HCN channel inhibitor ZD7288 in the lateral septum attenuates methamphetamine-induced behavior sensitization and...

Drug addiction involves dysregulation in limbic circuits, with the lateral septum (LS) playing a critical role in regulating drug reward and behavioral sensitization. Although chronic methamphetamine (METH) upregulates hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in the LS, the therapeutic potential of targeting these channels remains unclear. Here, using pharmacological approaches in mice, we demonstrate that the HCN channel inhibitor ZD7288-administered either locally into the LS or systemically-attenuates METH-induced memory retrieval, the development and expression of locomotor sensitization, without impairing memory acquisition. Furthermore, ZD7288 reduced both METH self-administration acquisition and cue-induced reinstatement. These effects were associated with the normalization of METH-induced neuronal hyperexcitability in the LS. Importantly, ZD7288 did not affect natural reward processing, such as food consumption and social interaction. Our results identify LS HCN channels as potential therapeutic targets for METH use disorder.