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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 1  |  Issue : 2  |  Page : 84-90

Detecting serotonin system in rats with myocardial infarction and/or depression after selective serotonin reuptake inhibitor therapy


1 Department of Geriatric-Cardiovascular, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
2 Department of Cardiology, Beijing Anzhen Hospital Affiliated to Capital Medical University, Beijing 100029, China
3 Department of Cardiology, PLA Army General Hospital, Beijing, 100700, China

Date of Web Publication16-Nov-2017

Correspondence Address:
Meiyan Liu
Department of Cardiology, Beijing Anzhen Hospital Affiliated to Capital Medical University, No. 2 Anzhen Road, Chaoyang District, Beijing 100029
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/hm.hm_16_17

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  Abstract 


Objectives: The aim of this study is to explore the effects on serotonergic system of sertraline in the Sprague–Dawley (SD) rats of myocardial infarction (MI), depression, and depression post-MI. Methods: A total of 80 SD rats were randomly allocated into two pretreatment groups, including saline-pretreated group and sertraline-pretreated group. The sertraline-pretreated rats received sertraline and the saline-pretreated rats received saline for the past 4 weeks. Then, the two groups were randomly divided into four subgroups, respectively, including sham, MI, depression, and depression post-MI (MI + depression) subgroup. All animals were then sacrificed after 3 days to observe the effects of sertraline on levels of 5-HT, 5-HT2AR, and SERT in the rat serum, platelet, and brain. Results: As compared with saline treatment group, serum 5-HT decreased significantly in sham subgroup and increase significantly in MI, depression, and MI-depression subgroups, platelet 5-HT increased significantly, brain 5-HT decreased significantly in the four subgroups after sertraline treatment (all P < 0.05). As compared with saline treatment group, platelet 5-HT2AR decreased significantly in the sham subgroup and increased significantly in MI and depression subgroups, brain 5-HT2AR increased significantly in MI subgroup and decreased significantly in depression and MI + depression subgroups after sertraline treatment (all P < 0.05). As compared with saline treatment group, serum SERT decreased significantly in the sham subgroup and increased significantly in depression subgroup, platelet SERT decreased significantly in the four subgroups and brain SERT increased significantly in sham and depression subgroups and decrease significantly in MI subgroup after sertraline treatment (all P < 0.05). Conclusion: Sertraline regulated 5-HT concentration of peripheral blood and brain according to 5-HT2AR and SERT, thereby regulating the platelet function in various pathological states including MI, depression, and depression post-MI.

Keywords: Depression, myocardial infarction, serotonin


How to cite this article:
Ren Y, Zhang L, Wei W, Liu M. Detecting serotonin system in rats with myocardial infarction and/or depression after selective serotonin reuptake inhibitor therapy. Heart Mind 2017;1:84-90

How to cite this URL:
Ren Y, Zhang L, Wei W, Liu M. Detecting serotonin system in rats with myocardial infarction and/or depression after selective serotonin reuptake inhibitor therapy. Heart Mind [serial online] 2017 [cited 2019 Jul 16];1:84-90. Available from: http://www.heartmindjournal.org/text.asp?2017/1/2/84/218518




  Background Top


Cardiovascular disease (CVD) ranks first in the magnitude of disease burden in established market economies. Depression has been shown to join the list of heart disease risk factors which include obesity, diabetes, hypertension, and smoking. Moreover, the link between CVD and depression is well-established. However, the mechanism of the two comorbid conditions remains unclear. According to some previous studies, sympathetic nervous activation, endothelial dysfunction, and abnormal platelet activation induced by the serotonergic system have been involved in the mechanism.[1]

Previous studies demonstrate that platelet reactivity to serotonin is significantly increased in depressed patients compared with nondepressed matched controls. Further, depressed patients did not have excess platelet reactivity to adenosine diphosphate. These data suggest that serotonin-mediated platelet reactivity may play a role in the link between depression and acute coronary syndrome.[2]

Previous research suggests that selective serotonin reuptake inhibitors (SSRIs) may normalize platelet reactivity in depressed patients.[3] Since significant improvements in depressive symptoms were observed in this study, it is not known if the decrease in platelet reactivity was due to symptomatic improvement in depressive symptoms or the antidepressant's direct effect on platelet function, or both.

There is multi-evidence that SSRIs may reduce CHD morbidity and mortality.[4] Subgroup analysis of the enhancing recovery in coronary heart disease study of 1849 depressed patients followed-up over 29 months showed a survival benefit for those patients taking an SSRI.[5] Compared with patients not taking any of SSRI, treated patients had a significant 43% lower risk of death or recurrent myocardial infarction (MI), adjusted for disease severity and other factors. Moreover, the improvement in survival afforded by the SSRIs for depressed patients was in addition to that provided by the best practice care.

Sertraline is an important treatment for depression according to affect serotonin in the brain. In the Sertraline AntiDepressant Heart Attack Randomized Trial, although the study was not powered to evaluate the efficacy of sertraline on mortality, there was a tendency for sertraline-treated patients to show an improvement in a composite measure of adverse cardiovascular events.[6] Regardless of randomization to intervention or control group, those patients treated with sertraline had a decreased risk of death and reinfarction compared to untreated patients.

The possibility of using a blood test to detect depression has been demonstrated by researchers. Since almost 99% 5-HT is stored inside platelets, whole-blood analysis together with the assessment of platelet count gives a reasonable approximation of 5-HT in platelet.[7] Platelet was chosen because their demonstrated similarity to neurons suggested a potential for diagnostic use, considering that a blood test is much less invasive and less expensive than nervous tissue biopsy.

In the present study, we aimed to establish the effects of sertraline pretreatment on the comorbidity of MI and depression post-MI by qualifying levels of 5-HT, 5-HT2AR and SERT in the serum, platelet, and brain. To study the possible mechanism of sertraline on MI and depression.


  Methods Top


Subjects

In this study, we used 80 SD rats, both male and female, weighing 180–200 g (Pharmaceutical Base, Jiangsu Province). The rats were randomly allocated to two pretreatment groups including saline-pretreated group and sertraline-pretreated group. The sertraline-pretreated rats received sertraline by gavages at 20 mg/kg dissolved in 2 ml saline once a day for 4 weeks while the saline-pretreated rats received an equivalent volume of placebo saline for the same period. Then, the two groups were randomly divided into four subgroups, respectively, including sham subgroup, MI subgroup, depression subgroup and depression post-MI subgroup. All animals were then sacrificed after 3 days to observe the effects of sertraline on levels of 5-HT, 5-HT2AR and SERT in the rat serum, platelet, and brain.

Different pathological states

Myocardial infarction model

According to the surgical model of MI, the SD rats were anesthetized with ketamine (40 mg/kg) and xylazine (1 mg/kg) by intramuscular application, and then conduct surgical model of MI according to Akbay et al.[8] previously described. Anesthetized rats were placed in the supine position. After disinfecting, the thorax was opened in the fourth intercostal space. The left anterior descending artery was cauterized at the midpoint through the starting point and the cardiac apex. After cauterization, the air in the thorax was squeezed out by the forefinger and the thorax was closed with suture.

Depression model

Depression was induced with the modified forced swimming test (FST) described previously by Porsolt.[9] Rats were plunged individually in a cylinder (40 cm height, 20 cm diameter) containing 30 cm water maintained at 25°C. After 15 min in the cylinder, they were removed and allowed to dry for 25 min in a heated enclosure (32°C) before returning to their individual cages. This procedure involved long periods of immobility in the water (10–12 min total) and hypoactivity for 30 min. After 24 h, the FST was repeated except this time, the rats were placed in the cylinder for only 5 min.

Depression post-myocardial infarction model

Depression post-MI were induced by first performing MI surgery, and then, the FST 3 days after the surgery, following the procedures described above.

Sample collection and storage

The blood samples were collected from the tail vein and placed into chilled tubes containing ethylendiminetraacetic acid. Whole blood was aliquoted and stored at −70°C until the time of assay. The blood was centrifuged within 30 min for 15 min at 200 ×g at room temperature to obtain platelet-rich plasma (PRP) as described previously. Successively, PRP was aspirated and sonicated with three cycles of 10s on ice. To prepare isolated platelets, PRP was centrifuged for 10 min at 2100 ×g at 4°C.

Enzyme linked immunosorbent assay

Protein levels were determined using enzyme linked immunosorbent assay (ELISA) kits specific of 5-HT (product #: MEXN-M136), 5-HT2AR (product #: MEXN-M142) and SERT (product #: MEXN-M849) obtained from Shanghai Meixuan Biological Science and Technology Ltd. 5-HT, 5-HT2AR, and SERT levels were measured according to the introduction of ELISA kits.

Statistical analysis

We used SPSS Version 19.0; (IBM Corp., Chicago, IL, USA) for all data processing and analysis. Data were represented as the mean ± standard deviation. Comparisons between two subgroups were assessed using the independent t-test. The values of P < 0.05 were considered to be statistically significant.


  Results Top


As compared with saline treatment group, 5-HT levels in serum decrease significantly in the sham subgroup and increase significantly in MI, depression, and MI-depression subgroups after sertraline treatment (P < 0.05) [Figure 1]a. As compared with saline treatment group, 5-HT levels in platelet increase significantly in sham, MI, depression, and MI-depression subgroups after sertraline treatment (P < 0.05) [Figure 1]b. As compared with saline treatment group, 5-HT levels in brain decrease in sham group, MI group, depression group, and MI-depression group after sertraline treatment (P < 0.05)[Figure 1]c.
Figure 1: a) As compared with saline treatment group, 5-HT levels in serum decrease significantly in the sham subgroup and increase significantly in MI, depression, and MI-depression subgroups after sertraline treatment (P<0.05), b) As compared with saline treatment group, 5-HT levels in platelet increase significantly in sham, MI, depression, and MI-depression subgroups after sertraline treatment (P<0.05), c) As compared with saline treatment group, 5-HT levels in brain decrease in sham group, MI group, depression group, and MI-depression group after sertraline treatment (P<0.05)

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As compared with saline treatment group, 5-HT2AR levels in platelet decrease significantly in sham subgroup and increase significantly in MI subgroup and depression subgroup after sertraline treatment, but no significance in MI + depression subgroup (P < 0.05) [Figure 2]a. There was no difference between sertraline-pretreated and saline-pretreated in sham group (P > 0.05) in brain 5-HT2AR. As compared with saline treatment group, 5-HT2AR levels in brain increase significantly in MI subgroup and decrease significantly in depression subgroup and MI + depression subgroup after sertraline treatment (P < 0.05) [Figure 2]b.
Figure 2: a) As compared with saline treatment group, 5-HT2AR levels in platelet decrease significantly in sham subgroup and increase significantly in MI subgroup and depression subgroup after sertraline treatment, but no significance in MI + depression subgroup (P< 0.05), b) There was no difference between sertraline-pretreated and saline-pretreated in sham group (P>0.05) in brain 5-HT2AR. As compared with saline treatment group, 5-HT2AR levels in brain increase significantly in MI subgroup and decrease significantly in depression subgroup and MI + depression subgroup after sertraline treatment (P<0.05)

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As compared with saline treatment group, SERT levels decrease significantly in sham subgroup (P < 0.05) and increase significantly in depression subgroup in serum after sertraline treatment (P < 0.05). There was no difference between sertraline-pretreated and saline-pretreated in MI subgroup and MI + depression subgroup (P > 0.05) in serum after sertraline treatment [Figure 3]a. As compared with saline treatment group, SERT levels decrease significantly in sham subgroup, MI subgroup, depression subgroup and MI + depression subgroup (P < 0.05) in platelet after sertraline treatment [Figure 3]b. As compared with saline treatment group, SERT levels in brain increase significantly in sham subgroup and depression subgroup and decrease significantly in MI subgroup after sertraline treatment (P < 0.05). There was no difference between sertraline-pretreated and saline-pretreated in MI + depression subgroup (P > 0.05) in the brain after sertraline treatment [Figure 3]c.
Figure 3: a) As compared with saline treatment group, SERT levels decrease significantly in sham subgroup (P<0.05) and increase significantly in depression subgroup in serum after sertraline treatment (P<0.05). There was no difference between sertraline-pretreated and saline-pretreated in MI subgroup and MI + depression subgroup (P>0.05) in serum after sertraline treatment, b) As compared with saline treatment group, SERT levels decrease significantly in sham subgroup, MI subgroup, depression subgroup and MI + depression subgroup (P<0.05) in platelet after sertraline treatment, c) As compared with saline treatment group, SERT levels in brain increase significantly in sham subgroup and depression subgroup and decrease significantly in MI subgroup after sertraline treatment (P<0.05). There was no difference between sertraline-pretreated and saline-pretreated in MI + depression subgroup (P>0.05) in the brain after sertraline treatment

Click here to view



  Discussion Top


This study observed the inconsistent trend of 5-HT levels in periphery and brain after sertraline treatment compared to saline treatment. The 5-HT levels in serum and platelet increase in MI, depression, and MI-depression subgroups; but decrease in brain in the same subgroups. The result of this study found that 5-HT2A receptor (5-HT2AR) in platelet levels increased in MI, depression, and MI-depression subgroup after sertraline treatment. However, 5-HT2AR levels in the brain increased in MI subgroup but decreased in depression and MI-depression subgroup. As compared with saline treatment group, platelet SERT (serotonin transporter) decreased significantly in the four subgroups, and brain SERT increased significantly in depression subgroups, but decrease significantly in MI subgroup after sertraline treatment.

Serotonin (also called 5-HT), an intermediate product of tryptophan metabolism, is primarily located in the enterochromaffin cells of the intestine, the serotoninergic neurons of the brain, and platelets of blood. 5-HT is well-established as a neurotransmitter in the central nervous system, and plays diverse roles in the cardiovascular system, including platelet aggregation and regulation of vascular tone.[10]

Platelets have been known to release 5-HT at vascular injury sites. 5-HT has been shown be critical to promoting vasoconstriction,[11],[12] thrombosis, platelet aggregation, vascular wall repair, and proliferation of vascular endothelial cells. Increased total blood serotonin has been associated with coronary artery disease and subsequent cardiac events and increased risk of cardiac events in MI patients.[13],[14]

The role of serotonin in depression and antidepressant treatment remains unsolved despite decades of research. Although the idea that the single neurochemical is the cause of depression is now considered as simplistic, the low serotonin hypothesis still lies at the foundation of most research on depression. The serotoninergic system related to depression is mainly located in the central nervous system, while that related to the coronary artery is mainly located in the periphery.

Low level of central serotonin has been related to the state of depression, and 5-HT is the major target of a new type of antidepressant drugs, such as SSRIs. The development of SSRIs further suggested that increased 5-HT function could be sufficient to ameliorate depressive symptoms in depressed patients according to inhibiting SERT on synapse, reducing the reputation of 5-HT and increasing the content of 5-HT in the synaptic cleft.

Neurons and platelets display structural and functional similarities and hence that the latter have been proposed as a peripheral model of central functions. In particular, in blood >99% of 5-HT is contained in platelet and hence that one could consider changes in 5-HT levels in platelet as a mirror of changes in central 5-HT. Previous study suggests that serotoninergic system of platelet and central nervous system have the same biochemical and morphological characteristics.[15],[16] Therefore, it is supposed that there may be consistent regulation of 5-HT in periphery and brain. However, inconsistent result has been discovered in our study which showed that 5-HT levels in serum and platelet increased in MI, depression and MI-depression subgroups; but decreased in brain in the same subgroups. We infer that it may be related to the function of blood brain barrier (BBB) which is selective to specific substances. As it was demonstrated that SERT was identified in the largest pial vessels of the BBB, explaining 5-HT was able to pass brain through BBB. The observation of 5-HT decrease in brain in our study could be related with this function. As it has reported, low endogenous serotonin in platelet has been considered as a sign of platelet activation.[17] Platelet 5-HT increase is an indicator of decreasing platelet activation.

Moreover, the actions of 5-HT are mediated by different types of receptors and terminated by a single 5-HT transporter; therefore, it is confirmed that 5-HT receptors and transporter may play an important role in 5-HT regulation.

It has been controversial which serotonergic receptor subtype actually mediates the coronary hyperconstriction or spasm in humans. Chester et al.[18] reported that in nonatherosclerotic isolated human coronary arteries, the 5-HT2A receptor largely mediated the serotonin-induced contraction, whereas in atherosclerotic coronary arteries, the relative contribution of 5-HT1 receptor was increased.

5-HT2A receptor has been studied widely in imaging investigations in depressed patients and MI patients. 5-HT2AR is a G protein coupled receptor, is a kind of special protein in the cell membrane or intracellular, can specifically recognize and bind extracellular 5-HT, then activate a series of biochemical reactions, the cells produce the corresponding effect to external stimuli. A study by Oliver [19] demonstrate that sustained SERT loss of function reduces 5-HT2AR surface expression that is critical for the synergistic activation of αIIbβ3 by 5-HT and ADP. These results highlight an antiplatelet strategy centered on blocking or desensitizing 5-HT2AR to attenuate ADP-mediated αIIbβ3 activation.

5-HT2AR is linked to the platelet phosphoinositide–signaling system and is responsible for activating 5-HT-mediated platelet aggregation. Since there is a direct correlation between the number of platelet 5-HT2AR and the magnitude of the aggregation response to 5-HT,[20] the increase in 5-HT-mediated platelet reactivity may be a consequence of 5-HT2AR upregulation. This is supported by several studies indicating that depression is associated with an upregulation of the platelet 5-HT2AR, and an increased response of the platelet phosphoinositide signaling system to 5-HT.

Previous study indicated that 5-HT2AR changes involved in the pathophysiology of both MI and depression occur predominantly in the same brain regions: mechanisms leading to increased 5-HT2AR associated with the depressive state are counterbalanced by mechanisms associated with MI, which are associated with decreased 5-HT2AR.[12]

Moreover, Hrirna's study [21] indicated that the density of 5-HT2AR was found to be significantly increased (by 52%) in platelets from depressed patients, particularly females. The results suggest that upregulation of platelet 5-HT2AR is a useful biological marker in major depression, particularly in females.

Some previous studies show that the mechanism of antidepressant drugs is not regulating the level of 5-HT2AR.[22] However Hrdina's study found that fluoxetine treatment for 3 weeks can increase 5-HT2AR levels in brain tissue.[23] With the increase of 5-HT, 5-HT2AR on the platelet appear to a certain amount of increase which has been proved by our study that 5-HT2AR in platelet levels increased in MI, depression and MI-depression subgroup after sertraline treatment.

SERT is widely expressed throughout the body. In the periphery, SERT is commonly expressed in many organs that taking up serotonin from the bloodstream.[24] The total content of serotonin in the brain is composed of the intracellular pool and extracellular pool. With acute SSRI treatment, SERT blockade prevents reuptake from the synapse. Increasing extracellular serotonin with minutes to hours of administration.[24],[25]

Therefore, SERT is a major mechanism that regulates plasma 5-HT levels to prevent vasoconstriction and thereby securing a stable blood flow. The study indicated that exogenous 5-HT altered the 5-HT uptake rates by changing the density of SERT molecules on the plasma membrane in a biphasic manner.[26] Therefore, the study hypothesize that in hypertensive state, the elevated plasma 5-HT levels induces a loss in 5-HT uptake function in platelets via a decrease in the density of SERT molecules on the plasma membrane. Through the feedback effect of this proposed mechanism, plasma 5-HT controls its own concentration levels by modulating the uptake properties of platelet SERT.

The uptake of 5-HT from the plasma and transfer to platelets occurs rapidly, by a saturable mechanism, which makes platelets the fundamental regulators of plasma 5-HT concentration. Platelet uptake of 5-HT from the plasma is dependent on the SERT. After 5-HT is transported by SERT across the platelet plasma membrane, it is either sequestered into dense granules by vesicular monomine transporters or degraded by monoamine oxidase. Specifically, plasma membrane SERT levels and 5-HT uptake initially rise as platelets are exposed to increasing 5-HT levels, but this initial response is followed by a second phase, whereby higher concentrations of 5-HT cause SERT levels to fall below baseline.

SSRIs, such as sertraline, act primarily at the serotonin transporter protein and have limited, if any, reaction with other neurotransmitter systems. SSRIs appear to bind with the serotonin transporter with different rates of occupancy, duration, and potency.

In the present study, sertraline reduced amount of platelet SERT through combining with SERT, decreased the binding sites of 5-HT and SERT, blocked 5-HT reuptake of the platelet. Thereby sertraline increased the 5-HT levels in serum. Sertraline can close the SERT, affect platelet function of alpha granule, decrease the secretion of 5-HT, which increase the storage capacity of platelets of 5-HT. However, brain SERT increased significantly in depression subgroups, but decreased significantly in MI subgroup after sertraline treatment.


  Conclusion Top


In summary, sertraline regulated 5-HT concentration of peripheral blood and brain according to pathways of 5-HT2AR and SERT in platelet and brain, thereby regulating the platelet function in various pathological states including MI, depression, and depression post-MI. However, the function of 5-HT regulation in platelet is different from brain, which still need further exploration in the future study.

Acknowledgment

The authors would like to thank Yingbin Ge for his hard work in the animal experiments.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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