Involvement of the lateral habenula in the processing of methamphetamine withdrawal-induced anxiety-like behaviors

Anxiety disorders, commonly observed during methamphetamine (METH) withdrawal, are important negative reinforcement factors that contribute to relapse. The lateral habenula (LHb) serves as a negative reinforcement center, however its role in METH withdrawal-induced anxiety remains unclear. Here, we used the open field test (OFT) and elevated plus maze (EPM) to assess anxiety-like behaviors in METH-withdrawn male mice, combined with c-Fos immunofluorescence and chemogenetics approach. Our results showed that METH-withdrawn mice exhibited anxiety-like behaviors, along with activation of LHb neurons. Furthermore, suppressing LHb neurons activity in METH-withdrawn mice alleviated the anxiety-like behaviors. In normal (naïve) mice, activation of LHb also induced anxiety-like behaviors, highlighting the importance of LHb activity homeostasis in emotional regulation. Taken together, our findings provide evidence for the role of LHb in METH withdrawal-induced anxiety, demonstrating that maintaining the homeostasis of LHb activity is crucial for preventing maladaptive behaviors associated with anxiety.