CCL2/CCR2-mediated monocyte-macrophages infiltration drives methamphetamine-induced depressive-like behaviors

Methamphetamine (METH) abuse is frequently associated with persistent depressive symptoms, representing a major contributor to psychiatric comorbidity in substance use disorders; however, the underlying mechanisms remain poorly defined. Here, we show that binge METH exposure induces robust and persistent depressive-like behaviors in mice, accompanied by systemic cytokine elevation and expansion of Ly6C ^hi inflammatory monocytes in the peripheral circulation. These monocyte-derived macrophages infiltrated the medial prefrontal cortex (mPFC) via the choroid plexus and meninges in a CCR2-dependent manner. Single-cell RNA sequencing of mPFC immune cells identified distinct proinflammatory CCR2 ⁺ macrophage subsets enriched for IL-1β expression, which in turn amplified neuronal CCL2 production, establishing a self-sustaining macrophage–microglia crosstalk that perpetuated local inflammation. Pharmacological inhibition or genetic disruption of CCR2 prevented immune infiltration, reduced neuroinflammation, preserved synaptic integrity, and rescued both depressive-like and cognitive deficits. Together, these findings identify CCR2-dependent monocyte infiltration as a key mechanism linking METH exposure to affective dysfunction and highlight the CCL2/CCR2 axis as a potential therapeutic target in substance use–associated mood disorders.