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Background <p>Phosphodiesterase 7&#xa0;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.</p> Methods <p>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).</p> Results <p>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&#xa0;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.</p> Conclusion <p>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.</p>

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Neuronal deletion of PDE7A averts morphine-induced behavioral plasticity and impairs downstream AKT signaling

  • 期刊论文

  • 发表日期：

    2026年5月7日

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  • Zizhen Liu,
  • Axiang Li,
  • Chengyou Zheng,
  • Ruyan Gao,
  • Kaiwu He,
  • Zhen Tan,
  • Tahir Ali,
  • Liangliang Hao,
  • Tao Li,
  • Shupeng Li

摘要

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.