Increased activity of GSK3β in NAc D2-MSNs contributes to methamphetamine-induced conditioned place prefernence

Glycogen synthase kinase 3β (GSK3β) in the nucleus accumbens (NAc) is implicated in drug addiction, but its specific role in methamphetamine (METH)-induced conditioned place preference (CPP), including the critical phase and the involved medium spiny neuron (MSN) subtype, remains unclear. Here, we targeted three critical phases of the CPP paradigm (acquisition, consolidation, expression) by either systemic delivering or localized intra-NAc microinjecting inhibitor of GSK3β to investigate the phase-specific roles of GSK3β in METH-induced CPP. And the effects of GSK3β on D1-/D2-type MSN activity dynamics were delineated through in vivo fiber photometry calcium imaging. Our study found that METH-paired context enhanced GSK3β activity in NAc. Systemic GSK3β suppression with lithium chloride (LiCl) attenuated METH-induced CPP across all phases, whereas intra-NAc suppression with 0.1 ng SB216763 was effective only when administered during acquisition phase. Furthermore, we identified that the METH-paired context-associated elevation in GSK3β activity predominantly localized to NAc D2-MSNs but not NAc D1-MSNs. Selective knockdown of GSK3β expression in NAc D2-MSNs attenuated METH-induced CPP by reactivating D2-MSNs coupled with concurrent suppression of D1-MSN activity. This study reveals a cell-type-specific dysregulation of GSK3β signaling in the context of METH reward processing, highlighting the contrasting roles of D1-and D2-MSNs in addiction-related plasticity.