Control of methamphetamine-induced place preference behavior by the glutamatergic neural projections from IC to BLA in mice

Drug addiction is closely related to the dysregulation of complex neural circuits. However, the specific neural pathways underlying methamphetamine (METH)-induced addiction remain unclear. First, we performed ∆FosB (Delta FBJ murine osteosarcoma viral oncogene homolog B)-mediated immunofluorescence and fiber photometry recording experiments to assess the neural activity of glutamatergic neurons in the insular cortex (IC) in METH-treated mice. Then, we evaluated the effect of activation or inhibition of glutamatergic neurons in IC on METH-induced conditioned place preference (CPP) behavior through chemogenetic manipulations. Finally, we used adeno-associated virus (AAV)-mediated neural tracing to verify the projections connectivity from IC to the basolateral amygdala (BLA), and investigated their blocking role in METH-induced CPP behavior using chemogenetic and neural ablation strategies. We found that glutamatergic neurons in the IC were activated by METH. Activation of these neurons enhanced METH-induced CPP behavior, whereas inhibition of their activity attenuated the CPP expression. Furthermore, we observed robust projections from IC neurons to the BLA. Activation of IC neurons projecting to the BLA enhanced METH-induced CPP behavior, whereas ablation of BLA neurons receiving projections from IC significantly impaired METH-mediated CPP performance. These results highlight the IC glutaminergic neurons are a major target of METH addiction, with the IC-BLA glutamatergic neural projection playing an important role in regulating METH-induced CPP behavior. This pathway may provide new insights into the pathophysiology of METH-induced addiction and serve as a potential target for therapeutic strategies.