Molecular biology reports · 2026
Neuronal deletion of PDE7A averts morphine-induced behavioral plasticity and impairs downstream AKT signaling.
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Liu Zizhen, Li Axiang, Zheng Chengyou, Gao Ruyan, He Kaiwu, Tan Zhen, Ali Tahir, Hao Liangliang, Li Tao, Li Shupeng
Аннотация
BACKGROUND: Phosphodiesterase 7 A (PDE7A) is a key regulator of cyclic adenosine monophosphate (cAMP) signaling, expressed prominently in brain regions associated with reward and addiction. Despite its strategic localization within reward-related neurocircuitry, the functional contribution of PDE7A to substance use disorders remains poorly defined.
METHODS: We investigated the role of PDE7A in morphine-induced behavioral plasticity using a combination of genetic deletion (Nestin-Cre-mediated neuronal PDE7A knockout) and pharmacological inhibition (BRL-50481) in male C57BL/6J mice (8-10 weeks of age). Behavioral assessments included conditioned place preference (CPP) and locomotor sensitization. Biochemical analyses (ELISA, Western blotting, co-immunoprecipitation) were performed on striatal tissue to assess dopamine levels, cAMP levels, and signaling pathways (AKT/GSK3β, D2R-β-arrestin2 complex).
RESULTS: Mice with neuronal PDE7A deficiency failed to develop morphine-induced CPP, highlighting a critical requirement for PDE7A in drug-associated memory formation. Consistently, administration of the PDE7 inhibitor BRL-50,481 (10 mg/kg, i.p.) significantly disrupted established drug memories and attenuated morphine-induced behavioral sensitization in wild-type mice. Mechanistically, PDE7A deletion led to a hyper-dopaminergic state in the striatum, characterized by elevated dopamine levels and D1 receptor expression, yet a paradoxical impairment in downstream signaling. Specifically, the behavioral effects of PDE7 inhibition were reversed by the D2 receptor antagonist haloperidol and the AKT inhibitor oridonin, suggesting a reliance on the D2R-AKT-GSK3β axis. Biochemical analyses further revealed that PDE7A deficiency suppresses the AKT/GSK3β signaling pathway, a defect validated through pharmacological manipulation of PDE7, D2R, and AKT.
CONCLUSION: Collectively, these findings identify PDE7A as a pivotal modulator of morphine-induced addiction and suggest that targeting the PDE7A-D2R-AKT signaling cascade represents a novel therapeutic strategy for managing substance use disorders.
METHODS: We investigated the role of PDE7A in morphine-induced behavioral plasticity using a combination of genetic deletion (Nestin-Cre-mediated neuronal PDE7A knockout) and pharmacological inhibition (BRL-50481) in male C57BL/6J mice (8-10 weeks of age). Behavioral assessments included conditioned place preference (CPP) and locomotor sensitization. Biochemical analyses (ELISA, Western blotting, co-immunoprecipitation) were performed on striatal tissue to assess dopamine levels, cAMP levels, and signaling pathways (AKT/GSK3β, D2R-β-arrestin2 complex).
RESULTS: Mice with neuronal PDE7A deficiency failed to develop morphine-induced CPP, highlighting a critical requirement for PDE7A in drug-associated memory formation. Consistently, administration of the PDE7 inhibitor BRL-50,481 (10 mg/kg, i.p.) significantly disrupted established drug memories and attenuated morphine-induced behavioral sensitization in wild-type mice. Mechanistically, PDE7A deletion led to a hyper-dopaminergic state in the striatum, characterized by elevated dopamine levels and D1 receptor expression, yet a paradoxical impairment in downstream signaling. Specifically, the behavioral effects of PDE7 inhibition were reversed by the D2 receptor antagonist haloperidol and the AKT inhibitor oridonin, suggesting a reliance on the D2R-AKT-GSK3β axis. Biochemical analyses further revealed that PDE7A deficiency suppresses the AKT/GSK3β signaling pathway, a defect validated through pharmacological manipulation of PDE7, D2R, and AKT.
CONCLUSION: Collectively, these findings identify PDE7A as a pivotal modulator of morphine-induced addiction and suggest that targeting the PDE7A-D2R-AKT signaling cascade represents a novel therapeutic strategy for managing substance use disorders.