Targeting the noradrenergic-metabolic axis: A new strategy for sugar-induced depression subtypes

Background and Purpose: Lifestyle is closely related to major depressive disorder (MDD). Given the growing focus on the impact of diet on mental health, this study examined how dietary habits affect the pathophysiology of MDD. Experimental Approach: Health check-up data were analysed. Mice received sucrose under chronic unpredictable mild stress (CUMS) and were evaluated by behavioural, neurochemical and metabolic analysis. Key Results: Health check-up data showed increased sucrose intake in MDD patients. When mice received sucrose under CUMS, hyperactivity and aggression were attenuated, although social deficits or behavioural despair induced by CUMS persisted, and recognition memory was impaired. The behavioural changes were associated with dysfunction of the locus coeruleus-prefrontal cortex circuit, caused by impaired noradrenaline release due to presynaptic α₂-adrenoceptor upregulation, and postsynaptic α₁-adrenoceptor and β₁-adrenoceptor downregulation. α₂-Adrenoceptor antagonism by atipamezole rescued behavioural changes induced by sucrose intake under CUMS, whereas α₂-adrenoceptor agonism by guanfacine in CUMS mice mimicked these behavioural changes. Among the antidepressants, mirtazapine effectively increased noradrenaline release and rescued behavioural changes induced by sucrose intake under CUMS. Sucrose intake under CUMS induced peripheral hyperglycaemia and dysregulation of central glucose metabolism. Glucose transporter inhibition by phloretin rescued behavioural changes induced by sucrose intake under CUMS. Intracerebroventricular and systemic streptozotocin administration reproduced these behavioural changes and α₂-adrenoceptor upregulation. Conclusions and Implications: Our findings suggest that the observed behavioural changes are associated with dysfunction of the noradrenergic α₂-adrenoceptor system induced by impaired glucose metabolism. These insights targeting the noradrenergic-metabolic axis might be a new strategy for sugar-induced depression subtypes.