Chronic Administration Of Clomipramine And Amitriptyline In The Five-week-old-age Rats Leads To Depressive Changes In Behavior And Hypothalamic Orexin Content

Introduction: Depression is a disorder associated with the dysfunction of theserotoninergic neurons. These neurons suppress the orexinergic neurons, which in turn activate the serotoninergic neurons, involve in the regulation of stress response and may have anti-depressant function. Recent researches found that adult rats with neonatal CLI treatment initiate a series of symptoms and the pathology changes similar to human depression, such as increase of immobility and obvious decrease of brain orexins. This evidence implies that the orexins are likely to be involved in the pathological regulation of depression.Objective: (1) To observe the adult effect of ethology of chronic administeringCLI or amitriptyline in juvenile rats via the Forced swimming test and (2) to detect the level of orexin A and B in there hypothalamus, hippocampus and frontal cortex by RIA. .Methods: Twenty-five male Sprague-Dawley (SD) rats were randomly dividedinto three groups at age of 35 days for the treatment with clomipramine (CLI)/ amitriptyline, or saline (SAL), respectively. Rats were subjected to treatment of I.P. injection twice daily with an interval of nine hours for four weeks. Forced swim test was then carried out for evaluation of immobility and swimming behaviors on the next day and one-week after the end of treatment. And then, rats were sacrificed the day after and orexin levels in multiple brain regions were determined by radioimmunoassay accordingly. All tests were conducted between 9:00 am and 12:00 noon.SPSS (10.0 edition ) were used for all statistical evaluations. All of the date were presented as mean±standard error. The changes in behaviors and content of orexin were analyzed by One-way ANOVA analysis and Independent-Sample t test. While P value less than 0.05 was considered as significant.Results:1. Compared with the control rats, the adult rats treated with CLI and amitriptyline for four weeks in juvenile period had an increase in immobility and decrease in swimming by forced swim test and the differences were statistical significant (P<0.05). CLI group rats exhibited much more swimming than immobility during the test(P<0.01).2. The adult rats treated with CLI and amitriptyline have the highest concentration of orexin A and orexin B in the hypothalamus.3. Compared with the control rats, the level of orexin A and B were decreased in hypothalamus and frontal cortex of adult rat treated with CLI and amitriptyline in juvenile period. But, only reduction in hypothalamus is statistical significance (P<0.05). The differences of both orexin A and B levels in other brain regions among groups were not significant. Meanwhile, there is no significant changes between treatment and control groups (P>0.05).Conclusions: In the forced swim test, the adult rats treated with CLI andamitriptyline in juvenile stage show longer immobility, a sign of depressive disorder in rats. CLI and amitriptyline obviously suppressed the expression of orexin A and B in the hypothalamus. This is consistent with the finding of CLI administration in neonatal period. We concluded that juvenile administration of both CLI and amitriptyline leads to depressive development.