Behavioral and Neuro pharmacological Screening of Potential Serotonergic Ligands for the Management of Depression and Anxiety Co morbid with Type 1 Diabetes Mellitus

Abstract

Depression is a highly prevalent, severely disabling, mood disorder characterized by sad newlinemood, hopelessness, loss of motivation and disinterest. People with depression often newlineexperience symptoms similar to those of an anxiety disorder. There are several newlinecausative factors that can lead to depression and anxiety, among which, chronic metabolic illness such as diabetes mellitus (DM) is an important one. Epidemiological data suggests that diabetic patients are almost three times as likely to develop depression as those, who do not have a chronic medical condition. Despite the presence of a multitudinous pharmacotherapy, depression and anxiety co-morbid with DM (in particular, Type-1; T1DM) remains undertreated. This could, partly be, attributed to the unclear complex pathophysiology, severe and frequent side newlineeffects of current drugs (in particular, adverse impact on glucose level, being the most). Hence, there is a grave need to develop novel candidates balanced with as high efficacy and minimum untoward effects as possible to further improve the pharmacotherapy. 5-HT3 receptors have been identified as potential target for depression and related psychiatric disorders. 5-HT3 receptor signaling is involved in mood, emotion, cognition, learning and memory, whereas 5-HT3 receptor antagonists have been reported as potential antidepressant agents. In addition, 5-HT3 receptor antagonists are suggested to have quick onset of action, specific and dose dependent therapeutic potential and wide safety margin. Interestingly, 5-HT3 receptor antagonists are shown to have favorable effects on glucose homeostasis. Therefore, the present work focuses on investigating the potential effect of standard (ondansetron, OND) and novel 5-HT3 ntagonists (synthesized in house in medicinal Chemistry laboratory of the Department, 4i and 6z), to ameliorate depression and anxiety co-morbid with T1DM. The work was conducted in adherence to three major objectives namely, (1) preliminary screening of antidepressant-like effects of test drug candidates