الفهرس 
Introduction& aim of the workOnly 14 pages are availabe for public view
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Abstract
The neurobiology underlying depression and the associated cognitive dysfunction has not yet been fully identified. Additionally, the currently available antidepressants have significant limitation including persistent cognitive deficits even after improvement of depressive symptoms.
Significant efforts have been directed toward identifying novel therapeutic targets for management of cognitive dysfunction associated with depression. 5HT7 receptor is a promising target as its blockade has procognitive effects. Additionally it modulates the activity of microglia and the Wnt/β-catenin pathway which are implicated in the pathogenesis of depression and the associated cognitive dysfunction.
Accordingly, our study was designed to evaluate whether 5HT7 blockade by amisulpride may improve the depressive like behavior and the cognitive dysfunction induced by the UCMS model of depression in rats. Furthermore, we would investigate the effect of the model and the treatment on the Wnt/β-catenin pathway and microglial activation in the PFC.
Induction of UCMS was associated with depressive like symptoms in wistar rats manifested by significant decline in struggling time in FST, sucrose preference, number of crossed squares and central zone entries in OFT and significant increase in immobility time in FST, latency to leave central zone in OFT. Treatment with amisulpride significantly improved these behavioral changes in stressed rats.
Induction of UCMS was associated with other depressive manifestations like significant decrease in body weight gain and significant increase in relative adrenal gland weight Treatment with amisulpride in the last 2 weeks of the UCMS caused significant increase in body weight gain and significant decrease in adrenal gland weight in stressed rats.
On cognitive functions, Induction of UCMS caused a significant decline in cognitive functions in the form of increase in the number of trials to reach criterion in the ASST and decrease in the recognition index in NORT. Amisulpride treatment significantly reversed this cognitive dysfunction in stressed rats.
At the molecular level, induction of UCMS produced significant increase in phosphorylated β-catenin level and significant decrease in total β-catenin, Wnt3a and DVL3 in PFC. Treatment with amisulpride significantly reversed these UCMS induced changes in the Wnt/β-catenin pathway.
Histological sections of the mPFC showed that rats’ exposure to UCMS caused apparent neurodegenerative changes indicated by shrunken deeply stained pyramidal neurons with perineuronal spaces. Additionally, UCMS caused significant decrease in the number of viable neurons.
Treatment with amisulpride was apparently able to reverse these neurodegenerative changes to some degree and was associated with significant increase in the number of viable neurons in the mPFC of stressed rats.
Immunohistochemical staining showed significant increase in Iba-1 immunoreactivity and microglial activation in mPFC of rats exposed to UCMS. Amisulpride treatment significantly decreased Iba-1 immunoreactivity in stressed rats and apparently reversed the UCMS induced microglial activation.
Conclusion and Recommendations:
Amisulpride can serve as a new therapeutic approach that can be used to treat cognitive impairment associated with depression.
Although our study aimed to explore the effect of 5HT7 blockade on cognitive functions in depression and the role of microglial activity and the Wnt/β-catenin pathway in the PFC. Yet, further investigations are needed to confirm that the effects of amisulpride are caused by 5HT7 blockade by using selective 5HT7 agonist e.g. AS19 or selective 5HT7 blocker e.g. SB269970.
Furthermore, future researches are required to examine the role of 5HT7 receptor, microglial activity and the Wnt/β-catenin pathway in other brain areas involved in the pathophysiology of depression and cognitive dysfunction e.g. the hippocampus.
Additionally, using a Wnt receptor blocker is recommended to clarify whether the changes in β-catenin levels are due to solely the parallel changes in Wnt or due to modulation of other intracellular targets.
In-vitro studies in the form of neuronal and glial cell cultures are required to identify the source of the changes in the Wnt/β-catenin pathway and to study the effect of 5HT7 blockade in isolated cells outside the neuronal milieu intérieur.
In addition, controlled clinical trial is needed to explore the potential of our results in depressed patients.