a significant effect of treatment [F (1, 42) = 18.681, P = 0.000] and dose-effect [F (2, 42) = 4.490, P = 0.043] but no significant effect of treatment × dose interaction [F (2, 42) = 0.168, P = 0.846] on jumping behavior in acute treatment-vs. chronic treatment of bile duct ligated animals. Moreover, Post-hoc analyses indicated that chronic treatment with morphine, tramadol, and morphine + tramadol increased jumping in chronic treatment-vs. acute treatment of both sham-operated and bile duct ligated animals.

Fig. 3.

Fig. 3

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Effects of acute and chronic injection of morphine, tramadol, or both on expression of naloxone-induced jumping behavior. (A) In sham-operated mice. (B) In bile duct ligated animals. Data expressed as mean ± S.E.M. +P < 0.05 compared to the respective groups. * P < 0.05 and ** P < 0.01 compared to saline control group

The effect of bile duct ligation and drug dependence on social behaviors

Session I

As is indicated in Fig. 4 A, independent t-test results displayed that there was a statistically significant difference between stranger1 and empty means in the sham-operated mice treated with opioid drugs. The mice treated with alone administration of morphine [t = 2.518, P = 0.025] or tramadol [t = 6.349, P = 0.000] and co-administration of morphine plus tramadol [t = 4.783, P = 0.000] spent significantly more time in the compartment with stranger 1 compared to the empty compartment. This behavioral response was alike to the response produced by saline [t = 2.390, P = 0.031] in the control group. On the other hand, the animals were treated with an alone injection of naloxone [t = 2.502, P = 0.025] and co-injection of morphine plus naloxone [t = 2.113, P = 0.050], as well as tramadol plus naloxone [t = 2.494, P = 0.026], spent significantly less time in the chamber with stranger 1 compared to the empty chamber.

Session II

In the second session, the mice were allowed to select to communicate with the mouse that they have previously interacted with (stranger 1) or the mouse that has just entered the empty compartment (stranger 2). The animal’s tendency to communicate with the newer mouse displays a healthy social memory and a preference for novel experiences. Outcomes in Fig. 4B showed that sham-operated mice receiving morphine [t = 3.471, P = 0.004] and tramadol [t = 2.726, P = 0.016] as well as morphine + tramadol [t = 5.590, P = 0.000] indicated a predilection for the compartment with a new hosted mouse (stranger 2) over the compartment with the now-familiar mouse (stranger 1). This behavioral response was alike to the response produced by saline [t = 2.716, P = 0.017] in the control group. However, sham-operated mice receiving naloxone [t = 2.833, P = 0.013], morphine + naloxone [t = 2.270, P = 0.40] and tramadol + naloxone [t = 2.720, P = 0.015] spent significantly less time in the section with stranger 2 compared to the section with stranger 1.

Fig. 4.

Fig. 4

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Effect of bile duct ligation and drug dependence on social behaviors. (A) Time length in the section with stranger 1 in comparison to the opposite empty section in sham-operated animals. (B) Mean duration of time (mean ± S.E.M.) in the compartment with the familiar mouse from sociability phase stranger 1 and the opposite compartment with a new mouse stranger 2. (C) Time length in the section with stranger 1 in comparison with the opposite empty section in bile duct ligated mice. (D) Mean duration of time (mean ± S.E.M.) in the chamber with the familiar animal from sociability phase stranger 1 and the opposite chamber with a new animal stranger 2. Each bar showed a mean ± S.E.M of time length

Significant differences: * P < 0.05, ** P < 0.01 and *** P < 0.001 compared to saline group

Session I

The independent t-test in Fig. 4 C showed that the bile duct ligated mice that were treated by alone application of naloxone [t = 2.502, P = 0.015] and co-application of morphine + naloxone [t = 2.220, P = 0.047] as well as tramadol + naloxone [t = 2.152, P = 0.039] spent significantly less time in the part with stranger 1 in comparison to the empty part. This behavioral response was similar to the response elicited by the saline group [t = 3.138, P = 0.007]. Nevertheless, the bile duct ligated mice treated with an alone injection of morphine [t = 6.287, P = 0.000] or tramadol [t = 2.381, P = 0.032] and co-injection of morphine + tramadol [t = 7.278, P = 0.000] spent significantly more time in the section with stranger 1 in comparison to the empty section.

Session II

The results of the test in Fig. 4D showed that bile duct ligated mice treated by saline [t = 3.075, P = 0.008], naloxone [t = 2.402, P = 0.030], and morphine + naloxone [t = 2.641, P = 0.019] as well as tramadol + naloxone [t = 2.430, P = 0.029] spent significantly less time in the compartment with stranger 2 compared to the compartment with stranger 1. Nonetheless, bile duct ligated mice treated by morphine [t = 4.729, P = 0.000], tramadol [t = 2.849, P = 0.011] as well as morphine + tramadol [t = 7.867, P = 0.000] exhibited a predilection for the chamber with stranger 2 over the chamber with stranger 1.

The effect of bile duct ligation and drug dependence on depression

Figure 5 A indicated the effect of bile duct ligation and drug dependence on immobility time in the FST. Two-way ANOVA indicated that there was no significant interaction between bile duct ligation and drug dependence on immobility time in the FST [bile duct ligation effect: F (1, 112) = 3.588, P = 0.05; drug dependence effect: F (15, 112) = 6.471, P = 0.004; bile duct ligation × drug dependence interaction: F (15, 112) = 0.478, P = 0.849]. However, Tukey’s Post-hoc analysis showed that bile duct ligated mice receiving saline indicated higher immobility time in the FST when compared with the sham-operated control group.

Fig. 5.

Fig. 5

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Effect of bile duct ligation and drug dependence on depression related behaviors. (A) Immobility time in Forced Swim Test. (B) Immobility time in the Tail Suspension Test. (C) Locomotor activity. Data presented as mean ± S.E.M. * P < 0.05 and ** P < 0.01 compared to saline control group. + P < 0.05 and + + P < 0.01 compared with the saline group

The effect of bile duct ligation and drug dependence on immobility time in the TST is seen in Fig. 5B. Two-way ANOVA showed that there was any significant interaction among bile duct ligation and drug dependence on immobility time in the TST [bile duct ligation effect: F (1, 112) = 20.343, P = 0.000; drug dependence effect: F (15, 112) = 4.696, P = 0.024; bile duct ligation × drug dependence interaction: F (15, 112) = 0.340, P = 0.934]. Nevertheless, Post-hoc analysis exhibited that bile duct ligated mice receiving saline displayed more immobility time in the TST when compared with the sham-operated control group.

Figure 5 C showed the effect of bile duct ligation and drug dependence on locomotor activity in the OFT. Two-way ANOVA indicated no significant effect between bile duct ligation and drug dependence on locomotion [bile duct ligation effect: F (1, 112) = 1.308, P = 0.255; drug dependence effect: F (15, 112) = 0.198, P = 0.985; bile duct ligation × drug dependence interaction: F (15, 112) = 0.141, P = 0.995].

Discussion

Social interaction, a set of motivated behaviors necessary for survival, is the suite of interactions between individuals of the same species [21]. Social interest can be evaluated as the time that a male mouse spends investigating a male mouse when they are located together, in comparison with the time spent on empty means in the Three-Chamber Paradigm Test. The time a rodent spends investigating another rodent located in close vicinity has been used as a validated method of social exploration and interest. Usually, animals display intense interest to communicate with the newer animal [32]. The results of the current study indicated that treatment with morphine or tramadol and co-treatment of them enhanced social motivation and novelty, whereas treatment with naloxone and co-injection of it along with morphine or tramadol reversed the responses induced by morphine and tramadol in the sham-operated and bile duct ligated mice. Therefore, we proposed that bile duct ligation and naloxone, µ-opioid antagonist, caused less innate social behaviors as well as less social motivation and novelty in mice, while opioid agonists including morphine and tramadol induced intact social memory and novelty. Our results are in agreement with previous findings, in which a loss of social interest was detected in cholestatic rats. The results are also similar to findings that drug dependence on drugs of abuse affected social behaviors [35]. For instance, investigations evaluating social behavior in humans propose that drugs of abuse can trigger aggressive behaviors and that aggressive individuals show a higher rate of substance abuse than the general population [36]. The relationship between substance abuse and aggressive behavior has already been proven in experimental animals. Likewise, reciprocal interactions between drugs of abuse and social behaviors have been thoroughly demonstrated in human and animal studies [21].

Having and maintaining close social bonds is so important to health, well-being, and normal activities that bonding has been referred to as a basic need, similar to the need for food and water [28]. Data from animal and human studies support the theory that the opioid system is involved in social bonding [25]. For instance, in chicks, blocking opioid function through an opioid antagonist caused enhanced distress vocalizations when chicks were located together in a group, proposing that the chicks were no longer experiencing the pleasure of being in a group [25]. In addition, clinical research indicated a relationship between social isolation and the use of various drugs of abuse [35]. A growing body of investigations revealed that the endogenous opioid system is centrally involved in responses to social stimuli, modulating the distress of social rejection [37, 38], and mediating positive responses to social acceptance as well as affiliative behavior [20]. However, there are contradictory results. For example, Slamberova et al. (2016) reported that morphine decreased the social interaction of male rats [39]. On the other hand, studies in rats have exhibited that endogenous opioids are released in various brain areas during social play behavior [26]. Opioid antagonists (such as naloxone) can decrease social play behavior in rodents [40]. Further research has revealed that endogenous opioids have an overall modulatory effect on social play behavior in rats whereas non-social play behavior does not modulate through the endogenous opioid system [26]. Furthermore, regarding the effect of opioids on social rewards, morphine (vs. naltrexone) causes higher attractiveness scores for the most attractive faces indicated, proposing that opioids can improve the social reward of some stimuli [41]. Additionally, Hsu et al. (2013) reported that enhanced desire for social interaction is related to µ-opioid receptor coupling in the left ventral striatum, a reward, and association-related area, in response to receiving social feedback which one is ‘liked’ by an opposite-sex stranger (vs. baseline) [38, 42]. Together, reports from the human and animal literature show the probability that µ-opioid receptors involve in the experience of social bonding as well as connecting with close others. These findings highlight the importance of opioids for social behaviors and lending support to the brain opioid theory of social behaviors [25].

Due to the relation between cholestasis and loss of social interest that may be consistent with depression behavior in mice [29], we examined the effect of bile duct ligation and drug dependence on depression behavior. Our results showed no significant interaction between bile duct ligation and drug dependence on depression behavior. Moreover, the results indicated that naloxone increased depression behavior in sham-operated mice. On the other hand, injection of morphine and tramadol, as well as co-injection of them, decreased depression behavior in bile duct ligated mice. Also, the doses of drugs used in the current research did not change the locomotor activity of animals. Additionally, decreased social motivation in cholestatic animals may induce behaviors that are related to depression-like behaviors. The reason for this proposition is presumed by the eminence of energy-correlated difficulties in depressive disease [29]. As mentioned previously, endogenous opioids increased in cholestasis conditions [10]. Several investigations revealed that endogenous opioids participate in the regulation of mood. Also, endogenous opioids are dysregulated in depressive disorder. The participation of opioids in mood modulation may cause the disproportionate use of them in patients with mood disorders e.g. depressive disorder [20, 43–46]. In agreement with our results, some investigations reported that opioids (such as morphine and tramadol) decreased immobility time in FST [47] and TST [43]. These effects were blocked through pretreatment with µ-opioid receptor antagonists (e.g. naloxone) [20]. In addition to the analgesic properties of opioids, they are also well-known for their anxiolytic and antidepressant properties. In preclinical and clinical research, some opioids indicated encouraging results to alleviate depression-like behaviors. It is demonstrated that opiates have a direct effect on depressed mood via direct actions on µ-opioid receptors [24]. So preclinical studies have reported that activation of µ-opioid receptors has antidepressant-like activities [20, 43–45]. Also, opiates may have an additional antidepressant influence by promoting serotonin release via neurons placed in the raphe nucleus. For example, tramadol is a synthetically produced, low potency µ-opioid receptor agonist, which is also well-known to be an inhibitor of the reuptake of the brain monoamines serotonin and noradrenaline. The idea of using tramadol as an antidepressant drug is not new as several animal types of research have revealed antidepressant properties [48–51]. Furthermore, it has previously been reported that tramadol is effective in the FST in mice and the learned helplessness model in rats, two behavioral models predictive of antidepressant response [44]. Some results showed that tramadol has an effect comparable to clinically effective antidepressants in a test predictive of antidepressant effect, without behavioral implications [45]. It has been suggested that together with clinical and experimental data, tramadol has an inherent antidepressant-like (mood-improving) effect and this effect could have clinical repercussions on the affective component of pain behavior. Many investigations have revealed that tramadol can prevent the reuptake of noradrenaline and serotonin in the CNS [52, 53], a mechanism like that of numerous antidepressants [45]. However, tramadol needs to be more assessed for the treatment of depression, as it is short-acting, has a large therapeutic range as a weak µ-receptor agonist, and has a comparatively low risk for producing neurochemical tolerance, and relatively low risk for abuse [51, 54, 55].

Briefly, this study indicated destructive effects of both cholestasis and drug dependence on social motivation and depression behaviors as well as protective effects of morphine and tramadol against cholestasis and drug dependence produced abnormal behaviors which revealed the role of µ-opioid receptors in the control of social motivation and depression behaviors in mice.

Acknowledgements

We are thankful to all contributors for their participation. We did not receive any funding for our work.

Contributors

Rezaei N. and Esazadeh Y. acquired the animal data. Khakpai F. wrote the manuscript. Zarrindast M.R. was responsible for the study concept, and design, and assisted with the data analysis and interpretation of findings. All authors reviewed the content and approved the final version for publication. The authors declare that all data were generated in-house and that no paper mill was used.

Declarations

Conflict of interest

No financial or other conflicts of interest are declared.

Compliance with ethical standards

The study was performed under ethical standards in all aspects.

Footnotes

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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