Basolateral Amygdala SIRT1/PGC-1α Mitochondrial Biogenesis Pathway Mediates Morphine Withdrawal-Associated Anxiety in Mice

Abstract

Background Anxiety is a negative emotion that contributes to craving and relapse during drug withdrawal. SIRT1 has been reported to be critical in both negative emotions and drug addiction. However, it remains incompletely elucidated whether SIRT1 is involved in morphine withdrawal-associated anxiety. Methods We established a mouse model of anxiety-like behaviors induced by morphine withdrawal, and then detected neuronal activity with immunofluorescence and mitochondrial morphology with electron microscopy, mtDNA contents with qPCR, and mitochondrial function with the ATP content detection kit and the Mitochondrial Complex IV Activity Kit in the basolateral amygdala (BLA). The mitochondrial molecules were detected by Western blot. Then, we used virus-mediated down-regulation and overexpression of SIRT1 in BLA to investigate the effect of SIRT1 on anxiety and mitochondrial function. Finally, we examine the effects of pharmacological inhibition of SIRT1 on anxiety and mitochondrial function. Results We found that BLA neuronal activity, mitochondrial function, and mtDNA content were significantly higher in morphine withdrawal mice. Furthermore, the expression levels of mitochondrial molecules were increased in BLA cells. Virus-mediated down-regulation of SIRT1 in BLA prevented anxiety-like behaviors in morphine withdrawal mice, while overexpression of SIRT1 in BLA facilitated anxiety-like behaviors in untreated mice through the SIRT1/PGC-1α pathway. Intra-BLA infusion of selective SIRT1 antagonist EX527 effectively ameliorated anxiety-like behaviors and mitochondrial dysfunction in mice with morphine withdrawal. Conclusion Our results implicate a causal role for SIRT1 in the regulation of anxiety through actions on mitochondrial biogenesis. Inhibitors targeting SIRT1 may have therapeutic potential for the treatment of opioids withdrawal-associated anxiety.

Exploring neuroadaptive cellular pathways in chronic morphine exposure: An in‐vitro analysis of cabergoline and Mdivi‐1 co‐treatment effects on the autophagy–apoptosis axis

“…In the context of the U87‐MG cell line, we observed an interesting deviation where chronic morphine treatment did not significantly alter DRP1 expression, but increased autophagy level. This leads us to postulate, based on preceding validated evidence, the potential activation of AMP‐activated protein kinase (AMPK)/Sirtuin‐1 (SIRT1) pathways, instigating autophagy in in‐vitro glioma cells through DRP1‐independent mechanism, a hypothesis awaiting experimental validation 115–117 …”

“…This leads us to postulate, based on preceding validated evidence, the potential activation of AMP-activated protein kinase (AMPK)/Sirtuin-1 (SIRT1) pathways, instigating autophagy in in-vitro glioma cells through DRP1-independent mechanism, a hypothesis awaiting experimental validation. [115][116][117] Furthermore, recently discerned distinctive roles of PINK1 in glial cells, implicating it in managing proinflammatory responses and growth factor-induced proliferation, 118 highlighting a greater adaptive capacity of gliomas in orchestrating mitophagy in response to diverse stimuli compared to neurons.…”