Salidroside attenuates the acquisition of morphine‐induced conditioned place preference in mice via improving neurosynaptic plasticity in the ventral tegmental area

Abstract Background and Purpose Rhodiola rosea has therapeutic effects in several neurological disease models and its ethanolic extract prevents the acquisition of morphine‐induced conditioned place preference (CPP). We investigate the potential mechanism by which the active component of R. rosea attenuates the acquisition of morphine‐induced CPP and explore its association with synaptic plasticity. Experimental Approach Using systematic network pharmacology, morphine‐treated SH‐SY5Y cells and cortical primary neurons, we identified the active component of R. rosea against morphine addiction in vitro . Morphine‐induced CPP and additional behavioural tests were conducted after salidroside treatment. Synaptic function and structural plasticity changes in the ventral tegmental area (VTA) were characterised via immunofluorescence staining, fibre photometry and western blot. RNA sequencing, qPCR and western blotting were used to elucidate the mechanism of salidroside in attenuating the acquisition of morphine‐induced CPP. Key Results We identified salidroside as the key active component, which reduced intracellular Ca 2+ levels in morphine‐treated SH‐SY5Y cells and reversed morphine‐induced growth impairment in primary cortical neurons. Salidroside significantly inhibited the acquisition of morphine‐induced CPP. Furthermore, salidroside reversed chronic morphine‐induced alterations in synaptic function and structural plasticity in the VTA, as evidenced by both in vitro and in vivo data. Critically, salidroside enhanced neurosynaptic plasticity of dopaminergic neurons by upregulating PI3K‐AKT signalling. Conclusion and Implications Our findings demonstrate that salidroside improves the synaptic structural and functional plasticity of VTA dopaminergic neurons through upregulating PI3K‐AKT signalling, thereby attenuating the acquisition of morphine‐induced CPP. Overall, salidroside exhibits promising preclinical potential as a therapeutic candidate for attenuating the acquisition of morphine‐induced CPP.