I= NEUROCHEMICAL AND BEHAVIORAL STUDIES ON THE EFFECTS OF SOME POTENTIAL DRUGS ON ADAPTATION TO SINGLE AND REPEATED RESTRAINT STRESS IN RATS
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Title of Thesis
NEUROCHEMICAL AND BEHAVIORAL STUDIES ON THE EFFECTS OF SOME POTENTIAL DRUGS ON ADAPTATION TO SINGLE AND REPEATED RESTRAINT STRESS IN RATS

Author(s)
Noreen Samad
Institute/University/Department Details
Department of Biochemistry/ University of Karachi
Session
2007
Subject
Biochemistry
Number of Pages
269
Keywords (Extracted from title, table of contents and abstract of thesis)
single restraint stress, repeated restraint stress, rats, neurotransmitter, depression, stress situation, neurochemical mechanism, antidepressants, biogenic amines, monoamines

Abstract
A considerable body of evidence points to the involvement of the neurotransmitter 5-hydroxytryptamine (5-HT; serotonin) in anxiety and depression. Stress life events precipitate depression. Studies on experimental animals show that an uncontrollable stress situation increases brain 5-HT metabolism and precipitates behavioral deficits. Inability to cope a stress-induced situation is an animal model of depression. It has been also reported that restraint induced behavioral deficits do not occur when similar type of stress is given repeatedly suggesting adaptation occurs when similar type of stress administered repeatedly. A concept of receptor responsiveness in adaptation to stress emerged because the aforementioned results on the metabolism and synthesis of serotonin were not relevant with the 5-HT hypothesis of depression. According to 5-HT hypothesis of depression an increase in 5-HT function would be expected to produce adaptation. It was therefore suggested that a change in receptor responsiveness is possibly involved in adaptation to stress. Subsequent studies have shown that a desensitization of somatodendritic 5-HT -1A and terminal 5-HT -1B receptors is involved in adaptation to repeated restraint stress. The present study was initially designed to change the effectiveness of somatodendritic 5-HT -1A receptors by two weeks of administration of 5-HT-1A agonist buspirone and antagonist propranolol and to monitor responses to stress in these animals. Important findings of the present study are as follows:

1 Repeated administration of buspirone and propranolol attenuated restraint-induced behavioral deficits and anxiogenic-like effects of stress but the animals did not adapt in the schedule of 2-h/day restraint for 5 days and exhibited deficits of food intake and body weight after 4th and 5th 2-h/day restraints. Stress-induced increases of 5-HT metabolism were normalized in saline treated restrained animals but not in buspirone treated restrained animals.

2 Single and repeated administration of buspirone attenuated restraint-induced behavioral deficits and restraint-induced increases of 5-HT metabolism in the hippocampus and midbrain comparably. The attenuation of stress-induced increases of 5-HT metabolism in the hippocampus but not the attenuation of stress-induced behavioral deficits was greater following single than repeated administration of buspirone.

3 Desensitization of somatodendritic 5-HT -1A receptors by 3 days administration of 8-hydroxy (2-n-dipropylamino) tetraline (8-OH-DP AT) also attenuated restraint-induced behavioral deficits and anxiogenic-like effects of stress, the animals were adapted following exposure to restraint sessions of 2-h/day for 4-5 days similar to saline injected animals. Administration of a low dose of 8-OH-DP AT decreased 5-HT metabolism in unrestrained animals and these decreases did not occur in animals adapted to 5th restraint session of 2-h/day suggesting a decrease in the effectiveness of somatodendritic 5-HT-1A receptor. The intensity of 8-OH-DPAT-induced 5-HT syndrome was comparable in repeatedly restrained and unrestrained animals suggesting functional activity of postsynaptic 5-HT-1A receptors comparable in unrestrained and repeatedly restrained animals.

4 Following acute exposure to a first episode of 2-h restraint 8-OH-DP AT-induced hyperphagia was comparable in restrained and unrestrained animals. 8-OH-DP A T-induced 5-HT syndrome was smaller in restrained than unrestrained animals suggesting a decrease in the effectiveness of postsynaptic 5-HT-1A receptors. 8-OH-DPAT-induced decreases of 5-HT metabolism in different brain regions were greater in restrained than unrestrained animals suggesting an increase in the effectiveness of somatodendritic 5-HT-1A receptors following exposure to single restraint period of 2-h which may also be involved in the decrease postsynaptic response.

5 1-(3-chlorophenyl) piperazine (m-CPP)-induced hyplocomotion and anxiogenic-like behavior if greater in restrained than unrestrained animals were not statistically significant because of floor effect. Administration of m-CPP increased 5-HT metabolism and decreased dopamine (DA) metabolism in both unrestrained as well restrained animals. Changes of 5-HT were smaller and those of DA were greater in restrained than unrestrained animals suggesting that the effectiveness of postsynaptic 5-HT-2C receptors is also altered following exposure to 2-h restraint stress.

6 Apomorphine-induced increases of motor activity and decreases of DA metabolism were smaller in restrained than unrestrained animals suggesting a decrease in the effectiveness of pre- and postsynaptic D2 receptors following exposure to 2-h restraint stress but apomorphine-induced changes of 5-HT metabolism were different in different brain regions.

The results tend to suggest that an episode of 2-h restraint stress increased the effectiveness of somatodendritic 5-HT -1A receptors the resultant decrease in the availability of 5-HT in terminal regions may be involved in restraint-induced behavioral deficits. Buspirone and 8-OH-OP A T produced anxiolytic effect via the stimulation of somatodendritic 5-HT-1A receptors that decreased the availability of 5-HT at terminal anxiogenic 5-HT-2C receptors. The results also suggest that single restraint stress altered the responsiveness of 5-HT-2C and decreased the responsiveness of OA 02 pre- and postsynaptic receptors. The results support the notion that a decrease in the effectiveness of somatodendritic receptors involved in adaptation to stress can not attenuated anxiogenic effects of stress. The present findings imply that acute as well as repeated administration of drugs acting via somatodendritic 5-HT-1A receptors may attenuate anxiety and tolerance is not developed in the anxiolytic profile of these drugs. Moreover long term administration of these drugs that desensitized somatodendritic 5-HT-1A receptors may be of use in the treatment of depression.

Download Full Thesis
5884.49 KB
S. No. Chapter Title of the Chapters Page Size (KB)
1 0 Contents
327.34 KB
2 1 General Introduction 1
810.92 KB
  1.1 Stress 1
  1.2 Physiological Responses To Stress 1
  1.3 Stress And Depression 3
  1.4 Animals Model Of Depression And Adaptation To Stress 4
  1.5 Neurochemical Responses To Stress 4
  1.6 Neurochemical Mechanism In Adaptation To Stress 18
  1.7 Mechanism Of Action Of Antidepressants 20
3 2 Materials And Methods 30
551.39 KB
  2.1 Animals And Treatments 30
  2.2 Chemicals And Drugs 30
  2.3 Behavioral Methods 30
  2.4 Brain Dissection Technique 37
  2.5 Biochemical Estimation 40
  2.6 Determination Of Biogenic Amines And Their Metabolites By High Performance Liquid Chromatography With Electrochemical Detector (HPLC-EC ) 45
  2.7 Extraction Of Monoamines And Their Metabolites And TRP From Brain Tissues 48
4 3 Experiment 1: Effects Of Single Restraint Stress On 5-Ht And DA Metabolism In Rats 73
969.92 KB
  3.1 Experiment 2: Effects Of Propranolol On Adaptation To Repeated Restraint Stress 80
  3.2 Experiment 3: Effects Of Buspirone On Adaptation To Repeated Restraint Stress 93
  3.3 Experiment 4: Effects Of Single And Repeated Administration Of Buspirone On Restraint-Induced Behavioral Deficits And Brain Regional 5-Ht Metabolism L06
5 4 Experiment 1: Effects Of 8-0H-DPAT On Adaptation To Repeated Restraint Stress 121
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  4.1 Experiment 2: 8-0H-DPAT-Induced Hyperphagia And Decreases Of 5-Ht Metabolism In Rats Exposed To Single Restraint Period Of 2-H 138
  4.2 Experiment 3: 8-0H-DPAT-Induced 5-Ht Syndrome And Decreases Of 5-Ht Metabolism In Rats Exposed To Single Restraint Period Of 2-H 158
6 5 Behavioral And Neurochemical Effects Of M- Cpp Following Exposure To Single Restraint Stress 176
337.73 KB
  5.1 Introduction 176
  5.2 Experimental Protocol 176
  5.3 Statistical Analysis 177
  5.4 Results 177
  5.5 Discussion 185
7 6 Behavioral And Neurochemical Effects Of Apomorphine Following Exposure To Single Restraint Stress 189
536.62 KB
  6.1 Introduction 189
  6.2 Experimental Protocol 189
  6.3 Statistical Analysis 90
  6.4 Results 190
  6.5 Discussion 205
8 7 General Discussion 209
1510.65 KB
  7.1 Behavioral Effects Of Single And Repeated Restraint Stress 210
  7.2 Role Of 5-HT In Restraint-Induced Behavioral Deficits And Adaptation To Repeated Restraint Stress 211
  7.3 Role Of 5-HT-IA Receptors In Restraint-Induced Behavioral Deficits And Adaptation To Repeated Restraint Stress 212
  7.4 Role Of 5-HT-2C Receptors In Restraint-Induced Behavioral Deficits 215
  7.5 Role Of DA D2 Receptors In Restraint-Induced Behavioral Deficits 216
  7.6 Serotonergic Influences On HPA-Axis In Unrestrained And Restrained Animals 217
  7.7 Conclusion 220
  7.8 Implication 222
  7.9 Future Prospects 223
  7.10 References 224
  7.11 Publications From Thesis 268