Abstract
Aim: Stress-related disorders like depression and anxiety represent one of the greatest therapeutic challenges globally. Although previous studies have revealed the antidepressant-like potentials of naringin, the neurotransmitter receptor interaction mechanisms of action have not been studied, hence, this study was carried out to evaluate the role of neurotransmitter-receptor antagonists in the antidepressant-like effects of naringin in mice.
 Method: Male Swiss mice were subjected to chronic unpredictable mild stress (CUMS) apart from mice in the control group. The mice were then pretreated with different neurotransmitter antagonists; metergoline (4 mg /kg i.p.), a 5-HT1 - and 5-HT2 -receptor antagonist; propranolol; (0.2 mg/kg i.p.), β1,2-noradrenoceptor antagonist or haloperidol (0.2 mg/kg i.p.), D 2 -dopaminergic receptor antagonists prior to the administration of naringin or vehicle (10 mL/kg). The antidepressant-like and anxiolytic effects of naringin were evaluated 30 min later using the tail suspension test (TST), open-field test (OFT), sucrose preference test (SPT) and elevated plus maze (EPM) tests paradigms.
 Results: Administration of naringin following CUMS significantly decrease immobility time and locomotion activity in TST and OFT respectively, relative to control while increasing preference to sucrose in SPT, open arm entries as well as time spent in open arm in EPM, relative to control suggesting antidepressant-like property. Pretreatment with metergoline, propranolol, and haloperidol following CUMS increased immobility time in TST, locomotor activity in OFT and IOAA in the EPM. Reduced preference for sucrose in SPT, open arm entry and duration in EPM relative to control (p < 0.05), however, these effects were attenuated by naringin.
 Conclusion: These findings suggest that the antidepressant-like activity exhibited by naringin might be mediated via interactions with 5-HTergic, noradrenergic, and dopaminergic receptors, while the anxiolytic effect might involve interaction with both 5-HTergic and noradrenergic receptors.
Highlights
Stress-related disorders such as depression and anxiety represent one of the greatest therapeutic challenges in the twenty-first century
Common findings suggest that monoamine oxidase inhibitors (MAOI) in monoamine hypotheses play a major role in depression [10], as monoamine oxidase inhibitors has been used to relieve some of the depressive symptoms and anxiety [11]
A 5-HT 1 - and 5-HT 2 -receptor antagonist (4 mg/kg, i.p.) had no significant effect on immobility time, locomotion activity, open arm entries, duration and IOAA in TST, Open field test (OFT), sucrose preference test (SPT) and EPM respectively as compared with the chronic unpredictable mild stress (CUMS) group but significantly (p < 0.05) suppressed locomotion activities, sucrose preference and open arm entries and duration when compared to the control group
Summary
Stress-related disorders such as depression and anxiety represent one of the greatest therapeutic challenges in the twenty-first century. It is burdensome as it has a high lifetime prevalence rate and a high level of comorbidity with other psychiatric diseases [1]. There is a growing research interest on the treatment of these stress-related disorders, albeit findings in drug discovery research have implicated the involvement of neuroactive peptides in the pathophysiology of these disorders [2,3,4]. Neuropsychiatric disorders are seen as a complex disorder, the mechanisms underlying their pathogenesis remain unclear some peptide neurotransmitters in the brain has been implicated in previous researches [7,8,9]. Common findings suggest that monoamine oxidase inhibitors (MAOI) in monoamine hypotheses play a major role in depression [10], as monoamine oxidase inhibitors has been used to relieve some of the depressive symptoms and anxiety [11]
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