Abstract
Methamphetamine (METH) misuse-induced affective and cognitive dysfunctions cause severe global health and economic burdens. However, the mechanisms underlying METH withdrawal-induced negative emotions and cognitive deficits, as well as the treatment strategies for them, remain elusive. Previous findings suggest that METH use triggers neuroinflammation and neuronal apoptosis, and protein kinase B (AKT), forkhead box protein 1 (FOXO1), and heme-oxygenase-1 (HO-1) are implicated in these processes. In the present study, we aimed to reveal the role and potential mechanisms of luteolin, a flavonoid phytochemical with anti-inflammatory and antioxidative properties, in METH withdrawal-induced negative emotions and cognitive deficits. We found that prolonged METH withdrawal led to an increase in neuronal activity and a decrease in the protein expression of phosphorylated AKT (p-AKT) and HO-1 in the prefrontal cortex (PFC) and caudate putamen (CPu). Luteolin pretreatment partially mitigated these METH withdrawal-induced negative emotions and cognitive deficits, and prevented the abnormal activation of PFC and CPu as well as the downregulation of AKT/HO-1 expression. Notably, we further observed that luteolin inhibited the METH-induced nuclear translocation of FOXO1. Our findings suggest that luteolin may alleviate METH withdrawal-induced affective and cognitive dysfunctions by reducing oxidative injury in the brain through the AKT/FOXO1/HO-1 pathway, highlighting its potential for treating drug addiction-related health issues.