Investigating the effect of cabergoline and melatonin on the expression of conditioned place preference for morphine in male mice

Number of pages: 104 File Format: word File Code: 32024
Year: 2016 University Degree: Master's degree Category: Medical Sciences
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  • Summary of Investigating the effect of cabergoline and melatonin on the expression of conditioned place preference for morphine in male mice

    Thesis

    To receive the degree of Doctor of Pharmacy

    Persian abstract

    The opioid system can interfere with various neurotransmissions including the dopaminergic, serotonergic, GABAergic, glutamergic and noradrenergic system. It has been shown that opioids (such as morphine) cause an increase in the amount of dopamine in the mesolimbic system, and increasing the amount of dopamine in the nucleus accumbens plays a key role in the rewarding or positive reinforcing effects of opioids. Morphine creates its rewarding or reinforcing effects by activating mu opioid receptors, so that its reinforcing effect is blocked by mu receptor selective antagonists, and rats whose mu receptors are knocked out do not show the symptoms of morphine deprivation syndrome. The aim of the present study is to investigate the effect of combined melatonin with cabergoline on the expression of the place preference of stereomorphine in male mice. In this experimental study, NMRI male mice were used in the weight range of 20-30 grams. In this 6 consecutive days method test; Including three separate stages of preconditioning, conditioning and post-conditioning were used. In the first part of the study, instead of morphine, in order to determine the induction of conditioned place preference (CPP) or conditioned place aversion (CPA), rats received different doses of melatonin (2.5, 10, 30, and 10 mg/kg) and cabergoline (2.5, 10, and 5 mg/kg) in the conditioning phase and after conditioning. In the second part of the study, rats after conditioning with morphine (5 mg/kg) received different doses of melatonin and cabergoline in the post-conditioning phase. The control group received normal saline instead of the mentioned drug. Intraperitoneal injection of different doses of morphine induces CPP (P<0.001). Intraperitoneal injection of different doses of melatonin and cabergoline alone did not cause significant CPP or CPA, but when combined with morphine, doses of 30 mg/kg melatonin (P<0.05) and 10 mg/kg cabergoline (P<0.01) induced morphine-like conditioned place preference. Of course, this effect was also strengthened when they were consumed together. The results of the present study show that melatonin and cabergoline probably enhance the induction of morphine-like conditioned place preference by dopaminergic mechanism. However, to determine their exact mechanism, more studies are needed. Keywords: cabergoline, melatonin, morphine, positive reinforcing effect, conditioned place preference, intraperitoneal injection, male mouse. And it is reversible, which manifests itself with obsessive and searching behavior in order to consume and find medicine. Today, addiction is considered as one of the most important health problems in the whole world, which causes dangerous physical and mental damage, many social, economic and cultural problems in different societies. One of the most important and most common cases of drug addiction is addiction to opioids, especially morphine, which due to the pain-relieving effects that people have, willingly or unwillingly, tend to use them repeatedly due to the creation of tolerance, the positive reinforcing effect (reward) that occurs after their repeated use, causes physical dependence, and after stopping the use, causes physical deprivation syndrome, craving for drug use (craving) and recurrence of symptoms (relapse).

    morphine is one of the strongest opioid painkillers and the main alkaloid of opium, and compared to other substances, it has higher addictive properties. Various studies on animals show that opioids exert their positive reinforcing effect by activating the mesolimbic dopamine pathway. By increasing the activity of dopamine neurons in the ventral tegmental area, these substances increase the release of dopamine in the nucleus accumbens. There are valid evidences that show that this system plays an essential role in the mechanism of opioid addiction. On the other hand, studies have shown that antidepressants may reduce opioid abuse by directly affecting the rewarding properties of opioids or indirectly by improving depression caused by withdrawal syndrome. Therefore, according to these studies, the aim of the present study is to investigate the effect of combined use of cabergoline and melatonin on the expression of conditioned place preference for morphine.Therefore, according to these studies, the aim of the current study is to investigate the effect of combined use of cabergoline and melatonin on the expression of conditioned place preference for morphine, both of which have antidepressant properties due to their dopaminergic mechanism. rtl;"> 

     

     

    1-1-Statement of the problem (necessity and importance of the issue)

    Drug addiction manifests itself with uncontrollable consumption and obsessive desire to consume and search for the drug. Morphine is one of the strongest painkillers. Opium is the main opioid and alkaloid, which compared to other substances, has high addictive properties and creates severe physical and psychological dependence. They have shown that the dopamine neurons that started from the ventral tegmental area and extended to the nucleus accumbens and the prefrontal cortex. They form the mesocorticolimbic dopamine system. Valid evidence suggests that this system plays an essential role in the mechanism of opioid addiction. Melatonin is a hormone that is produced in the pineal gland, a small gland in the brain, and helps regulate the sleep and wake cycle in the body. A very small amount of melatonin is found in foods such as meats, legumes, fruits and vegetables. Melatonin is also available in the market as a food supplement, melatonin food supplements are sometimes used to treat jet lag or insomnia. Studies in animal models have shown the antidepressant effect of melatonin (). Cabergoline is one of the most common and newest long-acting dopamine agonists, which compared to other dopamine agonists such as bromocriptine, quinogolide, and pergolide have a good half-life, tolerance, and effectiveness. Cabergoline indications are used in cases such as hyperprolactinemia, treatment of Parkinson's disease (in the early phase) as monotherapy and combined with levodopa and carbi-dopa (in the advanced phase), treatment of uterine fibrosis, etc. Cabergoline acts as an agonist on dopamine (D2) receptors. Researches have shown that this drug has some effect on dopamine D1 receptors and ?1 and ?2 adrenergic receptors. Of course, it has been shown that in addition to neurotransmitters such as serotonin, dopamine also plays a role in the pathophysiology of depression, and dopamine agonists (such as pramipexol) improve the symptoms of depression. On the other hand, studies have shown that antidepressants may directly affect the rewarding properties of opioids or indirectly by improving depression caused by withdrawal syndrome. Therefore, according to the background, the aim of the present study is to investigate the combined use of cabergoline and melatonin on the expression of conditioned place preference for morphine in male mice.       

    Abstract:

    Evaluation of the effect of concurrent use of melatonin with cabergoline on expression of morphine induced-conditioned place preference in male mice.

    The aim of this study was to investigate the effect of concurrent use of melatonin and cabergoline on expression of morphine. induced conditioned place preference in male mice. In this experimental study, male NMRI mice (20-30g) were used. The study took place on six consecutive days, consisting of three phases: preconditioning, conditioning, and postconditioning. In the first section of the study, melatonin (2.5, 10 and 30 mg/kg) and Cabergoline (2.5, 5 and 10 mg/kg) alone were administered in conditioning and postconditioning phases to see if they induced conditioned place preference (CPP) or aversion (CPA). In the second set, mice received melatonin and Cabergoline in the postconditioning phase after conditioning with morphine. Control groups received normal saline whereas these drugs. Intraperitoneal administration of different doses of morphine (5 and 10 mg/kg, p<0.001) induced CPP. Different doses of melatonin and Cabergoline alone did not induce any significant CPP or CPA. However, co-administration with morphine, only high doses of melatonin (30mg/kg; P<0.

  • Contents & References of Investigating the effect of cabergoline and melatonin on the expression of conditioned place preference for morphine in male mice

    List:

    Persian summary. 1

    Introduction. 3

    Chapter One: Generalities

    1-1-Statement of the problem (necessity and importance of the issue) 6

    1-2-Goals: 7

    1-2-1-main goals. 7

    1-2-2-sub-goals. 7

    1-2-3- practical goals. 8

    1-2-4-Research assumptions.  8

    Chapter Two: Literature review

    2-1- The connection between brain and behavior 10

    2-1-1- Drug addiction as a behavioral disorder. 10

    2-1-2- Addiction and the role of disorder in the brain's neurochemical function. 11

    2-1-3-limbic device and its role in reward and punishment. 14

    2-1-3-1- reward centers and neural pathways. 14

    2-1-3-1-1- The role of reward and punishment in learning, memory, reinforcing effect and habit. 17

    2-1-3-1-2- important concepts in reward. 18

    2-1-3-1-2-1- motivation. 19

    2-1-3-2- Punishment centers in the brain and related concepts. 20

    2-2- Types of animal models to study the neurobiological basis of reward and drug addiction. 20

    2-2-1- Self-administration of medicine. 21

    2-2-2- conditional place preference (CPP) 22

    2-2-2-1- History. 22

    2-2-2-2- Principles, advantages and disadvantages of the method of conditional location preference. 23

    2-2-3- Spatial hatred. 28

    2-2-4- Motion sensitivity. 29

    2-3-dopamine. 30

    2-3-1- History. 31

    2-3-2- Biochemistry. 31

    2-3-3- Dopamine functions in the brain. 33

    2-3-3-1- movement. 33

    2-3-3-2- Understanding and frontal cortex. 34

    2-3-3-3- regulation of prolactin secretion.  34

    2-3-3-4- motivational and rewarding effect.  34

    2-3-3-5- Connection with psychosis 35

    2-3-3-6- Depression.  35

    2-3-3-7- Dopamine therapeutic uses 35

    2-3-3-8- dopaminergic.  36

    2-4- The role of dopaminergic system in addiction 37

    2-4-1- Mesolimbic pathway 38

    2-4-2- Mesocortical pathway.  39

    2-4-3- nigrostriatal pathway.  40

    2-4-4- Tuberoinfundibular pathway 40

    2-5- The role of serotonergic system in addiction process.  41

    2-6- The role of the noradrenergic system in the reward process and drug addiction 43

    2-7- The role of the GABAergic system in the addiction process. 45

    2-8- The role of the glutamatergic system in drug addiction 47

    2-9- The role of the opioidergic system in the addiction process of drug dependence.  49

    2-10- The role of other neurotransmitters in the process of addiction.  51

    2-10-1- Calcium channels.  52

    2-11- Opioids and painkillers.  52

    2-11-1- Morphine-like drugs. 52

    2-11-2- Chemical properties 53

    2-11-3- Types of opioid receptors 55

    2-11-4- Opioid agonists and antagonists 56

    2-11-5- Mechanism of action of opioids 57

    2-11-5-1- Effect of opioids on On the nosceptive pathway 60

    2-11-5-2- Pharmacological effects of opioids 61

    2-11-5-2-1- Opioids on the central nervous system 61

    2-11-5-2-1-1- Analgesia 61

    2-11-5-2-1-2- Euphoria 61

    2-11-5-2-2- weakening of breathing.  62

    2-11-5-2-2-1- Cough reflex weakening 63

    2-11-5-2-3- Nausea and vomiting 63

    2-11-5-2-4- eye pupil contraction.  64

    2-11-5-2-5- Effect on the digestive system 64

    2-11-5-2-6- Other actions of opioids 65

    2-11-5-2-6-1- Tolerance and dependence on opioids 66

    2-11-5-2-6-1-1- Tolerance.  66

    2-11-5-2-6-1-2- physical dependence.  67

    2-12- Morphine 68

    2-12-1- Chemical characteristics. 69

    2-12-2- Pharmacokinetic information. 70

    2-12-3- Treatment considerations. 70

    2-12-4- Therapeutic applications of morphine. 71

    2-12-5- Cases of non-use or contraindications of morphine. 72

    2-12-6- Pharmacology. 72

    2-12-7- History of morphine abuse. 74

    2-12-7-1- Addiction. 75

    2-12-7-1-1- morphine deprivation syndrome. 76

    2-12-7-1-2- Hepatitis C and discontinuation of morphine. 77

    2-13- Cabergoline. 78

    2-13-1- History. 78

    2-13-2- Pharmacology. 79

    2-13-3- Pharmacokinetics. 79

    2-13-4- Clinical applications. 80

    2-13-4-1- hyperprolactinemia. 80

    2-13-4-2- Parkinson. 80

    2-13-4-3- Other uses. 81

    2-13-5- Contraindications and cases81

    2-13-5- Contraindications and precautions. 81

    2-13-6- Unwanted complications. 81

    2-13-6-1-Poisoning. 82

    2-13-7- Medicinal forms. 82

    2-14- melatonin. 82

    2-14-1- How to make melatonin in the body. 83

    2-14-2-function and effective factors in melatonin production. 84

    2-14-3 - melatonin metabolism. 85

    2-14-4- Physiological effects of melatonin. 86

    2-14-5- Mechanism of action of melatonin. 87

    2-14-5-1- antioxidant role. 87

    2-14-6- Clinical applications of melatonin. 88

    2-14-6-1- Other uses. 88

    2-14-7- Medicinal forms. 89

    Chapter Three: Materials and Working Methods

    3-1- Animals. 91

    3-2- Required materials and working methods 91

    3-2-1- Required tools and materials including: 91

    3-2-2- Medicines 92

    3-2-3- CPP test box and method. 92

    3-2-3-1- CPP box. 92

    3-2-3-2- CPP test method. 93

    3-2-4- Grouping. 95

    3-2-5- Ethical considerations. 97

    3-2-6- Method of data analysis 97

    3-2-7- Testing problems and requirements. 98

    Chapter Four: Results

    4-1-The conditioned place preference effect caused by morphine sulfate. 100

    4-2- The effect of melatonin alone (without using morphine for conditioning) to investigate CPP or CPA caused by it. 101

    4-3- The effect of melatonin on the conditioned place preference of morphine. 102

    4-4- The effect of cabergoline alone (without using morphine for conditioning) to investigate CPP or CPA caused by it. 102

    4-5- The effect of cabergoline on the conditioned place preference of morphine. 103

    4-6- The effect of cabergoline and melatonin as a combination on conditioned place preference caused by morphine 104

    Chapter five: Discussion and conclusion

    5-1- Discussion and conclusion 107

    5-2- Suggestions 111

    English summary 112

    Resources. 113

     

     

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Investigating the effect of cabergoline and melatonin on the expression of conditioned place preference for morphine in male mice